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1
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Lee KSW, Zhang Q, Suwa T, Clark H, Olcina MM. The role of the complement system in the response to cytotoxic therapy. Semin Immunol 2025; 77:101927. [PMID: 39765018 DOI: 10.1016/j.smim.2024.101927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 12/09/2024] [Accepted: 12/16/2024] [Indexed: 03/12/2025]
Abstract
The complement system is increasingly recognised as a key player in tumour progression and response to cancer treatment. Cytotoxic therapies, including chemo- and radiotherapy are standard-of-care for the majority of cancer patients. Cytotoxics have been found to alter the expression of complement system proteins and activation of components. Many recent reports highlight the role of local dysregulation of complement proteins in the tumour microenvironment and how targeting such dysregulation can have either anti- or pro-tumoricidal effects depending on several factors including treatment scheduling, the tumour type and its microenvironment characteristics. This review will explore the complex effects of cytotoxic therapy on complement regulation and what lessons can be learnt to identify the most effective way to therapeutically modulate complement system proteins for cancer therapy.
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Affiliation(s)
- Kelly S W Lee
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom
| | - Qingyang Zhang
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom
| | - Tatsuya Suwa
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom
| | - Heather Clark
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom
| | - Monica M Olcina
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom.
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2
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Ricciuti J, Liu Q, Khan ANMNH, Joseph JM, Veuskens BR, Giridharan T, Suzuki S, Emmons TR, Yaffe MB, Kuijpers TW, Jongerius I, Brouwer MC, Pouw RB, Odunsi K, Frederick P, Mager KL, Lele S, Gaulin N, Hakim C, Edwards RP, Olawaiye AB, Sukumanovich P, Taylor S, Elishaev E, Zsiros E, Modugno F, Moysich KB, Segal BH. Prognostic significance of serum complement activation, neutrophil extracellular traps and extracellular DNA in newly diagnosed epithelial ovarian cancer. Gynecol Oncol 2025; 193:49-57. [PMID: 39764857 PMCID: PMC11871990 DOI: 10.1016/j.ygyno.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 11/25/2024] [Accepted: 12/05/2024] [Indexed: 02/02/2025]
Abstract
PURPOSE We observed that the tumor microenvironment (TME) in metastatic epithelial ovarian cancer (EOC) and in other solid tumors can reprogram normal neutrophils to acquire a complement-dependent suppressor phenotype characterized by inhibition of stimulated T cell activation. This study aims to evaluate whether serum markers of neutrophil activation and complement at diagnosis of EOC would be associated with clinical outcomes. EXPERIMENTAL DESIGN We conducted a two-center prospective study of patients with newly diagnosed EOC (N = 188). Blood and ascites fluid were collected at diagnosis for biomarker analysis. Patients were evaluated for progression-free survival (PFS) and overall survival (OS). RESULTS The median OS was 47 months (95 % CI: 34-58) and the median PFS was 12 months (95 % CI: 11-15). Pre-treatment serum levels of genomic DNA (gDNA), markers of neutrophil degranulation (myeloperoxidase [MPO]) and neutrophil extracellular traps (NETs) (citrullinated histone H3 [CitH3]), and complement activation (C3b/c) were each associated with worse OS in univariate analysis. In multivariate analyses controlling for age, stage, and optimal debulking, serum gDNA, MPO, and CitH3 remained associated with worse OS, while C3b/c levels were not. In an exploratory analysis, the largest magnitude of difference in 2-year OS occurred in patients with low C3b/c and low CitH3 compared to all other patients (87 % vs 46 % survival, respectively). In ascites fluid, increased factor H, a negative regulator of complement activation, was associated with improved OS in univariate analysis. CONCLUSIONS These results point to serum gDNA, NETs, and complement activation as potential prognostic biomarkers in patients with newly diagnosed EOC.
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Affiliation(s)
- Jason Ricciuti
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
- Dr. Ricciuti is currently in the Division of Gynecologic Oncology, Saint Louis University School of Medicine, Saint Louis, MO
| | - Qian Liu
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - ANM Nazmul H. Khan
- Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Janine M. Joseph
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Bert R.J. Veuskens
- Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Centre, Amsterdam Institute for Immunology and Infection Diseases, Amsterdam, the Netherlands
| | | | - Sora Suzuki
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Tiffany R. Emmons
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Michael B. Yaffe
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
- Division of Acute Care Surgery, Trauma and Surgical Critical Care, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Taco W. Kuijpers
- Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC, Amsterdam, the Netherlands
- Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Centre, Amsterdam Institute for Immunology and Infection Diseases, Amsterdam, the Netherlands
| | - Ilse Jongerius
- Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC, Amsterdam, the Netherlands
- Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Centre, Amsterdam Institute for Immunology and Infection Diseases, Amsterdam, the Netherlands
- Current affiliation Genmab, Utrecht, the Netherland
| | - Mieke C. Brouwer
- Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Centre, Amsterdam Institute for Immunology and Infection Diseases, Amsterdam, the Netherlands
| | - Richard B. Pouw
- Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Centre, Amsterdam Institute for Immunology and Infection Diseases, Amsterdam, the Netherlands
- Sanquin Diagnostic Services, Amsterdam, the Netherlands
| | - Kunle Odunsi
- University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL
| | - Peter Frederick
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Katherine LaVigne Mager
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
- Dr. Ricciuti is currently in the Division of Gynecologic Oncology, Saint Louis University School of Medicine, Saint Louis, MO
| | - Shashikant Lele
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
- Dr. Ricciuti is currently in the Division of Gynecologic Oncology, Saint Louis University School of Medicine, Saint Louis, MO
| | - Nicole Gaulin
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
- Dr. Ricciuti is currently in the Division of Gynecologic Oncology, Saint Louis University School of Medicine, Saint Louis, MO
| | - Christiane Hakim
- Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Robert P. Edwards
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA
- Women’s Cancer Research Center, Hillman Cancer Center and Magee-Womens Research Institute, Pittsburgh, PA
| | - Alexander B. Olawaiye
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Paniti Sukumanovich
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Sarah Taylor
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA
- Women’s Cancer Research Center, Hillman Cancer Center and Magee-Womens Research Institute, Pittsburgh, PA
| | - Esther Elishaev
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
- Women’s Cancer Research Center, Hillman Cancer Center and Magee-Womens Research Institute, Pittsburgh, PA
| | - Emese Zsiros
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
- Dr. Ricciuti is currently in the Division of Gynecologic Oncology, Saint Louis University School of Medicine, Saint Louis, MO
| | - Francesmary Modugno
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA
- Department of Epidemiology, University of Pittsburgh Graduate School of Public Health
- Women’s Cancer Research Center, Hillman Cancer Center and Magee-Womens Research Institute, Pittsburgh, PA
| | - Kirsten B. Moysich
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Brahm H. Segal
- Departments of Internal Medicine and Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
- Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY
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3
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Ni Q, Yang H, Rao H, Zhang L, Xiong M, Han X, Deng B, Wang L, Chen J, Shi Y. The role of the C5a-C5aR pathway in iron metabolism and gastric cancer progression. Front Immunol 2025; 15:1522181. [PMID: 39850877 PMCID: PMC11754390 DOI: 10.3389/fimmu.2024.1522181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 12/23/2024] [Indexed: 01/25/2025] Open
Abstract
Gastric cancer continues to be a leading global health concern, with current therapeutic approaches requiring significant improvement. While the disruption of iron metabolism in the advancement of gastric cancer has been well-documented, the underlying regulatory mechanisms remain largely unexplored. Additionally, the complement C5a-C5aR pathway has been identified as a crucial factor in gastric cancer development. The impact of the complement system on iron metabolism and its role in gastric cancer progression is an area warranting further investigation. Our research demonstrates that the C5a-C5aR pathway promotes gastric cancer progression by enhancing iron acquisition in tumor cells through two mechanisms. First, it drives macrophage polarization toward the M2 phenotype, which has a strong iron-release capability. Second, it increases the expression of LCN2, a high-affinity iron-binding protein critical for iron export from tumor-associated macrophages, by activating endoplasmic reticulum stress in these cells. Both mechanisms facilitate the transfer of iron from macrophages to cancer cells, thereby promoting tumor cell proliferation. This study aims to elucidate the connection between the complement C5a-C5aR pathway and iron metabolism within the tumor microenvironment. Our data suggest a pivotal role of the C5a-C5aR pathway in tumor iron management, indicating that targeting its regulatory mechanisms may pave the way for future iron-targeted therapeutic approaches in cancer treatment.
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Affiliation(s)
- Qinxue Ni
- The First Affiliated Hospital of Army Military Medical University, Department of General Surgery, Chongqing, China
| | - Hong Yang
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Hang Rao
- The First Affiliated Hospital of Army Military Medical University, Department of General Surgery, Chongqing, China
| | - Liyong Zhang
- The First Affiliated Hospital of Army Military Medical University, Department of General Surgery, Chongqing, China
| | - Mengyuan Xiong
- The First Affiliated Hospital of Army Military Medical University, Department of General Surgery, Chongqing, China
| | - Xiao Han
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Boshao Deng
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Lulu Wang
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jian Chen
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yan Shi
- The First Affiliated Hospital of Army Military Medical University, Department of General Surgery, Chongqing, China
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Krattli RP, Do AH, El-Khatib SM, Alikhani L, Markarian M, Vagadia AR, Usmani MT, Madan S, Baulch JE, Clark RJ, Woodruff TM, Tenner AJ, Acharya MM. C5aR1 inhibition alleviates cranial radiation-induced cognitive decline. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.02.601806. [PMID: 39005286 PMCID: PMC11245020 DOI: 10.1101/2024.07.02.601806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Cranial radiation therapy (RT) for brain cancers leads to an irreversible decline in cognitive function without an available remedy. Radiation-induced cognitive deficits (RICD) are a particularly pressing problem for the survivors of pediatric and low grade glioma (LGG) cancers who often live long post-RT lives. Radiation-induced elevated neuroinflammation and gliosis, triggered by the detrimental CNS complement cascade, lead to excessive synaptic and cognitive loss. Using intact and brain cancer-bearing mouse models, we now show that targeting anaphylatoxin complement C5a receptor (C5aR1) is neuroprotective against RICD. We used a genetic knockout, C5aR1 KO mouse, and a pharmacologic approach, employing the orally active, brain penetrant C5aR1 antagonist PMX205 to reverse RICD. Irradiated C5aR1 KO and WT mice receiving PMX205 showed significant neurocognitive improvements in object recognition memory and memory consolidation tasks. Inhibiting C5a/C5aR1 axis reduced microglial activation, astrogliosis, and synaptic loss in the irradiated brain. Importantly, C5aR1 blockage in two syngeneic, orthotopic glioblastoma-bearing mice protected against RICD without interfering with the therapeutic efficacy of RT to reduce tumor volume in vivo . PMX205 clinical trials with healthy individuals and amyotrophic lateral sclerosis (ALS) patients showed no toxicity, drug-related adverse events, or infections. Thus, C5aR1 inhibition is a translationally feasible approach to address RICD, an unmet medical need. SIGNIFICANCE Cranial radiotherapy for brain cancers activates CNS complement cascade, leading to cognitive decline. Ablation of the complement C5a/C5aR1 axis alleviates radiation-induced neuroinflammation, synaptic loss, and cognitive dysfunction, providing a novel tractable approach.
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Yang H, Li G, Zhang J, Zhao J, Zhao Y, Wu Y, Sun Z, Song S, Zou Y, Zou Z, Han X, Deng B, Wang L, Rao H, Xu G, Wang S, Guo S, Ding H, Shi Y, Wu Y, Chen J. A novel hollow iron nanoparticle system loading PEG-Fe 3O 4 with C5a receptor antagonist for breast cancer treatment. Front Immunol 2024; 15:1466180. [PMID: 39483473 PMCID: PMC11524822 DOI: 10.3389/fimmu.2024.1466180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 09/30/2024] [Indexed: 11/03/2024] Open
Abstract
Breast cancer is the most diagnosed malignancy and major cause of cancer death among women population in the worldwide. Ferroptosis is a recently discovered iron-dependent regulated cell death involved in tumor progression and therapeutic response. Moreover, increasing studies have implied that ferroptosis is a promising approach to eliminating cancer cells like developing iron nanoparticles as a therapeutic agent. However, resistance to ferroptosis is a vital distinctive hallmark of cancer. Therefore, further investigation of the mechanism of ferroptosis resistance to enhance its tumor sensitivity is essential for ferroptosis-target breast cancer therapy. Our results revealed that the activation of C5a/C5aR pathway can drive resistance to ferroptosis and reshaping breast cancer immune microenvironment. Accordingly, loading PEG-Fe3O4 with C5aRA significantly improved the anti-tumor effect of PEG- Fe3O4 by inhibiting ferroptosis resistance and increasing macrophage polarization toward M1 phenotype. Our findings presented a novel cancer therapy strategy that combined cancer cell metal metabolism regulation and immunotherapy. The study also provided support for further evaluation of PEG- Fe3O4@C5aRA as a novel therapeutic strategy for breast cancer in clinical trials.
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Affiliation(s)
- Hong Yang
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Guiqing Li
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ji Zhang
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jing Zhao
- Biomedical Analysis Center, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yunpei Zhao
- Department of Cardio-renal, Chinese People’s Liberation Army 74th Group Military Hospital, Guangzhou, China
| | - Yufei Wu
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Zihan Sun
- Breast Disease Center, Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shuangshuang Song
- The First Affiliated Hospital of Army Military Medical University, Department of General Practice, Chongqing, China
| | - Ying Zou
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Zhihao Zou
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xiao Han
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Boshao Deng
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Lulu Wang
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Hang Rao
- Department of General Surgery, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Guilian Xu
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Shufeng Wang
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Sheng Guo
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Huanyu Ding
- Institute of Medical Technology, Chongqing Medical and Pharmaceutical College, Chongqing, China
| | - Yan Shi
- Department of General Surgery, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yuzhang Wu
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jian Chen
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
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6
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Li J, Wang K, Starodubtseva MN, Nadyrov E, Kapron CM, Hoh J, Liu J. Complement factor H in molecular regulation of angiogenesis. MEDICAL REVIEW (2021) 2024; 4:452-466. [PMID: 39444793 PMCID: PMC11495524 DOI: 10.1515/mr-2023-0048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 06/07/2024] [Indexed: 10/25/2024]
Abstract
Angiogenesis, the process of formation of new capillaries from existing blood vessels, is required for multiple physiological and pathological processes. Complement factor H (CFH) is a plasma protein that inhibits the alternative pathway of the complement system. Loss of CFH enhances the alternative pathway and increases complement activation fragments with pro-angiogenic capacity, including complement 3a, complement 5a, and membrane attack complex. CFH protein contains binding sites for C-reactive protein, malondialdehyde, and endothelial heparan sulfates. Dysfunction of CFH prevents its interaction with these molecules and initiates pro-angiogenic events. Mutations in the CFH gene have been found in patients with age-related macular degeneration characterized by choroidal neovascularization. The Cfh-deficient mice show an increase in angiogenesis, which is decreased by administration of recombinant CFH protein. In this review, we summarize the molecular mechanisms of the anti-angiogenic effects of CFH and the regulatory mechanisms of CFH expression. The therapeutic potential of recombinant CFH protein in angiogenesis-related diseases has also been discussed.
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Affiliation(s)
- Jiang Li
- Laboratory of Translational Medicine in Microvascular Regulation, Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong Province, China
- Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong Province, China
- Shandong Provincial Key Medical and Health Laboratory of Translational Medicine in Microvascular Aging, Jinan, Shandong Province, China
| | - Kaili Wang
- Laboratory of Translational Medicine in Microvascular Regulation, Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong Province, China
- Shandong Provincial Key Medical and Health Laboratory of Translational Medicine in Microvascular Aging, Jinan, Shandong Province, China
| | - Maria N. Starodubtseva
- Gomel State Medical University, Gomel, Belarus
- Institute of Radiobiology of NAS of Belarus, Gomel, Belarus
| | | | | | - Josephine Hoh
- Department of Ophthalmology, Yale School of Medicine, New Haven, CT, USA
| | - Ju Liu
- Laboratory of Translational Medicine in Microvascular Regulation, Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong Province, China
- Gomel State Medical University, Gomel, Belarus
- Shandong Provincial Key Medical and Health Laboratory of Translational Medicine in Microvascular Aging, Jinan, Shandong Province, China
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Quiralte M, Barquín A, Yagüe-Fernández M, Navarro P, Grazioso TP, Sevillano-Fernández E, Rodriguez-Moreno JF, Balarezo-Saldivar A, Peinado H, Izquierdo E, Millán C, López-Carrasco I, Prieto M, Madurga R, Fernández-Miranda I, Ruiz-Llorente S, García-Donas J. Proteomic profiles of peritoneal fluid-derived small extracellular vesicles correlate with patient outcome in ovarian cancer. J Clin Invest 2024; 134:e176161. [PMID: 38564289 PMCID: PMC11093605 DOI: 10.1172/jci176161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 03/21/2024] [Indexed: 04/04/2024] Open
Abstract
Cancer-derived small extracellular vesicles (sEVs) are capable of modifying the tumor microenvironment and promoting tumor progression. Ovarian cancer (OvCa) is a lethal malignancy that preferentially spreads through the abdominal cavity. Thus, the secretion of such vesicles into the peritoneal fluid could be a determinant factor in the dissemination and behavior of this disease. We designed a prospective observational study to assess the impact of peritoneal fluid-derived sEVs (PFD-sEVs) in OvCa clinical outcome. For this purpose, 2 patient cohorts were enrolled: patients with OvCa who underwent a diagnostic or cytoreductive surgery and nononcological patients, who underwent abdominal surgery for benign gynecological conditions and acted as the control group. Systematic extraction of PFD-sEVs from surgical samples enabled us to observe significant quantitative and qualitative differences associated with cancer diagnosis, disease stage, and platinum chemosensitivity. Proteomic profiling of PFD-sEVs led to the identification of molecular pathways and proteins of interest and to the biological validation of S100A4 and STX5. In addition, unsupervised analysis of PFD-sEV proteomic profiles in high-grade serous ovarian carcinomas (HGSOCs) revealed 2 clusters with different outcomes in terms of overall survival. In conclusion, comprehensive characterization of PFD-sEV content provided a prognostic value with potential implications in HGSOC clinical management.
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Affiliation(s)
- Miguel Quiralte
- Laboratory of Innovation in Oncology, Clara Campal Comprehensive Cancer Centre (HM CIOCC), HM Sanchinarro University Hospital, Madrid, Spain
- Institute of Applied Molecular Medicine, Faculty of Medicine, Universidad San Pablo–CEU, Alcorcón, Madrid, Spain
| | - Arantzazu Barquín
- Laboratory of Innovation in Oncology, Clara Campal Comprehensive Cancer Centre (HM CIOCC), HM Sanchinarro University Hospital, Madrid, Spain
- HM CIOCC, HM Sanchinarro University Hospital, Madrid, Spain
| | - Mónica Yagüe-Fernández
- Laboratory of Innovation in Oncology, Clara Campal Comprehensive Cancer Centre (HM CIOCC), HM Sanchinarro University Hospital, Madrid, Spain
| | - Paloma Navarro
- Laboratory of Innovation in Oncology, Clara Campal Comprehensive Cancer Centre (HM CIOCC), HM Sanchinarro University Hospital, Madrid, Spain
- Institute of Applied Molecular Medicine, Faculty of Medicine, Universidad San Pablo–CEU, Alcorcón, Madrid, Spain
| | - Tatiana P. Grazioso
- Laboratory of Innovation in Oncology, Clara Campal Comprehensive Cancer Centre (HM CIOCC), HM Sanchinarro University Hospital, Madrid, Spain
| | - Elena Sevillano-Fernández
- Laboratory of Innovation in Oncology, Clara Campal Comprehensive Cancer Centre (HM CIOCC), HM Sanchinarro University Hospital, Madrid, Spain
- HM CIOCC, HM Sanchinarro University Hospital, Madrid, Spain
| | - Juan F. Rodriguez-Moreno
- Laboratory of Innovation in Oncology, Clara Campal Comprehensive Cancer Centre (HM CIOCC), HM Sanchinarro University Hospital, Madrid, Spain
- HM CIOCC, HM Sanchinarro University Hospital, Madrid, Spain
| | - Alejandra Balarezo-Saldivar
- Laboratory of Innovation in Oncology, Clara Campal Comprehensive Cancer Centre (HM CIOCC), HM Sanchinarro University Hospital, Madrid, Spain
- Institute of Applied Molecular Medicine, Faculty of Medicine, Universidad San Pablo–CEU, Alcorcón, Madrid, Spain
| | - Héctor Peinado
- Microenvironment and Metastasis Laboratory, Molecular Oncology Program, Spanish National Cancer Research Centre, Madrid, Spain
| | - Elena Izquierdo
- Institute of Applied Molecular Medicine, Faculty of Medicine, Universidad San Pablo–CEU, Alcorcón, Madrid, Spain
| | - Carlos Millán
- Gynecologic Unit, HM Montepríncipe University Hospital, Boadilla del Monte, Madrid, Spain
| | - Irene López-Carrasco
- Gynecologic Unit, HM Montepríncipe University Hospital, Boadilla del Monte, Madrid, Spain
| | - Mario Prieto
- Department of Pathological Anatomy, Therapeutic Targets Laboratory, HM Sanchinarro University Hospital, Madrid, Spain
| | - Rodrigo Madurga
- Faculty of Experimental Sciences, Francisco de Vitoria University, Pozuelo de Alarcón, Madrid, Spain
| | - Ismael Fernández-Miranda
- R&D Oncology Business Unit, Pharmacogenomic and Cell Biology Departments, PharmaMar, Colmenar Viejo, Madrid, Spain
| | - Sergio Ruiz-Llorente
- Laboratory of Innovation in Oncology, Clara Campal Comprehensive Cancer Centre (HM CIOCC), HM Sanchinarro University Hospital, Madrid, Spain
- Department of Biomedicine and Biotechnology, Genetics Area, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
| | - Jesús García-Donas
- Laboratory of Innovation in Oncology, Clara Campal Comprehensive Cancer Centre (HM CIOCC), HM Sanchinarro University Hospital, Madrid, Spain
- Institute of Applied Molecular Medicine, Faculty of Medicine, Universidad San Pablo–CEU, Alcorcón, Madrid, Spain
- HM CIOCC, HM Sanchinarro University Hospital, Madrid, Spain
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8
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Chen B, Zhao L, Yang R, Xu T. New insights about endometriosis-associated ovarian cancer: pathogenesis, risk factors, prediction and diagnosis and treatment. Front Oncol 2024; 14:1329133. [PMID: 38384812 PMCID: PMC10879431 DOI: 10.3389/fonc.2024.1329133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 01/23/2024] [Indexed: 02/23/2024] Open
Abstract
Previous studies have shown that the risk of malignant transformation of endometriosis in premenopausal women is approximately 1%, significantly impacting the overall well-being and quality of life of affected women. Presently, the diagnostic gold standard for endometriosis-associated ovarian cancer (EAOC) continues to be invasive laparoscopy followed by histological examination. However, the application of this technique is limited due to its high cost, highlighting the importance of identifying a non-invasive diagnostic approach. Therefore, there is a critical need to explore non-invasive diagnostic methods to improve diagnostic precision and optimize clinical outcomes for patients. This review presents a comprehensive survey of the current progress in comprehending the pathogenesis of malignant transformation in endometriosis. Furthermore, it examines the most recent research discoveries concerning the diagnosis of EAOC and emphasizes potential targets for therapeutic intervention. The ultimate objective is to improve prevention, early detection, precise diagnosis, and treatment approaches, thereby optimizing the clinical outcomes for patients.
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Affiliation(s)
| | | | | | - Tianmin Xu
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, China
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Luan X, Lei T, Fang J, Liu X, Fu H, Li Y, Chu W, Jiang P, Tong C, Qi H, Fu Y. Blockade of C5a receptor unleashes tumor-associated macrophage antitumor response and enhances CXCL9-dependent CD8 + T cell activity. Mol Ther 2024; 32:469-489. [PMID: 38098230 PMCID: PMC10861991 DOI: 10.1016/j.ymthe.2023.12.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 09/17/2023] [Accepted: 12/11/2023] [Indexed: 12/25/2023] Open
Abstract
Macrophages play a crucial role in shaping the immune state within the tumor microenvironment (TME) and are often influenced by tumors to hinder antitumor immunity. However, the underlying mechanisms are still elusive. Here, we observed abnormal expression of complement 5a receptor (C5aR) in human ovarian cancer (OC), and identified high levels of C5aR expression on tumor-associated macrophages (TAMs), which led to the polarization of TAMs toward an immunosuppressive phenotype. C5aR knockout or inhibitor treatment restored TAM antitumor response and attenuated tumor progression. Mechanistically, C5aR deficiency reprogrammed macrophages from a protumor state to an antitumor state, associating with the upregulation of immune response and stimulation pathways, which in turn resulted in the enhanced antitumor response of cytotoxic T cells in a manner dependent on chemokine (C-X-C motif) ligand 9 (CXCL9). The pharmacological inhibition of C5aR also improved the efficacy of immune checkpoint blockade therapy. In patients, C5aR expression associated with CXCL9 production and infiltration of CD8+ T cells, and a high C5aR level predicted poor clinical outcomes and worse benefits from anti-PD-1 therapy. Thus, our study sheds light on the mechanisms underlying the modulation of TAM antitumor immune response by the C5a-C5aR axis and highlights the potential of targeting C5aR for clinical applications.
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Affiliation(s)
- Xiaojin Luan
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Ting Lei
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Jie Fang
- Department of Gynecology, The Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang 212001, Jiangsu, China
| | - Xue Liu
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China
| | - Huijia Fu
- Department of Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Yiran Li
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wei Chu
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Peng Jiang
- Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Chao Tong
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
| | - Hongbo Qi
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China.
| | - Yong Fu
- Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
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10
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Shi H, Liu L, Deng X, Xing X, Zhang Y, Djouda Rebecca Y, Han L. Exosomal biomarkers in the differential diagnosis of ovarian tumors: the emerging roles of CA125, HE4, and C5a. J Ovarian Res 2024; 17:4. [PMID: 38178252 PMCID: PMC10768525 DOI: 10.1186/s13048-023-01336-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 12/25/2023] [Indexed: 01/06/2024] Open
Abstract
OBJECTIVE Investigating the utility of serum exosomal markers CA125, HE4, and C5a, both individually and in combination, for distinguishing between benign and malignant ovarian tumors. METHODS In this study, we selected a total of 234 patients diagnosed with ovarian tumors, including 34 with malignant tumors, 10 with borderline ovarian tumors, and 190 with benign tumors. This study conducted comparisons of exosomal levels of CA125, HE4, and C5a among distinct groups, as well as making comparisons between serum and exosomal levels of CA125 and HE4. Furthermore, the diagnostic performance was assessed through Receiver Operating Characteristic (ROC) curve analysis. The Area Under the Curve (AUC) was computed, and a comparative evaluation of sensitivity and specificity was conducted to ascertain their effectiveness in determining the nature of ovarian tumors across different markers. RESULTS Serum CA125 and HE4 levels, the ROMA index, exosomal CA125, HE4, C5a levels, and their combined applied value (OCS value) were notably elevated in the ovarian non-benign tumor group compared to the benign tumor group, with statistical significance (P < 0.05). Exosomal and serum levels of CA125 and HE4 exhibited a positive correlation, with concentrations of these markers in serum surpassing those in exosomes. The combined OCS (AUC = 0.871) for CA125, HE4, and C5a in exosomes demonstrated superior sensitivity (0.773) and specificity (0.932) compared to serum tumor markers (CA125, HE4) and the ROMA index. The tumor stage represents an autonomous risk factor influencing the prognosis of individuals with ovarian malignancies. CONCLUSION The stage of ovarian malignancy is an independent risk factor for its prognosis. The combination of exosomal CA125, HE4 and C5a has a higher clinical value for the identification of the nature of ovarian tumours.
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Affiliation(s)
- Huihui Shi
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, 450000, China
| | - Liya Liu
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, 450000, China
| | - Xueli Deng
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, 450000, China
| | - Xiaoyu Xing
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, 450000, China
| | - Yan Zhang
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, 450000, China
| | - Yemeli Djouda Rebecca
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, 450000, China
| | - Liping Han
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Henan, Zhengzhou, 450000, China.
- , 1 East Jianshe Road, Zhengzhou, 450052, China.
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11
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Meri S, Magrini E, Mantovani A, Garlanda C. The Yin Yang of Complement and Cancer. Cancer Immunol Res 2023; 11:1578-1588. [PMID: 37902610 DOI: 10.1158/2326-6066.cir-23-0399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/07/2023] [Accepted: 09/12/2023] [Indexed: 10/31/2023]
Abstract
Cancer-related inflammation is a crucial component of the tumor microenvironment (TME). Complement activation occurs in cancer and supports the development of an inflammatory microenvironment. Complement has traditionally been considered a mechanism of immune resistance against cancer, and its activation is known to contribute to the cytolytic effects of antibody-based immunotherapeutic treatments. However, several studies have recently revealed that complement activation may exert protumoral functions by sustaining cancer-related inflammation and immunosuppression through different molecular mechanisms, targeting both the TME and cancer cells. These new discoveries have revealed that complement manipulation can be considered a new strategy for cancer therapies. Here we summarize our current understanding of the mechanisms by which the different elements of the complement system exert antitumor or protumor functions, both in preclinical studies and in human tumorigenesis. Complement components can serve as disease biomarkers for cancer stratification and prognosis and be exploited for tumor treatment.
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Affiliation(s)
- Seppo Meri
- Department of Bacteriology and Immunology and Translational Immunology Research Program, University and University Hospital of Helsinki, Helsinki, Finland
| | | | - Alberto Mantovani
- IRCCS-Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Cecilia Garlanda
- IRCCS-Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
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12
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Lasorsa F, Rutigliano M, Milella M, Ferro M, Pandolfo SD, Crocetto F, Simone S, Gesualdo L, Battaglia M, Ditonno P, Lucarelli G. Complement System and the Kidney: Its Role in Renal Diseases, Kidney Transplantation and Renal Cell Carcinoma. Int J Mol Sci 2023; 24:16515. [PMID: 38003705 PMCID: PMC10671650 DOI: 10.3390/ijms242216515] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 11/15/2023] [Accepted: 11/18/2023] [Indexed: 11/26/2023] Open
Abstract
The crosstalk among the complement system, immune cells, and mediators of inflammation provides an efficient mechanism to protect the organism against infections and support the repair of damaged tissues. Alterations in this complex machinery play a role in the pathogenesis of different diseases. Core complement proteins C3 and C5, their activation fragments, their receptors, and their regulators have been shown to be active intracellularly as the complosome. The kidney is particularly vulnerable to complement-induced damage, and emerging findings have revealed the role of complement system dysregulation in a wide range of kidney disorders, including glomerulopathies and ischemia-reperfusion injury during kidney transplantation. Different studies have shown that activation of the complement system is an important component of tumorigenesis and its elements have been proved to be present in the TME of various human malignancies. The role of the complement system in renal cell carcinoma (RCC) has been recently explored. Clear cell and papillary RCC upregulate most of the complement genes relative to normal kidney tissue. The aim of this narrative review is to provide novel insights into the role of complement in kidney disorders.
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Affiliation(s)
- Francesco Lasorsa
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Monica Rutigliano
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Martina Milella
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Matteo Ferro
- Division of Urology, European Institute of Oncology, IRCCS, 71013 Milan, Italy
| | - Savio Domenico Pandolfo
- Department of Neurosciences and Reproductive Sciences and Odontostomatology, University of Naples “Federico II”, 80131 Naples, Italy
| | - Felice Crocetto
- Department of Neurosciences and Reproductive Sciences and Odontostomatology, University of Naples “Federico II”, 80131 Naples, Italy
| | - Simona Simone
- Department of Precision and Regenerative Medicine and Ionian Area-Nephrology, Dialysis and Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Loreto Gesualdo
- Department of Precision and Regenerative Medicine and Ionian Area-Nephrology, Dialysis and Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Michele Battaglia
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Pasquale Ditonno
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Giuseppe Lucarelli
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
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13
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Li R, Sexton WJ, Dhillon J, Berglund A, Naidu S, Borjas G, Rose K, Kim Y, Wang X, Conejo-Garcia JR, Jain RK, Poch MA, Spiess PE, Pow-Sang J, Gilbert SM, Zhang J. A Phase II Study of Durvalumab for Bacillus Calmette-Guerin (BCG) Unresponsive Urothelial Carcinoma In Situ of the Bladder. Clin Cancer Res 2023; 29:3875-3881. [PMID: 37505486 DOI: 10.1158/1078-0432.ccr-23-0354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 05/04/2023] [Accepted: 07/26/2023] [Indexed: 07/29/2023]
Abstract
PURPOSE Immune checkpoint blockade holds promise for treating bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). In this phase II study, we investigated the safety and efficacy of durvalumab, a human IgG1 monoclonal antibody, against BCG-unresponsive carcinoma in situ (CIS). PATIENTS AND METHODS Patients with BCG-unresponsive CIS-containing NMIBC received durvalumab IV at 1,500 mg every 4 weeks for up to 12 months. The primary endpoint was complete response (CR) rate at month 6, defined by negative cystoscopy, urine cytology, and absence of high-grade recurrence on bladder mapping biopsy. The null hypothesis specified a CR rate of 18% and alternative hypothesis of 40%. According to the Simon two-stage design, if ≤3/13 patients achieved CR during stage 1, the trial is stopped due to futility. RESULTS Between March 8, 2017, and January 24, 2020, 17 patients were accrued whereas 4 withdrew from study treatment after bladder biopsy at month 3 was positive for CIS. Two of 17 (12%) achieved a CR at month 6, with duration of response of 10 and 18 months, respectively. A single grade 3 lipase elevation was attributed to durvalumab, and immune-related adverse events were observed in 7/17 (41%) patients. Only 1/17 patients had high programmed death-ligand 1 expression pretreatment. On RNA sequencing, complement activation genes were elevated posttreatment, along with enrichment of tumor-associated macrophage signature. CONCLUSIONS Durvalumab monotherapy conferred minimal efficacy in treating BCG-unresponsive CIS of the bladder, with 6-month CR of 12%. Complement activation is a potential mechanism behind treatment resistance.
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Affiliation(s)
- Roger Li
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Wade J Sexton
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Jasreman Dhillon
- Department of Pathology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Anders Berglund
- Department of Biostatistics/Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Shreyas Naidu
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Gustavo Borjas
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Kyle Rose
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Youngchul Kim
- Department of Biostatistics/Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Xuefeng Wang
- Department of Biostatistics/Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, Florida
| | | | - Rohit K Jain
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Michael A Poch
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Philippe E Spiess
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Julio Pow-Sang
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Scott M Gilbert
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Jingsong Zhang
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
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14
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Segal BH, Giridharan T, Suzuki S, Khan ANH, Zsiros E, Emmons TR, Yaffe MB, Gankema AAF, Hoogeboom M, Goetschalckx I, Matlung HL, Kuijpers TW. Neutrophil interactions with T cells, platelets, endothelial cells, and of course tumor cells. Immunol Rev 2023; 314:13-35. [PMID: 36527200 PMCID: PMC10174640 DOI: 10.1111/imr.13178] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Neutrophils sense microbes and host inflammatory mediators, and traffic to sites of infection where they direct a broad armamentarium of antimicrobial products against pathogens. Neutrophils are also activated by damage-associated molecular patterns (DAMPs), which are products of cellular injury that stimulate the innate immune system through pathways that are similar to those activated by microbes. Neutrophils and platelets become activated by injury, and cluster and cross-signal to each other with the cumulative effect of driving antimicrobial defense and hemostasis. In addition, neutrophil extracellular traps are extracellular chromatin and granular constituents that are generated in response to microbial and damage motifs and are pro-thrombotic and injurious. Although neutrophils can worsen tissue injury, neutrophils may also have a role in facilitating wound repair following injury. A central theme of this review relates to how critical functions of neutrophils that evolved to respond to infection and damage modulate the tumor microenvironment (TME) in ways that can promote or limit tumor progression. Neutrophils are reprogrammed by the TME, and, in turn, can cross-signal to tumor cells and reshape the immune landscape of tumors. Importantly, promising new therapeutic strategies have been developed to target neutrophil recruitment and function to make cancer immunotherapy more effective.
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Affiliation(s)
- Brahm H Segal
- Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
- Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA
| | - Thejaswini Giridharan
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Sora Suzuki
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Anm Nazmul H Khan
- Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Emese Zsiros
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Tiffany R Emmons
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Michael B Yaffe
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Angela A F Gankema
- Department of Molecular Hematology, Sanquin Research, University of Amsterdam, Amsterdam, The Netherlands
| | - Mark Hoogeboom
- Department of Molecular Hematology, Sanquin Research, University of Amsterdam, Amsterdam, The Netherlands
| | - Ines Goetschalckx
- Department of Molecular Hematology, Sanquin Research, University of Amsterdam, Amsterdam, The Netherlands
| | - Hanke L Matlung
- Department of Molecular Hematology, Sanquin Research, University of Amsterdam, Amsterdam, The Netherlands
| | - Taco W Kuijpers
- Department of Molecular Hematology, Sanquin Research, University of Amsterdam, Amsterdam, The Netherlands
- Department of Pediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital Amsterdam University Medical Center (Amsterdam UMC), University of Amsterdam, Amsterdam, The Netherlands
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15
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Li Y, Xie HQ, Guo TL, Liu Y, Zhang W, Ma H, Ma D, Xu L, Yu S, Chen G, Ji J, Jiang S, Zhao B. Subacute exposure to dechlorane 602 dysregulates gene expression and immunity in the gut of mice. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 249:114462. [PMID: 38321681 DOI: 10.1016/j.ecoenv.2022.114462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 12/07/2022] [Accepted: 12/21/2022] [Indexed: 02/08/2024]
Abstract
Dechlorane 602 (Dec 602) has biomagnification potential. Our previous studies suggested that exposure to Dec 602 for 7 days induced colonic inflammation even after 7 days of recovery. To shed some light on the underlying mechanisms, disturbances of gut immunity and gene expression were further studied. Adult C57BL/6 mice were administered orally with Dec 602 for 7 days, then allowed to recover for another 7 days. Colonic type 3 innate lymphoid cells (ILC3s) in lamina propria lymphocytes (LPLs) and lymphocytes in mesenteric lymph nodes (MLNs) were examined by flow cytometry. Expressions of genes in the gut were determined by RNA-Seq. It was found that Dec 602 exposure up-regulated the percentage of CD4+ T cells in MLNs. The mean fluorescent intensity (MFI) of interleukin (IL)- 22 in LPLs was decreased, while the MFI of IL-17a as well as the percentage of IL-17a+ ILC3s in LPLs were increased after exposure to Dec 602. Genes involved in the formation of blood vessels and epithelial-mesenchymal transition were up-regulated by Dec 602. Ingenuity pathway analysis of differentially expressed genes predicted that exposure to Dec 602 resulted in the activation of liver X receptor/retinoid X receptor (LXR/RXR) and suppression of muscle contractility. Our results, on one hand, verified that the toxic effects of Dec 602 on gut immunity could last for at least 14 days, and on the other hand, these results predicted other adverse effects of Dec 602, such as muscle dysfunction. Overall, our studies provided insights for the further investigation of Dec 602 and other emerging environmental pollutants.
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Affiliation(s)
- Yunping Li
- School of environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Heidi Qunhui Xie
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Tai L Guo
- Department of Veterinary Biomedical Sciences, University of Georgia, Athens, GA 30602, USA
| | - Yin Liu
- School of environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Wanglong Zhang
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China; College of Life Sciences, Qufu Normal University, Qufu, Shandong 273165, China
| | - Hui Ma
- State Key Laboratory of Natural Medicines & Jiangsu Provincial Key Laboratory of TCM Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Dan Ma
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Li Xu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shuyuan Yu
- Environment and Health Department, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong 518055, China
| | - Guomin Chen
- Environment and Health Department, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong 518055, China
| | - Jiajia Ji
- Environment and Health Department, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong 518055, China
| | - Shuai Jiang
- Environment and Health Department, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong 518055, China
| | - Bin Zhao
- School of environment, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
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16
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Janneh AH, Kassir MF, Atilgan FC, Lee HG, Sheridan M, Oleinik N, Szulc Z, Voelkel-Johnson C, Nguyen H, Li H, Peterson YK, Marangoni E, Saatci O, Sahin O, Lilly M, Atkinson C, Tomlinson S, Mehrotra S, Ogretmen B. Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis. Cell Rep 2022; 41:111742. [PMID: 36476873 PMCID: PMC9791981 DOI: 10.1016/j.celrep.2022.111742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 08/15/2022] [Accepted: 11/07/2022] [Indexed: 12/12/2022] Open
Abstract
Crosstalk between metabolic and signaling events that induce tumor metastasis remains elusive. Here, we determine how oncogenic sphingosine 1-phosphate (S1P) metabolism induces intracellular C3 complement activation to enhance migration/metastasis. We demonstrate that increased S1P metabolism activates C3 complement processing through S1P receptor 1 (S1PR1). S1P/S1PR1-activated intracellular C3b-α'2 is associated with PPIL1 through glutamic acid 156 (E156) and aspartic acid 111 (D111) residues, resulting in NLRP3/inflammasome induction. Inactivation mutations of S1PR1 to prevent S1P signaling or mutations of C3b-α'2 to prevent its association with PPIL1 attenuate inflammasome activation and reduce lung colonization/metastasis in mice. Also, activation of the S1PR1/C3/PPIL1/NLRP3 axis is highly associated with human metastatic melanoma tissues and patient-derived xenografts. Moreover, targeting S1PR1/C3/PPIL1/NLRP3 signaling using molecular, genetic, and pharmacologic tools prevents lung colonization/metastasis of various murine cancer cell lines using WT and C3a-receptor1 knockout (C3aR1-/-) mice. These data provide strategies for treating high-grade/metastatic tumors by targeting the S1PR1/C3/inflammasome axis.
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Affiliation(s)
- Alhaji H Janneh
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Mohamed Faisal Kassir
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - F Cansu Atilgan
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Han Gyul Lee
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Megan Sheridan
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Natalia Oleinik
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Zdzislaw Szulc
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Christina Voelkel-Johnson
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Hung Nguyen
- Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Hong Li
- Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Public Health, College of Medicine, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Yuri K Peterson
- Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | | | - Ozge Saatci
- Department of Drug Discovery and Biomedical Sciences, School of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
| | - Ozgur Sahin
- Department of Drug Discovery and Biomedical Sciences, School of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
| | - Michael Lilly
- Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Carl Atkinson
- Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Stephen Tomlinson
- Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Shikhar Mehrotra
- Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Besim Ogretmen
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
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17
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Inhibition of the immunoproteasome modulates innate immunity to ameliorate muscle pathology of dysferlin-deficient BlAJ mice. Cell Death Dis 2022; 13:975. [PMID: 36402750 PMCID: PMC9675822 DOI: 10.1038/s41419-022-05416-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 11/03/2022] [Accepted: 11/07/2022] [Indexed: 11/21/2022]
Abstract
Muscle repair in dysferlinopathies is defective. Although macrophage (Mø)-rich infiltrates are prominent in damaged skeletal muscles of patients with dysferlinopathy, the contribution of the immune system to the disease pathology remains to be fully explored. Numbers of both pro-inflammatory M1 Mø and effector T cells are increased in muscle of dysferlin-deficient BlAJ mice. In addition, symptomatic BlAJ mice have increased muscle production of immunoproteasome. In vitro analyses using bone marrow-derived Mø of BlAJ mice show that immunoproteasome inhibition results in C3aR1 and C5aR1 downregulation and upregulation of M2-associated signaling. Administration of immunoproteasome inhibitor ONX-0914 to BlAJ mice rescues muscle function by reducing muscle infiltrates and fibro-adipogenesis. These findings reveal an important role of immunoproteasome in the progression of muscular dystrophy in BlAJ mouse and suggest that inhibition of immunoproteasome may produce therapeutic benefit in dysferlinopathy.
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18
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Khan A, Das BC, Abiha U, Sisodiya S, Chikara A, Nazir SU, Das AM, Rodrigues AG, Passari AK, Tanwar P, Hussain S, Rashid S, Rashid S. Insights into the role of complement regulatory proteins in HPV mediated cervical carcinogenesis. Semin Cancer Biol 2022; 86:583-589. [PMID: 34087416 DOI: 10.1016/j.semcancer.2021.05.031] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 05/28/2021] [Accepted: 05/28/2021] [Indexed: 01/27/2023]
Abstract
The persistent infection of high-risk Human papillomavirus (HR-HPV) induced cervical cancer remains a challenge in women worldwide including India. Recent advances in cancer research have paved the way for advanced cancer treatment modalities including immunotherapy by manipulating the function or number of cytotoxic T cells. It is well established that anaphylatoxins like C3a and C5a of complement system influence tumor growth by evading apoptosis leading to progression of cancer. The role of the complement system, particularly the complement regulatory proteins (CRPs) which are important determinants of immune response play a crucial role in carcinogenesis. In a tumor microenvironment (TME) assisted suppression of immune effector cells may be achieved through CRPs. However, recent advances in pharmacogenomics including drug designing and combination of these approaches have provided a holistic understanding of signaling pathways and their crosstalk, to regulate cellular communications.This review describes the role of complement system; particularly CRPs in HPV induced cervical carcinogenesis which may be used for designing anti- HPV or cervical cancer therapeutics.
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Affiliation(s)
- Asiya Khan
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India; Laboratory Oncology Unit, Rotary Cancer Center, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Bhudev C Das
- Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Health & Allied Sciences Amity University, Noida, India
| | - Umme Abiha
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India
| | - Sandeep Sisodiya
- Division of Molecular Oncology & Molecular Diagnostics, ICMR-National Institute of Cancer Prevention and Research, Ministry of Health & Family Welfare, Noida, India; Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Atul Chikara
- Division of Molecular Oncology & Molecular Diagnostics, ICMR-National Institute of Cancer Prevention and Research, Ministry of Health & Family Welfare, Noida, India; Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Sheeraz Un Nazir
- Division of Molecular Oncology & Molecular Diagnostics, ICMR-National Institute of Cancer Prevention and Research, Ministry of Health & Family Welfare, Noida, India
| | - Ankan M Das
- Amity Institute of Public Health, Amity University, Noida, India
| | - Alexandre Gomes Rodrigues
- Alpha & Omega Labor, Messe-Alle, 23, 04158, Leipzig, Germany; University of Veterinary Medicine Hannover, Bischofsholer Damm 15, 30173, Hannover, Germany
| | - Ajit Kumar Passari
- Departmento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
| | - Pranay Tanwar
- Laboratory Oncology Unit, Rotary Cancer Center, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Showket Hussain
- Division of Molecular Oncology & Molecular Diagnostics, ICMR-National Institute of Cancer Prevention and Research, Ministry of Health & Family Welfare, Noida, India.
| | - Sabia Rashid
- Queen Elizabeth Hospital & King's College Hospital, Stadium Road, London, United Kingdom.
| | - Shazia Rashid
- Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India.
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19
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Senent Y, Tavira B, Pio R, Ajona D. The complement system as a regulator of tumor-promoting activities mediated by myeloid-derived suppressor cells. Cancer Lett 2022; 549:215900. [PMID: 36087681 DOI: 10.1016/j.canlet.2022.215900] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 11/16/2022]
Abstract
Tumor progression relies on the interaction between tumor cells and their surrounding tumor microenvironment (TME), which also influences therapeutic responses. The complement system, an essential part of innate immunity, has been traditionally considered an effector arm against tumors. However, established tumors co-opt complement-mediated immune responses in the TME to support chronic inflammation, activate cancer-related signaling pathways and hamper antitumor immune responses. In this context, myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid progenitors with immunosuppressive functions, are recognized as major mediators of tumor-associated complement activities. This review focuses on the impact of complement activation within the TME, with a special emphasis on MDSC functions and the involvement of the C5a/C5aR1 axis. We also discuss the translation of these findings into therapeutic advances based on complement inhibition.
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Affiliation(s)
- Yaiza Senent
- Cima-University of Navarra, Program in Solid Tumors, Pamplona, Spain; Cancer Center University of Navarra (CCUN), Pamplona, Spain; University of Navarra, School of Sciences, Department of Biochemistry and Genetics, Pamplona, Spain
| | - Beatriz Tavira
- Cima-University of Navarra, Program in Solid Tumors, Pamplona, Spain; Cancer Center University of Navarra (CCUN), Pamplona, Spain; University of Navarra, School of Medicine, Department of Pathology, Anatomy and Physiology, Pamplona, Spain
| | - Ruben Pio
- Cima-University of Navarra, Program in Solid Tumors, Pamplona, Spain; Cancer Center University of Navarra (CCUN), Pamplona, Spain; University of Navarra, School of Sciences, Department of Biochemistry and Genetics, Pamplona, Spain; Navarra Institute for Health Research (IdISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
| | - Daniel Ajona
- Cima-University of Navarra, Program in Solid Tumors, Pamplona, Spain; Cancer Center University of Navarra (CCUN), Pamplona, Spain; University of Navarra, School of Sciences, Department of Biochemistry and Genetics, Pamplona, Spain; Navarra Institute for Health Research (IdISNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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20
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Intracellular complement C5a/C5aR1 stabilizes β-catenin to promote colorectal tumorigenesis. Cell Rep 2022; 39:110851. [PMID: 35649359 DOI: 10.1016/j.celrep.2022.110851] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 03/25/2022] [Accepted: 04/29/2022] [Indexed: 11/23/2022] Open
Abstract
Complement is operative in not only the extracellular but also the intracellular milieu. However, little is known about the role of complement activation inside tumor cells. Here, we report that intracellular C5 is cleaved by cathepsin D (CTSD) to produce C5a in lysosomes and endosomes of colonic cancer cells. After stimulation by C5a, intracellular C5aR1 assembles a complex with KCTD5/cullin3/Roc-1 and β-catenin to promote the switch of polyubiquitination of β-catenin from K48 to K63, which enhances β-catenin stability. Genetic loss or pharmacological blockade of C5aR1 dramatically impedes colorectal tumorigenesis at least by destabilizing β-catenin. In human colorectal cancer specimens, high levels of C5aR1, C5a, and CTSD are closely correlated with elevated β-catenin levels and a poor prognosis. Importantly, intracellular C5a/C5aR1-mediated β-catenin stabilization is also observed ubiquitously in other cell types. Collectively, we identify a machinery for β-catenin activation and provide a potential target for tumor prevention and treatment.
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21
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Complement activation in cancer: Effects on tumor-associated myeloid cells and immunosuppression. Semin Immunol 2022; 60:101642. [PMID: 35842274 DOI: 10.1016/j.smim.2022.101642] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/28/2022] [Accepted: 07/05/2022] [Indexed: 01/15/2023]
Abstract
Cancer-related inflammation plays a central role in the establishment of tumor-promoting mechanisms. Tumor-associated myeloid cells, which engage in complex interactions with cancer cells, as well as stromal and tumor immune infiltrating cells, promote cancer cell proliferation and survival, angiogenesis, and the generation of an immunosuppressive microenvironment. The complement system is one of the inflammatory mechanisms activated in the tumor microenvironment. Beside exerting anti-tumor mechanisms such as complement-dependent cytotoxicity and phagocytosis induced by therapeutic monoclonal antibodies, the complement system may promote immunosuppression and tumor growth and invasiveness, in particular, through the anaphylatoxins which target both leukocytes and cancer cells. In this review, we will discuss complement-mediated mechanisms acting on leukocytes, in particular on cells of the myelomonocytic cell lineage (macrophages, neutrophils, myeloid derived suppressor cells), which promote myeloid cell recruitment and functional skewing, leading to immunosuppression and resistance to tumor-specific immunity. Pre-clinical studies, which have elucidated the role of complement in activating pro-tumor mechanisms in myeloid cells, showing the relevance of these mechanisms in human, and therapeutic approaches based on complement targeting support the hypothesis that complement directly and indirectly interferes with many of the effector pathways associated with the cancer-immunity cycle, suggesting the relevance of complement targeting to improve responses to immunotherapeutic approaches.
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22
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Talaat IM, Elemam NM, Saber-Ayad M. Complement System: An Immunotherapy Target in Colorectal Cancer. Front Immunol 2022; 13:810993. [PMID: 35173724 PMCID: PMC8841337 DOI: 10.3389/fimmu.2022.810993] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 01/14/2022] [Indexed: 12/26/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignant tumor and the second most fatal cancer worldwide. Several parts of the immune system contribute to fighting cancer including the innate complement system. The complement system is composed of several players, namely component molecules, regulators and receptors. In this review, we discuss the complement system activation in cancer specifically CRC and highlight the possible interactions between the complement system and the various TME components. Additionally, the role of the complement system in tumor immunity of CRC is reviewed. Hence, such work could provide a framework for researchers to further understand the role of the complement system in CRC and explore the potential therapies targeting complement activation in solid tumors such as CRC.
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Affiliation(s)
- Iman M. Talaat
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Noha Mousaad Elemam
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- *Correspondence: Noha Mousaad Elemam, ; Maha Saber-Ayad,
| | - Maha Saber-Ayad
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Faculty of Medicine, Cairo University, Cairo, Egypt
- *Correspondence: Noha Mousaad Elemam, ; Maha Saber-Ayad,
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23
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Abstract
Tumorigenesis has long been linked to the evasion of the immune system and the uncontrolled proliferation of transformed cells. The complement system, a major arm of innate immunity, is a key factor in the progression of cancer because many of its components have critical regulatory roles in the tumor microenvironment. For example, complement anaphylatoxins directly and indirectly inhibit antitumor T-cell responses in primary and metastatic sites, enhance proliferation of tumor cells, and promote metastasis and tumor angiogenesis. Many recent studies have provided evidence that cancer is able to hijack the immunoregulatory components of the complement system which fundamentally are tasked with protecting the body against abnormal cells and pathogens. Indeed, recent evidence shows that many types of cancer use C1q receptors (C1qRs) to promote tumor growth and progression. More importantly, most cancer cells express both C1q and its major receptors (gC1qR and cC1qR) on their surface which are essential for cell proliferation and survival. In this review, we discuss the ability of cancer to control and manipulate the complement system in the tumor microenvironment and identify possible therapeutic targets, including C1q and gC1qR.
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Affiliation(s)
- Danyaal Ain
- The Department of Medicine, Stony Brook University, 100 Nicholls Road, Stony Brook, NY 11794-8161, USA
| | - Talha Shaikh
- The Department of Medicine, Stony Brook University, 100 Nicholls Road, Stony Brook, NY 11794-8161, USA
| | - Samantha Manimala
- The Department of Medicine, Stony Brook University, 100 Nicholls Road, Stony Brook, NY 11794-8161, USA
| | - Berhane Ghebrehiwet
- The Department of Medicine, Stony Brook University, 100 Nicholls Road, Stony Brook, NY 11794-8161, USA
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24
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Lee MJ, Na K, Shin H, Kim CY, Cho JY, Kang CM, Kim SH, Kim H, Choi HJ, Lee CK, Bae S, Son S, Paik YK. Early Diagnostic Ability of Human Complement Factor B in Pancreatic Cancer Is Partly Linked to Its Potential Tumor-Promoting Role. J Proteome Res 2021; 20:5315-5328. [PMID: 34766501 DOI: 10.1021/acs.jproteome.1c00805] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Although plasma complement factor B (CFB, NX_P00751), both alone and in combination with CA19-9 (i.e., the ComB-CAN), previously exhibited a reliable diagnostic ability for pancreatic cancer (PC), its detectability of the early stages and the cancer detection mechanism remained elusive. We first evaluated the diagnostic accuracy of ComB-CAN using plasma samples from healthy donors (HDs), patients with chronic pancreatitis (CP), and patients with different PC stages (I/II vs III/IV). An analysis of the area under the curve (AUC) by PanelComposer using logistic regression revealed that ComB-CAN has a superior diagnostic ability for early-stage PC (97.1.% [95% confidence interval (CI): (97.1-97.2)]) compared with CFB (94.3% [95% CI: 94.2-94.4]) or CA19-9 alone (34.3% [95% CI: 34.1-34.4]). In the comparisons of all stages of patients with PC vs CP and HDs, the AUC values of ComB-CAN, CFB, and CA19-9 were 0.983 (95% CI: 0.983-0.983), 0.950 (95% CI: 0.950-0.951), and 0.873 (95% CI: 0.873-0.874), respectively. We then investigated the molecular mechanism underlying the detection of early-stage PC by using stable cell lines of CFB knockdown and CFB overexpression. A global transcriptomic analysis coupled to cell invasion assays of both CFB-modulated cell lines suggested that CFB plays a tumor-promoting role in PC, which likely initiates the PI3K-AKT cancer signaling pathway. Thus our study establishes ComB-CAN as a reliable early diagnostic marker for PC that can be clinically applied for early PC screening in the general public.
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Affiliation(s)
- Min Jung Lee
- Yonsei Proteome Research Center, Yonsei University, 50 Yonsei-ro, Seodaemoon-ku, Seoul 03722, South Korea
| | - Keun Na
- Yonsei Proteome Research Center, Yonsei University, 50 Yonsei-ro, Seodaemoon-ku, Seoul 03722, South Korea
| | - Heon Shin
- Yonsei Proteome Research Center, Yonsei University, 50 Yonsei-ro, Seodaemoon-ku, Seoul 03722, South Korea
| | - Chae-Yeon Kim
- Yonsei Proteome Research Center, Yonsei University, 50 Yonsei-ro, Seodaemoon-ku, Seoul 03722, South Korea
| | - Jin-Young Cho
- Yonsei Proteome Research Center, Yonsei University, 50 Yonsei-ro, Seodaemoon-ku, Seoul 03722, South Korea
| | | | | | | | | | | | - Sumi Bae
- JW Bioscience Corp., 2477, Nambusunhwan-ro, Seocho-gu, Seoul 06725, South Korea
| | - Sunghwa Son
- JW Holdings Corp., 2477, Nambusunhwan-ro, Seocho-gu, Seoul 06725, South Korea
| | - Young-Ki Paik
- Yonsei Proteome Research Center, Yonsei University, 50 Yonsei-ro, Seodaemoon-ku, Seoul 03722, South Korea
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25
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Tipping the balance: intricate roles of the complement system in disease and therapy. Semin Immunopathol 2021; 43:757-771. [PMID: 34698894 PMCID: PMC8547127 DOI: 10.1007/s00281-021-00892-7] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 09/14/2021] [Indexed: 12/13/2022]
Abstract
The ability of the complement system to rapidly and broadly react to microbial intruders, apoptotic cells and other threats by inducing forceful elimination responses is indispensable for its role as host defense and surveillance system. However, the danger sensing versatility of complement may come at a steep price for patients suffering from various immune, inflammatory, age-related, or biomaterial-induced conditions. Misguided recognition of cell debris or transplants, excessive activation by microbial or damaged host cells, autoimmune events, and dysregulation of the complement response may all induce effector functions that damage rather than protect host tissue. Although complement has long been associated with disease, the prevalence, impact and complexity of complement’s involvement in pathological processes is only now becoming fully recognized. While complement rarely constitutes the sole driver of disease, it acts as initiator, contributor, and/or exacerbator in numerous disorders. Identifying the factors that tip complement’s balance from protective to damaging effects in a particular disease continues to prove challenging. Fortunately, however, molecular insight into complement functions, improved disease models, and growing clinical experience has led to a greatly improved understanding of complement’s pathological side. The identification of novel complement-mediated indications and the clinical availability of the first therapeutic complement inhibitors has also sparked a renewed interest in developing complement-targeted drugs, which meanwhile led to new approvals and promising candidates in late-stage evaluation. More than a century after its description, complement now has truly reached the clinic and the recent developments hold great promise for diagnosis and therapy alike.
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26
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Sun Y, Liu G. Endometriosis-associated Ovarian Clear Cell Carcinoma: A Special Entity? J Cancer 2021; 12:6773-6786. [PMID: 34659566 PMCID: PMC8518018 DOI: 10.7150/jca.61107] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 09/12/2021] [Indexed: 02/06/2023] Open
Abstract
Endometriosis is an estrogen-dependent disease, which serves as a precursor of ovarian cancer, especially clear cell carcinoma (OCCC) and endometrial carcinoma. Although micro-environmental factors such as oxidative stress, immune cell dysfunction, inflammation, steroid hormones, and stem cells required for malignant transformation have been found in endometriosis, the exact carcinogenic mechanism remains unclear. Recent research suggest that many putative driver genes and aberrant pathways including ARID1A mutations, PIK3CA mutations, MET activation, HNF-1β activation, and miRNAs dysfunction, play crucial roles in the malignant transformation of endometriosis to OCCC. The clinical features of OCCC are different from other histological types. Patients usually present with a large, unilateral pelvic mass, and occasionally have thromboembolic vascular complications. OCCC patients are easier to be resistant to chemotherapy, have a worse prognosis, and are usually difficult to treat. To improve the survival of OCCC patients, it is necessary to better understand its specific carcinogenic mechanism and explore new treatment strategy, including molecular target.
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Affiliation(s)
- Yue Sun
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin, 300052, China
| | - Guoyan Liu
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, 300052, China.,Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin, 300052, China
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27
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Li P, Bai Y, Shan B, Zhang W, Liu Z, Zhu Y, Xu X, Chen Q, Sheng X, Deng X, Guo Z, Zhang D, Wang H, Zhang Y, Hu Y. Exploration of Potential Diagnostic Value of Protein Content in Serum Small Extracellular Vesicles for Early-Stage Epithelial Ovarian Carcinoma. Front Oncol 2021; 11:707658. [PMID: 34604046 PMCID: PMC8479155 DOI: 10.3389/fonc.2021.707658] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 08/19/2021] [Indexed: 12/20/2022] Open
Abstract
Epithelial ovarian carcinoma (EOC) is one of the most common gynecologic malignancies with a high mortality rate. Serum biomarkers and imaging approaches are insufficient in identifying EOC patients at an early stage. This study is to set up a combination of proteins from serum small extracellular vesicles (sEVs) for the diagnosis of early-stage EOC and to determine its performance. A biomarker for early-stage ovarian cancer (BESOC) cohort was used as a Chinese multi-center population-based biomarker study and registered as a Chinese Clinical Trial ChiCTR2000040136. The sEV protein levels of CA125, HE4, and C5a were measured in 299 subjects. Logistic regression was exploited to calculate the odds ratio and to create the sEV protein model for the predicted probability and subsequently receiver-operating characteristic (ROC) analysis. The combined sEV marker panel of CA125, HE4, and C5a as a sEV model obtained an area under curve (AUC) of 0.912, which was greater than the serum model (0.809), by ROC analysis to identify EOC patients from the whole cohort. With the cutoff of 0.370, the sensitivity and specificity of the sEV model were 0.80 and 0.89, which were much better performance than the serum markers (sensitivity: 0.55~0.66; specificity: 0.59~0.68) and the risk of ovarian malignancy algorithm (ROMA) index approved by the U.S. Food and Drug Administration (sensitivity: 0.65; specificity: 0.61), to identify EOC patients from patients with benign ovarian diseases or other controls. The sEV levels of CA125 significantly differed among early-stage and late-stage EOC (p < 0.001). Moreover, the AUC of ROC to identify early-stage EOC patients was 0.888. Further investigation revealed that the sEV levels of these 3 proteins significantly decreased after cytoreductive surgery (CA125, p = 0.008; HE4, p = 0.025; C5a, p = 0.044). In summary, our study showed that CA125, HE4, and C5a levels in serum sEVs can identify EOC patients at the early stage, elucidating the possibility of using a sEV model for the diagnosis of early-stage EOC.
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Affiliation(s)
- Pu Li
- Department of Gynecology Oncology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
| | - Yuezong Bai
- 3D Medicines Inc., Shanghai, China.,Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Boer Shan
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Wei Zhang
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | | | - Yingjie Zhu
- Department of Gynecology, Yunnan Tumor Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | | | - Qian Chen
- Department of Gynecology, Yunnan Tumor Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Xiujie Sheng
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, Gynecology Department of the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaoyang Deng
- Gynecology Department, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Zhengchen Guo
- Department of Gynecology Oncology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
| | | | - Huaying Wang
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | | | - Yuanjing Hu
- Department of Gynecology Oncology, Tianjin Central Hospital of Obstetrics and Gynecology, Tianjin, China
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Gomez-Arboledas A, Acharya MM, Tenner AJ. The Role of Complement in Synaptic Pruning and Neurodegeneration. Immunotargets Ther 2021; 10:373-386. [PMID: 34595138 PMCID: PMC8478425 DOI: 10.2147/itt.s305420] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 09/04/2021] [Indexed: 12/14/2022] Open
Abstract
The complement system, an essential part of the innate immune system, is composed of a group of secreted and membrane proteins that collectively participate in maintaining the function of the healthy and diseased brain. However, an inappropriate activation of the complement system has been related to an inflammatory response in multiple diseases, such as stroke, traumatic brain injury, multiple sclerosis, and Alzheimer's disease, as well as Zika infection and radiotherapy. In addition, C1q and C3 (initial activation components of the complement cascade) have been shown to play a key beneficial role in the refinement of synaptic circuits during developmental stages and adult plasticity. Nevertheless, excessive synaptic pruning in the adult brain can be detrimental and has been associated with synaptic loss in several pathological conditions. In this brief review, we will discuss the role of the complement system in synaptic pruning as well as its contribution to neurodegeneration and cognitive deficits. We also mention potential therapeutic approaches to target the complement system to treat several neuroinflammatory diseases and unintended consequences of radiotherapy.
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Affiliation(s)
- Angela Gomez-Arboledas
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA
| | - Munjal M Acharya
- Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, USA
- Department of Radiation Oncology, University of California, Irvine, Irvine, CA, USA
| | - Andrea J Tenner
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA
- Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA
- Department of Pathology and Laboratory Medicine, University of California, Irvine, School of Medicine, Irvine, CA, USA
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Senent Y, Ajona D, González-Martín A, Pio R, Tavira B. The Complement System in Ovarian Cancer: An Underexplored Old Path. Cancers (Basel) 2021; 13:3806. [PMID: 34359708 PMCID: PMC8345190 DOI: 10.3390/cancers13153806] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/25/2021] [Accepted: 07/26/2021] [Indexed: 12/15/2022] Open
Abstract
Ovarian cancer is one of the most lethal gynecological cancers. Current therapeutic strategies allow temporary control of the disease, but most patients develop resistance to treatment. Moreover, although successful in a range of solid tumors, immunotherapy has yielded only modest results in ovarian cancer. Emerging evidence underscores the relevance of the components of innate and adaptive immunity in ovarian cancer progression and response to treatment. Particularly, over the last decade, the complement system, a pillar of innate immunity, has emerged as a major regulator of the tumor microenvironment in cancer immunity. Tumor-associated complement activation may support chronic inflammation, promote an immunosuppressive microenvironment, induce angiogenesis, and activate cancer-related signaling pathways. Recent insights suggest an important role of complement effectors, such as C1q or anaphylatoxins C3a and C5a, and their receptors C3aR and C5aR1 in ovarian cancer progression. Nevertheless, the implication of these factors in different clinical contexts is still poorly understood. Detailed knowledge of the interplay between ovarian cancer cells and complement is required to develop new immunotherapy combinations and biomarkers. In this context, we discuss the possibility of targeting complement to overcome some of the hurdles encountered in the treatment of ovarian cancer.
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Affiliation(s)
- Yaiza Senent
- Translational Oncology Group, Program in Solid Tumors, Cima University of Navarra, 31008 Pamplona, Spain; (Y.S.); (A.G.-M.); (R.P.); (B.T.)
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IdISNA), 31008 Pamplona, Spain
| | - Daniel Ajona
- Translational Oncology Group, Program in Solid Tumors, Cima University of Navarra, 31008 Pamplona, Spain; (Y.S.); (A.G.-M.); (R.P.); (B.T.)
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IdISNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Antonio González-Martín
- Translational Oncology Group, Program in Solid Tumors, Cima University of Navarra, 31008 Pamplona, Spain; (Y.S.); (A.G.-M.); (R.P.); (B.T.)
- Department of Oncology, Clinica Universidad de Navarra, 28027 Madrid, Spain
| | - Ruben Pio
- Translational Oncology Group, Program in Solid Tumors, Cima University of Navarra, 31008 Pamplona, Spain; (Y.S.); (A.G.-M.); (R.P.); (B.T.)
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IdISNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Beatriz Tavira
- Translational Oncology Group, Program in Solid Tumors, Cima University of Navarra, 31008 Pamplona, Spain; (Y.S.); (A.G.-M.); (R.P.); (B.T.)
- Navarra Institute for Health Research (IdISNA), 31008 Pamplona, Spain
- Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain
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30
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Lu C, Luo X, Xing C, Mao Y, Xu Y, Gao W, Wang W, Zhan T, Wang G, Liu Z, Yu C. Construction of a novel mRNA-miRNA-lncRNA network and identification of potential regulatory axis associated with prognosis in colorectal cancer liver metastases. Aging (Albany NY) 2021; 13:14968-14988. [PMID: 34081622 PMCID: PMC8221294 DOI: 10.18632/aging.203049] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 04/29/2021] [Indexed: 12/24/2022]
Abstract
Liver metastasis is a leading cause of death in patients with colorectal cancer (CRC). Increasing evidence demonstrates that competing endogenous RNA (ceRNA) networks play important roles in malignant cancers. The purpose of this study was to identify molecular markers and build a ceRNA network as a significant predictor of colorectal liver metastases (CRLM). By integrated bioinformatics analysis, we found that apolipoprotein C1 (APOC1) was upregulated in CRLM and associated with prognosis in patients with CRC and thereby established an APOC1-dependent ceRNA network. By survival analysis, expression analysis, and correlation analysis of each element in the ceRNA network, we identified that ZEB1-AS1, miR-335-5p and APOC1 regulated each other. We further experimentally confirmed that ZEB1-AS1 promoted a CRC progression via regulating the expression of miR-335-5p that controlled the expression of APOC1. Our findings indicate that the ZEB1-AS1-miR-335-5p-APOC1 ceRNA regulatory network is significantly valuable for better prognosis of patients with CRC and as a new therapeutic target for the treatment of CRLM.
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Affiliation(s)
- Chen Lu
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, China
| | - Xiagang Luo
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, China
| | - Cheng Xing
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, China
| | - Yonghuan Mao
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, China
| | - Yuting Xu
- Department of Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
| | - Wenjie Gao
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, China
| | - Wulin Wang
- Department of Gastrointestinal Surgery, Jingzhou Central Hospital, Jingzhou 434000, Hubei, China
| | - Tian Zhan
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, China
| | - Guoguang Wang
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, China
| | - Zhengxia Liu
- Department of Geriatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, China
| | - Chunzhao Yu
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, China
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Emmons TR, Giridharan T, Singel KL, Khan ANH, Ricciuti J, Howard K, Silva-Del Toro SL, Debreceni IL, Aarts CEM, Brouwer MC, Suzuki S, Kuijpers TW, Jongerius I, Allen LAH, Ferreira VP, Schubart A, Sellner H, Eder J, Holland SM, Ram S, Lederer JA, Eng KH, Moysich KB, Odunsi K, Yaffe MB, Zsiros E, Segal BH. Mechanisms Driving Neutrophil-Induced T-cell Immunoparalysis in Ovarian Cancer. Cancer Immunol Res 2021; 9:790-810. [PMID: 33990375 DOI: 10.1158/2326-6066.cir-20-0922] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 02/05/2021] [Accepted: 05/12/2021] [Indexed: 11/16/2022]
Abstract
T-cell activation and expansion in the tumor microenvironment (TME) are critical for antitumor immunity. Neutrophils in the TME acquire a complement-dependent T-cell suppressor phenotype that is characterized by inhibition of T-cell proliferation and activation through mechanisms distinct from those of myeloid-derived suppressor cells. In this study, we used ascites fluid supernatants (ASC) from patients with ovarian cancer as an authentic component of the TME to evaluate the effects of ASC on neutrophil function and mechanisms for neutrophil-driven immune suppression. ASC prolonged neutrophil life span, decreased neutrophil density, and induced nuclear hypersegmentation. Mass cytometry analysis showed that ASC induced 15 distinct neutrophil clusters. ASC stimulated complement deposition and signaling in neutrophils, resulting in surface mobilization of granule constituents, including NADPH oxidase. NADPH oxidase activation and phosphatidylserine signaling were required for neutrophil suppressor function, although we did not observe a direct role of extracellular reactive oxygen species in inhibiting T-cell proliferation. Postoperative surgical drainage fluid also induced a complement-dependent neutrophil suppressor phenotype, pointing to this effect as a general response to injury. Like circulating lymphocytes, ASC-activated neutrophils caused complement-dependent suppression of tumor-associated lymphocytes. ASC-activated neutrophils adhered to T cells and caused trogocytosis of T-cell membranes. These injury and signaling cues resulted in T-cell immunoparalysis characterized by impaired NFAT translocation, IL2 production, glucose uptake, mitochondrial function, and mTOR activation. Our results demonstrate that complement-dependent priming of neutrophil effector functions in the TME induces a T-cell nonresponsiveness distinct from established checkpoint pathways and identify targets for immunotherapy.See related Spotlight by Cassatella, p. 725.
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Affiliation(s)
- Tiffany R Emmons
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Thejaswini Giridharan
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Kelly L Singel
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Anm Nazmul H Khan
- Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Jason Ricciuti
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Kaitlyn Howard
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - Ivy L Debreceni
- Inflammation Program and Immunology Graduate Training Program, University of Iowa, Iowa City, Iowa
| | - Cathelijn E M Aarts
- Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands
| | - Mieke C Brouwer
- Department of Immunopathology, Sanquin Research, Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Sora Suzuki
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Taco W Kuijpers
- Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands.,Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, Amsterdam, the Netherlands
| | - Ilse Jongerius
- Department of Immunopathology, Sanquin Research, Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.,Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, Amsterdam, the Netherlands
| | - Lee-Ann H Allen
- Inflammation Program, Departments of Medicine and Microbiology and Immunology, University of Iowa, Iowa City, Iowa
| | - Viviana P Ferreira
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Anna Schubart
- Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland
| | - Holger Sellner
- Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland
| | - Jörg Eder
- Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland
| | - Steven M Holland
- Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Sanjay Ram
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
| | - James A Lederer
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Kevin H Eng
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Kirsten B Moysich
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Kunle Odunsi
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.,Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Michael B Yaffe
- Center for Precision Cancer Medicine, Departments of Biological Engineering and Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.,Division of Acute Care Surgery, Trauma and Surgical Critical Care, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Emese Zsiros
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.,Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Brahm H Segal
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York. .,Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.,Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York
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32
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Lu P, Ma Y, Wei S, Liang X. The dual role of complement in cancers, from destroying tumors to promoting tumor development. Cytokine 2021; 143:155522. [PMID: 33849765 DOI: 10.1016/j.cyto.2021.155522] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 03/24/2021] [Accepted: 03/26/2021] [Indexed: 12/30/2022]
Abstract
Complement is an important branch of innate immunity; however, its biological significance goes far beyond the scope of simple nonspecific defense and involves a variety of physiological functions, including the adaptive immune response. In this review, to unravel the complex relationship between complement and tumors, we reviewed the high diversity of complement components in cancer and the heterogeneity of their production and activation pathways. In the tumor microenvironment, complement plays a dual regulatory role in the occurrence and development of tumors, affecting the outcomes of the immune response. We explored the differential expression levels of various complement components in human cancers via the Oncomine database. The gene expression profiling interactive analysis (GEPIA) tool and Kaplan-Meier plotter (K-M plotter) confirmed the correlation between differentially expressed complement genes and tumor prognosis. The tumor immune estimation resource (TIMER) database was used to statistically analyze the effect of complement on tumor immune infiltration. Finally, with a view to the role of complement in regulating T cell metabolism, complement could be a potential target for immunotherapies. Targeting complement to regulate the antitumor immune response seems to have potential for future treatment strategies. However, there are still many complex problems, such as who will benefit from this therapy and how to select the right therapeutic target and determine the appropriate drug concentration. The solutions to these problems depend on a deeper understanding of complement generation, activation, and regulatory and control mechanisms.
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Affiliation(s)
- Ping Lu
- Department of Medical Oncology, Hubei Cancer Hospital, the Seventh Clinical School Affiliated of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Colorectal Cancer Clinical Research Center of HuBei Province, Wuhan, China; Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, China
| | - Yifei Ma
- Department of Gastrointestinal Oncology Surgery, Hubei Cancer Hospital, the Seventh Clinical School Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Colorectal Cancer Clinical Research Center of HuBei Province, Wuhan, China; Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, China
| | - Shaozhong Wei
- Department of Gastrointestinal Oncology Surgery, Hubei Cancer Hospital, the Seventh Clinical School Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Colorectal Cancer Clinical Research Center of HuBei Province, Wuhan, China; Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, China.
| | - Xinjun Liang
- Department of Medical Oncology, Hubei Cancer Hospital, the Seventh Clinical School Affiliated of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Colorectal Cancer Clinical Research Center of HuBei Province, Wuhan, China; Colorectal Cancer Clinical Research Center of Wuhan, Wuhan, China.
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33
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Zhu H, Yu X, Zhang S, Shu K. Targeting the Complement Pathway in Malignant Glioma Microenvironments. Front Cell Dev Biol 2021; 9:657472. [PMID: 33869223 PMCID: PMC8047198 DOI: 10.3389/fcell.2021.657472] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 03/12/2021] [Indexed: 12/12/2022] Open
Abstract
Malignant glioma is a highly fatal type of brain tumor, and its reoccurrence is largely due to the ordered interactions among the components present in the complex microenvironment. Besides its role in immune surveillance and clearance under physiological conditions, the complement system is expressed in a variety of tumor types and mediates the interactions within the tumor microenvironments. Recent studies have uncovered the broad expression spectrum of complement signaling molecules in the tumor microenvironment and various tumor cells, in particular, malignant glioma cells. Involvement of the complement system in tumor growth, immunosuppression and phenotype transition have also been elucidated. In this review, we enumerate the expression and function of complement molecules in multiple tumor types reported. Moreover, we elaborate the complement pathways in glioma cells and various components of malignant glioma microenvironments. Finally, we summarize the possibility of the complement molecules as prognostic factors and therapeutic targets in the treatment of malignant glioma. Specific targeting of the complement system maybe of great significance and value in the future treatment of multi-type tumors including malignant glioma.
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Affiliation(s)
- Hongtao Zhu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xingjiang Yu
- Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Suojun Zhang
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Shu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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34
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Xiong J, Kuang X, Lu T, Yu K, Liu X, Zhang Z, Wang W, Zhao L, Fang Q, Wu D, Wang J. C3a and C5a facilitates the metastasis of myeloma cells by activating Nrf2. Cancer Gene Ther 2021; 28:265-278. [PMID: 32873871 DOI: 10.1038/s41417-020-00217-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 08/11/2020] [Accepted: 08/17/2020] [Indexed: 11/09/2022]
Abstract
Multiple myeloma (MM) is still an incurable hematological malignancy, with even poorer prognosis in MM patients with distant invasion. The present study was designed to explore the effects of C3a and C5a on the migration, invasion, and adhesion of MM tumor cells and to investigate the underlying mechanisms. As a result, the levels of C3a and C5a in plasma of MM patients were significantly higher than those of healthy donors. Consistently, the expression of C3a and C5a receptors on myeloma cells of MM patients was also significantly higher than that on sorted plasma cells of normal donors. C3a and C5a have been confirmed to increase the migration, invasion and adhesion of MM cell lines by activating the MEK/ERK pathway and increasing the nuclear transfer of Nrf2 in vitro. Moreover, the MM cell line U266 with Nrf2 downregulation was incubated with C3a and C5a, followed by injection into the tail vein of NOD-SCID mice. We found that Nrf2 downregulation attenuated the migration of anaphylatoxin C3a and C5a to MM tumor cells in bone marrow, liver and lung in vivo. In conclusion, our results indicate that activation of the complement cascade in MM patients may contribute to the migration, invasion and adhesion of MM cells, and this type of tumor cells dissemination in MM is, at least partially, regulated by Nrf2. Thereby, complement suppression or Nrf2 downregulation might offer a novel therapeutic opportunity for MM.
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Affiliation(s)
- Jie Xiong
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis under Ministry of Health, Collaborative Innovation Center of Hematology, Suzhou Institute of Blood and Marrow Transplantation, 188 Shizi Street, 215006, Suzhou, Jiangsu, China
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Xingyi Kuang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Tingting Lu
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Kunlin Yu
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Xu Liu
- Department of Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, 550001, Guiyang, China
| | - Zhaoyuan Zhang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Weili Wang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Lu Zhao
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China
| | - Qin Fang
- Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, 550001, Guiyang, China
| | - Depei Wu
- Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis under Ministry of Health, Collaborative Innovation Center of Hematology, Suzhou Institute of Blood and Marrow Transplantation, 188 Shizi Street, 215006, Suzhou, Jiangsu, China.
| | - Jishi Wang
- Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China.
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35
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O’Brien RM, Cannon A, Reynolds JV, Lysaght J, Lynam-Lennon N. Complement in Tumourigenesis and the Response to Cancer Therapy. Cancers (Basel) 2021; 13:1209. [PMID: 33802004 PMCID: PMC7998562 DOI: 10.3390/cancers13061209] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 12/16/2022] Open
Abstract
In recent years, our knowledge of the complement system beyond innate immunity has progressed significantly. A modern understanding is that the complement system has a multifaceted role in malignancy, impacting carcinogenesis, the acquisition of a metastatic phenotype and response to therapies. The ability of local immune cells to produce and respond to complement components has provided valuable insights into their regulation, and the subsequent remodeling of the tumour microenvironment. These novel discoveries have advanced our understanding of the immunosuppressive mechanisms supporting tumour growth and uncovered potential therapeutic targets. This review discusses the current understanding of complement in cancer, outlining both direct and immune cell-mediated roles. The role of complement in response to therapies such as chemotherapy, radiation and immunotherapy is also presented. While complement activities are largely context and cancer type-dependent, it is evident that promising therapeutic avenues have been identified, in particular in combination therapies.
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Affiliation(s)
- Rebecca M. O’Brien
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
- Cancer Immunology and Immunotherapy Group, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland
| | - Aoife Cannon
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
| | - John V. Reynolds
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
| | - Joanne Lysaght
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
- Cancer Immunology and Immunotherapy Group, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland
| | - Niamh Lynam-Lennon
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; (R.M.O.); (A.C.); (J.V.R.); (J.L.)
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Popeda M, Markiewicz A, Stokowy T, Szade J, Niemira M, Kretowski A, Bednarz-Knoll N, Zaczek AJ. Reduced expression of innate immunity-related genes in lymph node metastases of luminal breast cancer patients. Sci Rep 2021; 11:5097. [PMID: 33658651 PMCID: PMC7930267 DOI: 10.1038/s41598-021-84568-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 02/18/2021] [Indexed: 01/31/2023] Open
Abstract
Immune system plays a dual role in cancer by either targeting or supporting neoplastic cells at various stages of disease, including metastasis. Yet, the exact immune-related transcriptome profiles of primary tumours (PT) and lymph node metastases (LNM) and their evolution during luminal breast cancer (BCa) dissemination remain undiscovered. In order to identify the immune-related transcriptome changes that accompany lymphatic spread, we analysed PT-LNM pairs of luminal BCa using NanoString technology. Decrease in complement C3-one of the top-downregulated genes, in LNM was validated at the protein level using immunohistochemistry. Thirty-three of 360 analysed genes were downregulated (9%), whereas only 3 (0.8%) upregulated in LNM when compared to the corresponding PT. In LNM, reduced expression was observed in genes related to innate immunity, particularly to the complement system (C1QB, C1S, C1R, C4B, CFB, C3, SERPING1 and C3AR1). In validation cohort, complement C3 protein was less frequently expressed in LNM than in PT and it was associated with worse prognosis. To conclude, local expression of the complement system components declines during lymphatic spread of non-metastatic luminal BCa, whilst further reduction of tumoral complement C3 in LNM is indicative for poor survival. This points to context-dependent role of complement C3 in BCa dissemination.
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Affiliation(s)
- Marta Popeda
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, 80-211, Gdansk, Poland
| | - Aleksandra Markiewicz
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, 80-211, Gdansk, Poland
| | - Tomasz Stokowy
- Department of Clinical Science, University of Bergen, 5021, Bergen, Norway
| | - Jolanta Szade
- Department of Pathomorphology, Medical University of Gdansk, 80-211, Gdansk, Poland
| | - Magdalena Niemira
- Clinical Research Centre, Medical University of Bialystok, 15-276, Bialystok, Poland
| | - Adam Kretowski
- Clinical Research Centre, Medical University of Bialystok, 15-276, Bialystok, Poland
| | - Natalia Bednarz-Knoll
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, 80-211, Gdansk, Poland
| | - Anna J Zaczek
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdansk, 80-211, Gdansk, Poland.
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Nürge B, Schulz AL, Kaemmerer D, Sänger J, Evert K, Schulz S, Lupp A. Immunohistochemical identification of complement peptide C5a receptor 1 (C5aR1) in non-neoplastic and neoplastic human tissues. PLoS One 2021; 16:e0246939. [PMID: 33606748 PMCID: PMC7894821 DOI: 10.1371/journal.pone.0246939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 01/28/2021] [Indexed: 11/18/2022] Open
Abstract
The complement component C5a and its receptor C5aR1 are involved in the development of numerous inflammatory diseases. In addition to immune cells, C5aR1 is expressed in neoplastic cells of multiple tumour entities, where C5aR1 is associated with a higher proliferation rate, advanced tumour stage, and poor patient outcomes. The aim of the present study was to obtain a broad expression profile of C5aR1 in human non-neoplastic and neoplastic tissues, especially in tumour entities not investigated in this respect so far. For this purpose, we generated a novel polyclonal rabbit antibody, {5227}, against the carboxy-terminal tail of C5aR1. The antibody was initially characterised in Western blot analyses and immunocytochemistry using transfected human embryonic kidney (HEK) 293 cells. It was then applied to a large series of formalin-fixed, paraffin-embedded non-neoplastic and neoplastic human tissue samples. C5aR1 was strongly expressed by different types of immune cells in the majority of tissue samples investigated. C5aR1 was also present in alveolar macrophages, bronchial, gut, and bile duct epithelia, Kupffer cells, occasionally in hepatocytes, proximal renal tubule cells, placental syncytiotrophoblasts, and distinct stem cell populations of bone marrow. C5aR1 was also highly expressed in the vast majority of the 32 tumour entities investigated, where a hitherto unappreciated high prevalence of the receptor was detected in thyroid carcinomas, small-cell lung cancer, gastrointestinal stromal tumours, and endometrial carcinomas. In addition to confirming published findings, we found noticeable C5aR1 expression in many tumour entities for the first time. Here, it may serve as an interesting target for future therapies.
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Affiliation(s)
- Benjamin Nürge
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
| | - Alan Lennart Schulz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
| | - Daniel Kaemmerer
- Department of General and Visceral Surgery, Zentralklinik Bad Berka, Bad Berka, Germany
| | - Jörg Sänger
- Laboratory of Pathology and Cytology Bad Berka, Bad Berka, Germany
| | - Katja Evert
- Department of Pathology, University of Regensburg, Regensburg, Germany
- Institute of Pathology, University Medicine of Greifswald, Greifswald, Germany
| | - Stefan Schulz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
- * E-mail:
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38
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Complement activation promoted by the lectin pathway mediates C3aR-dependent sarcoma progression and immunosuppression. NATURE CANCER 2021; 2:218-232. [PMID: 34505065 PMCID: PMC8425276 DOI: 10.1038/s43018-021-00173-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Complement has emerged as a component of tumor promoting inflammation. We conducted a systematic assessment of the role of complement activation and effector pathways in sarcomas. C3-/-, MBL1/2-/- and C4-/- mice showed reduced susceptibility to 3-methylcholanthrene sarcomagenesis and transplanted sarcomas, whereas C1q and factor B deficiency had marginal effects. Complement 3a receptor (C3aR), but not C5aR1 and C5aR2, deficiency mirrored the phenotype of C3-/- mice. C3 and C3aR deficiency were associated with reduced accumulation and functional skewing of tumor-associated macrophages, increased T cell activation and response to anti-PD-1 therapy. Transcriptional profiling of sarcoma infiltrating macrophages and monocytes revealed the enrichment of MHC II-dependent antigen presentation pathway in C3-deficient cells. In patients, C3aR expression correlated with a macrophage population signature and C3 deficiency-associated signatures predicted better clinical outcome. These results suggest that the lectin pathway and C3a/C3aR axis are key components of complement and macrophage-mediated sarcoma promotion and immunosuppression.
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Jackson WD, Gulino A, Fossati-Jimack L, Castro Seoane R, Tian K, Best K, Köhl J, Belmonte B, Strid J, Botto M. C3 Drives Inflammatory Skin Carcinogenesis Independently of C5. J Invest Dermatol 2021; 141:404-414.e6. [PMID: 32682912 PMCID: PMC8150327 DOI: 10.1016/j.jid.2020.06.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/30/2020] [Accepted: 06/10/2020] [Indexed: 11/17/2022]
Abstract
Nonmelanoma skin cancer such as cutaneous squamous cell carcinoma (cSCC) is the most common form of cancer and can occur as a consequence of DNA damage to the epithelium by UVR or chemical carcinogens. There is growing evidence that the complement system is involved in cancer immune surveillance; however, its role in cSCC remains unclear. Here, we show that complement genes are expressed in tissue from patients with cSCC, and C3 activation fragments are present in cSCC biopsies, indicating complement activation. Using a range of complement-deficient mice in a two-stage mouse model of chemically-induced cSCC, where a subclinical dose of 7,12-dimethylbenz[a]anthracene causes oncogenic mutations in epithelial cells and 12-O-tetradecanoylphorbol-13-acetate promotes the outgrowth of these cells, we found that C3-deficient mice displayed a significantly reduced tumor burden, whereas an opposite phenotype was observed in mice lacking C5aR1, C5aR2, and C3a receptor. In addition, in mice unable to form the membrane attack complex, the tumor progression was unaltered. C3 deficiency did not affect the cancer response to 7,12-dimethylbenz[a]anthracene treatment alone but reduced the epidermal hyperplasia during 12-O-tetradecanoylphorbol-13-acetate-induced inflammation. Collectively, these data indicate that C3 drives tumorigenesis during chronic skin inflammation, independently of the downstream generation of C5a or membrane attack complex.
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MESH Headings
- 9,10-Dimethyl-1,2-benzanthracene/administration & dosage
- 9,10-Dimethyl-1,2-benzanthracene/toxicity
- Animals
- Carcinogens/administration & dosage
- Carcinogens/toxicity
- Carcinoma, Squamous Cell/chemically induced
- Carcinoma, Squamous Cell/immunology
- Carcinoma, Squamous Cell/pathology
- Complement Activation/genetics
- Complement Activation/immunology
- Complement C3/genetics
- Complement C3/metabolism
- Complement C5/metabolism
- Complement Membrane Attack Complex/metabolism
- Disease Models, Animal
- Disease Progression
- Humans
- Mice
- Mice, Knockout
- Mice, Transgenic
- Neoplasms, Experimental/blood
- Neoplasms, Experimental/chemically induced
- Neoplasms, Experimental/immunology
- Neoplasms, Experimental/pathology
- Receptor, Anaphylatoxin C5a/genetics
- Receptor, Anaphylatoxin C5a/metabolism
- Receptors, Complement/genetics
- Receptors, Complement/metabolism
- Signal Transduction/genetics
- Signal Transduction/immunology
- Skin/drug effects
- Skin/immunology
- Skin/pathology
- Skin Neoplasms/chemically induced
- Skin Neoplasms/immunology
- Skin Neoplasms/pathology
- Tumor Escape
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Affiliation(s)
- William D Jackson
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, United Kingdom
| | - Alessandro Gulino
- Tumor Immunology Unit, Department of Health Sciences, University of Palermo School of Medicine, Palermo, Italy
| | - Liliane Fossati-Jimack
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, United Kingdom
| | - Rocio Castro Seoane
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, United Kingdom
| | - Kunyuan Tian
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, United Kingdom
| | - Katie Best
- Department of Dermatology, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Jörg Köhl
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany; Division of Immunobiology, Cincinnati Children's Hospital and College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
| | - Beatrice Belmonte
- Tumor Immunology Unit, Department of Health Sciences, University of Palermo School of Medicine, Palermo, Italy
| | - Jessica Strid
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, United Kingdom.
| | - Marina Botto
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, United Kingdom
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40
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La-Beck NM, Islam MR, Markiewski MM. Nanoparticle-Induced Complement Activation: Implications for Cancer Nanomedicine. Front Immunol 2021; 11:603039. [PMID: 33488603 PMCID: PMC7819852 DOI: 10.3389/fimmu.2020.603039] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 11/23/2020] [Indexed: 12/23/2022] Open
Abstract
Nanoparticle-based anticancer medications were first approved for cancer treatment almost 2 decades ago. Patients benefit from these approaches because of the targeted-drug delivery and reduced toxicity, however, like other therapies, adverse reactions often limit their use. These reactions are linked to the interactions of nanoparticles with the immune system, including the activation of complement. This activation can cause well-characterized acute inflammatory reactions mediated by complement effectors. However, the long-term implications of chronic complement activation on the efficacy of drugs carried by nanoparticles remain obscured. The recent discovery of protumor roles of complement raises the possibility that nanoparticle-induced complement activation may actually reduce antitumor efficacy of drugs carried by nanoparticles. We discuss here the initial evidence supporting this notion. Better understanding of the complex interactions between nanoparticles, complement, and the tumor microenvironment appears to be critical for development of nanoparticle-based anticancer therapies that are safer and more efficacious.
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Affiliation(s)
- Ninh M La-Beck
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, United States.,Department of Pharmacy Practice, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, United States
| | - Md Rakibul Islam
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, United States
| | - Maciej M Markiewski
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX, United States
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41
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Akhir FNM, Noor MHM, Leong KWK, Nabizadeh JA, Manthey HD, Sonderegger SE, Fung JNT, McGirr CE, Shiels IA, Mills PC, Woodruff TM, Rolfe BE. An Immunoregulatory Role for Complement Receptors in Murine Models of Breast Cancer. Antibodies (Basel) 2021; 10:2. [PMID: 33430104 PMCID: PMC7838807 DOI: 10.3390/antib10010002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/20/2020] [Accepted: 12/07/2020] [Indexed: 12/25/2022] Open
Abstract
The complement system has demonstrated roles in regulating tumor growth, although these may differ between tumor types. The current study used two murine breast cancer models (EMT6 and 4T1) to investigate whether pharmacological targeting of receptors for complement proteins C3a (C3aR) and C5a (C5aR1) is protective in murine breast cancer models. In contrast to prior studies in other tumor models, treatment with the selective C5aR1 antagonist PMX53 had no effect on tumor growth. However, treatment of mice with a dual C3aR/C5aR1 agonist (YSFKPMPLaR) significantly slowed mammary tumor development and progression. Examination of receptor expression by quantitative polymerase chain reaction (qPCR) analysis showed very low levels of mRNA expression for either C3aR or C5aR1 by EMT6 or 4T1 mammary carcinoma cell lines compared with the J774 macrophage line or bone marrow-derived macrophages. Moreover, flow cytometric analysis found no evidence of C3aR or C5aR1 protein expression by either EMT6 or 4T1 cells, leading us to hypothesize that the tumor inhibitory effects of the dual agonist are indirect, possibly via regulation of the anti-tumor immune response. This hypothesis was supported by flow cytometric analysis of tumor infiltrating leukocyte populations, which demonstrated a significant increase in T lymphocytes in mice treated with the C3aR/C5aR1 agonist. These results support an immunoregulatory role for complement receptors in primary murine mammary carcinoma models. They also suggest that complement activation peptides can influence the anti-tumor response in different ways depending on the cancer type, the host immune response to the tumor and levels of endogenous complement activation within the tumor microenvironment.
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Affiliation(s)
- Fazrena Nadia Md Akhir
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia;
| | - Mohd Hezmee Mohd Noor
- School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia; (M.H.M.N.); (I.A.S.); (P.C.M.)
| | - Keith Weng Kit Leong
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
| | - Jamileh A. Nabizadeh
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
| | - Helga D. Manthey
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
| | - Stefan E. Sonderegger
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
| | - Jenny Nga Ting Fung
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
| | - Crystal E. McGirr
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
| | - Ian A. Shiels
- School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia; (M.H.M.N.); (I.A.S.); (P.C.M.)
| | - Paul C. Mills
- School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia; (M.H.M.N.); (I.A.S.); (P.C.M.)
| | - Trent M. Woodruff
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia;
| | - Barbara E. Rolfe
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia; (F.N.M.A.); (K.W.K.L.); (J.A.N.); (H.D.M.); (S.E.S.); (J.N.T.F.); (C.E.M.)
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42
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The Role of Complement in Angiogenesis. Antibodies (Basel) 2020; 9:antib9040067. [PMID: 33271774 PMCID: PMC7709120 DOI: 10.3390/antib9040067] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/20/2020] [Accepted: 11/23/2020] [Indexed: 12/16/2022] Open
Abstract
The link of the complement system to angiogenesis has remained circumstantial and speculative for several years. Perhaps the most clinically relevant example of possible involvement of complement in pathological neovascularization is age-related macular degeneration. Recent studies, however, provide more direct and experimental evidence that indeed the complement system regulates physiological and pathological angiogenesis in models of wound healing, retinal regeneration, age-related macular degeneration, and cancer. Interestingly, complement-dependent mechanisms involved in angiogenesis are very much context dependent, including anti- and proangiogenic functions. Here, we discuss these new developments that place complement among other important regulators of homeostatic and pathological angiogenesis, and we provide the perspective on how these newly discovered complement functions can be targeted for therapy.
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43
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Complement System: Promoter or Suppressor of Cancer Progression? Antibodies (Basel) 2020; 9:antib9040057. [PMID: 33113844 PMCID: PMC7709131 DOI: 10.3390/antib9040057] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/10/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022] Open
Abstract
Constituent of innate immunity, complement is present in the tumor microenvironment. The functions of complement include clearance of pathogens and maintenance of homeostasis, and as such could contribute to an anti-tumoral role in the context of certain cancers. However, multiple lines of evidence show that in many cancers, complement has pro-tumoral actions. The large number of complement molecules (over 30), the diversity of their functions (related or not to the complement cascade), and the variety of cancer types make the complement-cancer topic a very complex matter that has just started to be unraveled. With this review we highlight the context-dependent role of complement in cancer. Recent studies revealed that depending of the cancer type, complement can be pro or anti-tumoral and, even for the same type of cancer, different models presented opposite effects. We aim to clarify the current knowledge of the role of complement in human cancers and the insights from mouse models. Using our classification of human cancers based on the prognostic impact of the overexpression of complement genes, we emphasize the strong potential for therapeutic targeting the complement system in selected subgroups of cancer patients.
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Su KM, Lin TW, Liu LC, Yang YP, Wang ML, Tsai PH, Wang PH, Yu MH, Chang CM, Chang CC. The Potential Role of Complement System in the Progression of Ovarian Clear Cell Carcinoma Inferred from the Gene Ontology-Based Immunofunctionome Analysis. Int J Mol Sci 2020; 21:E2824. [PMID: 32316695 PMCID: PMC7216156 DOI: 10.3390/ijms21082824] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/27/2020] [Accepted: 04/15/2020] [Indexed: 02/07/2023] Open
Abstract
Ovarian clear cell carcinoma (OCCC) is the second most common epithelial ovarian carcinoma (EOC). It is refractory to chemotherapy with a worse prognosis after the preliminary optimal debulking operation, such that the treatment of OCCC remains a challenge. OCCC is believed to evolve from endometriosis, a chronic immune/inflammation-related disease, so that immunotherapy may be a potential alternative treatment. Here, gene set-based analysis was used to investigate the immunofunctionomes of OCCC in early and advanced stages. Quantified biological functions defined by 5917 Gene Ontology (GO) terms downloaded from the Gene Expression Omnibus (GEO) database were used. DNA microarray gene expression profiles were used to convert 85 OCCCs and 136 normal controls into to the functionome. Relevant offspring were as extracted and the immunofunctionomes were rebuilt at different stages by machine learning. Several dysregulated pathogenic functions were found to coexist in the immunopathogenesis of early and advanced OCCC, wherein the complement-activation-alternative-pathway may be the headmost dysfunctional immunological pathway in duality for carcinogenesis at all OCCC stages. Several immunological genes involved in the complement system had dual influences on patients' survival, and immunohistochemistrical analysis implied the higher expression of C3a receptor (C3aR) and C5a receptor (C5aR) levels in OCCC than in controls.
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Affiliation(s)
- Kuo-Min Su
- Department of Obstetrics and Gynecology, Tri-service General Hospital, National Defense Medical Center, Taipei 114, Taiwan; (K.-M.S.); (L.-C.L.); (M.-H.Y.)
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
| | - Tzu-Wei Lin
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan; (T.-W.L.); (Y.-P.Y.); (M.-L.W.); (P.-H.T.)
| | - Li-Chun Liu
- Department of Obstetrics and Gynecology, Tri-service General Hospital, National Defense Medical Center, Taipei 114, Taiwan; (K.-M.S.); (L.-C.L.); (M.-H.Y.)
- Division of Obstetrics and Gynecology, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei 105, Taiwan
| | - Yi-Pin Yang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan; (T.-W.L.); (Y.-P.Y.); (M.-L.W.); (P.-H.T.)
- School of Medicine, National Yang-Ming University, Taipei 112, Taiwan;
| | - Mong-Lien Wang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan; (T.-W.L.); (Y.-P.Y.); (M.-L.W.); (P.-H.T.)
- School of Medicine, National Yang-Ming University, Taipei 112, Taiwan;
| | - Ping-Hsing Tsai
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan; (T.-W.L.); (Y.-P.Y.); (M.-L.W.); (P.-H.T.)
- School of Medicine, National Yang-Ming University, Taipei 112, Taiwan;
| | - Peng-Hui Wang
- School of Medicine, National Yang-Ming University, Taipei 112, Taiwan;
- Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
| | - Mu-Hsien Yu
- Department of Obstetrics and Gynecology, Tri-service General Hospital, National Defense Medical Center, Taipei 114, Taiwan; (K.-M.S.); (L.-C.L.); (M.-H.Y.)
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
| | - Chia-Ming Chang
- School of Medicine, National Yang-Ming University, Taipei 112, Taiwan;
- Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Cheng-Chang Chang
- Department of Obstetrics and Gynecology, Tri-service General Hospital, National Defense Medical Center, Taipei 114, Taiwan; (K.-M.S.); (L.-C.L.); (M.-H.Y.)
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
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Wang H, Li Y, Shi G, Wang Y, Lin Y, Wang Q, Zhang Y, Yang Q, Dai L, Cheng L, Su X, Yang Y, Zhang S, Li Z, Li J, Wei Y, Yu D, Deng H. A Novel Antitumor Strategy: Simultaneously Inhibiting Angiogenesis and Complement by Targeting VEGFA/PIGF and C3b/C4b. Mol Ther Oncolytics 2020; 16:20-29. [PMID: 31909182 PMCID: PMC6940616 DOI: 10.1016/j.omto.2019.12.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 12/09/2019] [Indexed: 02/05/2023] Open
Abstract
Therapeutic antibodies targeting vascular endothelial growth factor (VEGF) have become a critical regimen for tumor therapy, but the efficacy of monotherapy is usually limited by drug resistance and multiple angiogenic mechanisms. Complement proteins are becoming potential candidates for cancer-targeted therapy based on their role in promoting cancer progression and angiogenesis. However, the antitumor abilities of simultaneous VEGF and complement blockade were unknown. We generated a humanized soluble VEGFR-Fc fusion protein (VID) binding VEGFA/PIGF and a CR1-Fc fusion protein (CID) targeting C3b/C4b. Both VID and CID had good affinities to their ligands and showed effective bioactivities. In vitro, angiogenesis effects induced by VEGF and hemolysis induced by complement were inhibited by VID and CID, respectively. Further, VID and CID confer a synergetic therapeutic effect in a colitis-associated colorectal cancer (CAC) model and an orthotopic 4T1 breast cancer model. Mechanically, combination therapy inhibited tumor angiogenesis, cell proliferation, and MDSC infiltration in the tumor microenvironment and promoted tumor cell apoptosis. Our study offers a novel therapeutic strategy for anti-VEGF-resistant tumors and chronic-inflammation-associated tumors.
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Affiliation(s)
- Huiling Wang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yiming Li
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Innovent Biologics (Suzhou) Co., Ltd., Suzhou, Jiangsu 215000, China
| | - Gang Shi
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yuan Wang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yi Lin
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Qin Wang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yujing Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Qianmei Yang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lei Dai
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lin Cheng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiaolan Su
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yang Yang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Shuang Zhang
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Zhi Li
- Innovent Biologics (Suzhou) Co., Ltd., Suzhou, Jiangsu 215000, China
| | - Jia Li
- Innovent Biologics (Suzhou) Co., Ltd., Suzhou, Jiangsu 215000, China
| | - Yuquan Wei
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Dechao Yu
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hongxin Deng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Riihilä P, Viiklepp K, Nissinen L, Farshchian M, Kallajoki M, Kivisaari A, Meri S, Peltonen J, Peltonen S, Kähäri V. Tumour-cell-derived complement components C1r and C1s promote growth of cutaneous squamous cell carcinoma. Br J Dermatol 2020; 182:658-670. [PMID: 31049937 PMCID: PMC7065064 DOI: 10.1111/bjd.18095] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/30/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND The incidence of epidermal keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is increasing worldwide. OBJECTIVES To study the role of the complement classical pathway components C1q, C1r and C1s in the progression of cSCC. METHODS The mRNA levels of C1Q subunits and C1R and C1S in cSCC cell lines, normal human epidermal keratinocytes, cSCC tumours in vivo and normal skin were analysed with quantitative real-time polymerase chain reaction. The production of C1r and C1s was determined with Western blotting. The expression of C1r and C1s in tissue samples in vivo was analysed with immunohistochemistry and further investigated in human cSCC xenografts by knocking down C1r and C1s. RESULTS Significantly elevated C1R and C1S mRNA levels and production of C1r and C1s were detected in cSCC cells, compared with normal human epidermal keratinocytes. The mRNA levels of C1R and C1S were markedly elevated in cSCC tumours in vivo compared with normal skin. Abundant expression of C1r and C1s by tumour cells was detected in invasive sporadic cSCCs and recessive dystrophic epidermolysis bullosa-associated cSCCs, whereas the expression of C1r and C1s was lower in cSCC in situ, actinic keratosis and normal skin. Knockdown of C1r and C1s expression in cSCC cells inhibited activation of extracellular signal-related kinase 1/2 and Akt, promoted apoptosis of cSCC cells and significantly suppressed growth and vascularization of human cSCC xenograft tumours in vivo. CONCLUSIONS These results provide evidence for the role of tumour-cell-derived C1r and C1s in the progression of cSCC and identify them as biomarkers and putative therapeutic targets in cSCC. What's already known about this topic? The incidences of actinic keratosis, cutaneous squamous cell carcinoma (cSCC) in situ and invasive cSCC are increasing globally. Few specific biomarkers for progression of cSCC have been identified, and no biological markers are in clinical use to predict the aggressiveness of actinic keratosis, cSCC in situ and invasive cSCC. What does this study add? Our results provide novel evidence for the role of complement classical pathway components C1r and C1s in the progression of cSCC. What is the translational message? Our results identify complement classical pathway components C1r and C1s as biomarkers and putative therapeutic targets in cSCC.
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Affiliation(s)
- P. Riihilä
- Department of DermatologyUniversity of Turku and Turku University HospitalHämeentie 11 TE6FI‐20520TurkuFinland
- MediCity Research LaboratoryUniversity of TurkuTurkuFinland
- The Western Cancer Centre of the Cancer Center Finland (FICAN West)University of Turku and Turku University HospitalHämeentie 11 TE6FI‐20520TurkuFinland
| | - K. Viiklepp
- Department of DermatologyUniversity of Turku and Turku University HospitalHämeentie 11 TE6FI‐20520TurkuFinland
- MediCity Research LaboratoryUniversity of TurkuTurkuFinland
- The Western Cancer Centre of the Cancer Center Finland (FICAN West)University of Turku and Turku University HospitalHämeentie 11 TE6FI‐20520TurkuFinland
| | - L. Nissinen
- Department of DermatologyUniversity of Turku and Turku University HospitalHämeentie 11 TE6FI‐20520TurkuFinland
- MediCity Research LaboratoryUniversity of TurkuTurkuFinland
- The Western Cancer Centre of the Cancer Center Finland (FICAN West)University of Turku and Turku University HospitalHämeentie 11 TE6FI‐20520TurkuFinland
| | - M. Farshchian
- Department of DermatologyUniversity of Turku and Turku University HospitalHämeentie 11 TE6FI‐20520TurkuFinland
- MediCity Research LaboratoryUniversity of TurkuTurkuFinland
| | - M. Kallajoki
- Department of PathologyTurku University HospitalTurkuFinland
| | - A. Kivisaari
- Department of DermatologyUniversity of Turku and Turku University HospitalHämeentie 11 TE6FI‐20520TurkuFinland
- MediCity Research LaboratoryUniversity of TurkuTurkuFinland
| | - S. Meri
- Haartman InstituteUniversity of HelsinkiHelsinkiFinland
| | - J. Peltonen
- Department of Anatomy and Cell BiologyUniversity of TurkuTurkuFinland
| | - S. Peltonen
- Department of DermatologyUniversity of Turku and Turku University HospitalHämeentie 11 TE6FI‐20520TurkuFinland
| | - V.‐M. Kähäri
- Department of DermatologyUniversity of Turku and Turku University HospitalHämeentie 11 TE6FI‐20520TurkuFinland
- MediCity Research LaboratoryUniversity of TurkuTurkuFinland
- The Western Cancer Centre of the Cancer Center Finland (FICAN West)University of Turku and Turku University HospitalHämeentie 11 TE6FI‐20520TurkuFinland
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Świerzko AS, Michalski M, Sokołowska A, Nowicki M, Szala-Poździej A, Eppa Ł, Mitrus I, Szmigielska-Kapłon A, Sobczyk-Kruszelnicka M, Michalak K, Gołos A, Wierzbowska A, Giebel S, Jamroziak K, Kowalski ML, Brzezińska O, Thiel S, Matsushita M, Jensenius JC, Gajek G, Cedzyński M. Associations of Ficolins With Hematological Malignancies in Patients Receiving High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantations. Front Immunol 2020; 10:3097. [PMID: 32047495 PMCID: PMC6997528 DOI: 10.3389/fimmu.2019.03097] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 12/18/2019] [Indexed: 01/08/2023] Open
Abstract
A prospective study of 312 patients [194 with multiple myeloma (MM) and 118 with lymphomas (LYMPH)] receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT) was conducted. Ficolins are innate immune defense factors, able to distinguish between "self" "abnormal self," and "non-self" and contribute to the elimination of the last two by direct opsonization and/or initiation of complement activation via the lectin pathway. Concentrations of ficolin-1, ficolin-2, and ficolin-3 in serially taken serum samples were determined as were the polymorphisms of the corresponding (FCN1, FCN2, and FCN3) genes. Serum samples were collected before conditioning chemotherapy, before HSCT, and once weekly post-HSCT (four to five samples in total); some patients were also sampled at 1 and/or 3 months post-transplantation. The control group (C) consisted of 267 healthy unrelated individuals. Median ficolin-1 and ficolin-2 (but not ficolin-3) levels in MM patients' sera taken before chemotherapy were lower (and correspondingly frequencies of the lowest concentrations were higher) compared with controls. That appeared to be associated with the malignant disease itself rather than with post-HSCT complications (febrile neutropenia, infections accompanied, or not with bacteremia). Higher frequencies of the FCN1 genotype G/A-C/C-G/G (corresponding to polymorphisms at positions -542, -144, and +6658, respectively) and FCN2 gene heterozygosity for the -857 C>A polymorphism were found among patients diagnosed with MM compared with the C group. Furthermore, FCN2 G/G homozygosity (-557 A>G) was found more frequently and heterozygosity G/T at +6424 less frequently among LYMPH patients than among the healthy subjects. Heterozygosity for +1637delC mutation of the FCN3 gene was more common among patients diagnosed with lymphomas who experienced hospital infections. Although no evidence for an association of low ficolin-1 or ficolin-2 with infections during neutropenia following chemotherapy before HSCT was found, we observed a possible protective effect of ficolins during follow-up.
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Affiliation(s)
- Anna S. Świerzko
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland
| | - Mateusz Michalski
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland
| | - Anna Sokołowska
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland
| | - Mateusz Nowicki
- Department of Hematology, Comprehensive Cancer Center and Traumatology, Copernicus Memorial Hospital, Łódz, Poland
| | - Agnieszka Szala-Poździej
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland
| | - Łukasz Eppa
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland
| | - Iwona Mitrus
- Department of Bone Marrow Transplantation and Oncohematology, Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | | | - Małgorzata Sobczyk-Kruszelnicka
- Department of Bone Marrow Transplantation and Oncohematology, Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Katarzyna Michalak
- Department of Bone Marrow Transplantation and Oncohematology, Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Aleksandra Gołos
- Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | | | - Sebastian Giebel
- Department of Bone Marrow Transplantation and Oncohematology, Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Krzysztof Jamroziak
- Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Marek L. Kowalski
- Department of Immunology and Allergy, Medical University of Łódz, Łódz, Poland
| | - Olga Brzezińska
- Department of Immunology and Allergy, Medical University of Łódz, Łódz, Poland
- Department of Rheumatology, Medical University of Łódz, Łódz, Poland
| | - Steffen Thiel
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Misao Matsushita
- Department of Applied Biochemistry, Tokai University, Hiratsuka, Japan
| | | | - Gabriela Gajek
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland
| | - Maciej Cedzyński
- Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, Łódz, Poland
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Roumenina LT, Daugan MV, Petitprez F, Sautès-Fridman C, Fridman WH. Context-dependent roles of complement in cancer. Nat Rev Cancer 2019; 19:698-715. [PMID: 31666715 DOI: 10.1038/s41568-019-0210-0] [Citation(s) in RCA: 221] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/14/2019] [Indexed: 12/16/2022]
Abstract
The tumour microenvironment (TME) highly influences the growth and spread of tumours, thus impacting the patient's clinical outcome. In this context, the complement system plays a major and complex role. It may either act to kill antibody-coated tumour cells, support local chronic inflammation or hamper antitumour T cell responses favouring tumour progression. Recent studies demonstrate that these opposing effects are dependent upon the sites of complement activation, the composition of the TME and the tumour cell sensitivity to complement attack. In this Review, we present the evidence that has so far accrued showing a role for complement activation and its effects on cancer control and clinical outcome under different TME contexts. We also include a new analysis of the publicly available transcriptomic data to provide an overview of the prognostic value of complement gene expression in 30 cancer types. We argue that the interplay of complement components within each cancer type is unique, governed by the properties of the tumour cells and the TME. This concept is of critical importance for the design of efficient therapeutic strategies aimed at targeting complement components and their signalling.
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Affiliation(s)
- Lubka T Roumenina
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Sorbonne Universités, Université de Paris, Paris, France.
| | - Marie V Daugan
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Sorbonne Universités, Université de Paris, Paris, France
| | - Florent Petitprez
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Sorbonne Universités, Université de Paris, Paris, France
- Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France
| | - Catherine Sautès-Fridman
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Sorbonne Universités, Université de Paris, Paris, France
| | - Wolf Herman Fridman
- INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Sorbonne Universités, Université de Paris, Paris, France.
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49
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Ajona D, Zandueta C, Corrales L, Moreno H, Pajares MJ, Ortiz-Espinosa S, Martínez-Terroba E, Perurena N, de Miguel FJ, Jantus-Lewintre E, Camps C, Vicent S, Agorreta J, Montuenga LM, Pio R, Lecanda F. Blockade of the Complement C5a/C5aR1 Axis Impairs Lung Cancer Bone Metastasis by CXCL16-mediated Effects. Am J Respir Crit Care Med 2019; 197:1164-1176. [PMID: 29327939 DOI: 10.1164/rccm.201703-0660oc] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
RATIONALE C5aR1 (CD88), a receptor for complement anaphylatoxin C5a, is a potent immune mediator. Its impact on malignant growth and dissemination of non-small cell lung cancer cells is poorly understood. OBJECTIVES To investigate the contribution of the C5a/C5aR1 axis to the malignant phenotype of non-small cell lung cancer cells, particularly in skeletal colonization, a preferential lung metastasis site. METHODS Association between C5aR1 expression and clinical outcome was assessed in silico and validated by immunohistochemistry. Functional significance was evaluated by lentiviral gene silencing and ligand l-aptamer inhibition in in vivo models of lung cancer bone metastasis. In vitro functional assays for signaling, migration, invasion, metalloprotease activity, and osteoclastogenesis were also performed. MEASUREMENTS AND MAIN RESULTS High levels of C5aR1 in human lung tumors were significantly associated with shorter recurrence-free survival, overall survival, and bone metastasis. Silencing of C5aR1 in lung cancer cells led to a substantial reduction in skeletal metastatic burden and osteolysis in in vivo models. Furthermore, metalloproteolytic, migratory, and invasive tumor cell activities were modulated in vitro by C5aR1 stimulation or gene silencing. l-Aptamer blockade or C5aR1 silencing significantly reduced the osseous metastatic activity of lung cancer cells in vivo. This effect was associated with decreased osteoclastogenic activity in vitro and was rescued by the exogenous addition of the chemokine CXCL16. CONCLUSIONS Disruption of C5aR1 signaling in lung cancer cells abrogates their tumor-associated osteoclastogenic activity, impairing osseous colonization. This study unveils the role played by the C5a/C5aR1 axis in lung cancer dissemination and supports its potential use as a novel therapeutic target.
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Affiliation(s)
- Daniel Ajona
- 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain.,2 IdiSNA (Navarra Institute for Health Research), Pamplona, Spain.,3 CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Spain.,4 Department of Biochemistry and Genetics, School of Sciences, and
| | - Carolina Zandueta
- 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain.,2 IdiSNA (Navarra Institute for Health Research), Pamplona, Spain.,3 CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Spain
| | - Leticia Corrales
- 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain
| | - Haritz Moreno
- 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain.,2 IdiSNA (Navarra Institute for Health Research), Pamplona, Spain
| | - María J Pajares
- 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain.,2 IdiSNA (Navarra Institute for Health Research), Pamplona, Spain.,3 CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Spain.,5 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain
| | - Sergio Ortiz-Espinosa
- 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain.,3 CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Spain.,4 Department of Biochemistry and Genetics, School of Sciences, and
| | - Elena Martínez-Terroba
- 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain.,5 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain
| | - Naiara Perurena
- 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain
| | - Fernando J de Miguel
- 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain.,4 Department of Biochemistry and Genetics, School of Sciences, and
| | - Eloisa Jantus-Lewintre
- 3 CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Spain.,6 Molecular Oncology Laboratory, Fundación Investigación, Hospital General Universitario de Valencia, Valencia, Spain.,7 Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain
| | - Carlos Camps
- 3 CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Spain.,6 Molecular Oncology Laboratory, Fundación Investigación, Hospital General Universitario de Valencia, Valencia, Spain.,8 Department of Medical Oncology, Hospital General Universitario de Valencia, Valencia, Spain; and.,9 Department of Medicine, Universitat de València, Valencia, Spain
| | - Silvestre Vicent
- 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain.,2 IdiSNA (Navarra Institute for Health Research), Pamplona, Spain.,3 CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Spain.,5 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain
| | - Jackeline Agorreta
- 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain.,2 IdiSNA (Navarra Institute for Health Research), Pamplona, Spain.,3 CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Spain.,5 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain
| | - Luis M Montuenga
- 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain.,2 IdiSNA (Navarra Institute for Health Research), Pamplona, Spain.,3 CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Spain.,5 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain
| | - Ruben Pio
- 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain.,2 IdiSNA (Navarra Institute for Health Research), Pamplona, Spain.,3 CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Spain.,4 Department of Biochemistry and Genetics, School of Sciences, and
| | - Fernando Lecanda
- 1 Center for Applied Medical Research, Program in Solid Tumors and Biomarkers, Pamplona, Spain.,2 IdiSNA (Navarra Institute for Health Research), Pamplona, Spain.,3 CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Spain.,5 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain
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50
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Riihilä P, Nissinen L, Knuutila J, Rahmati Nezhad P, Viiklepp K, Kähäri VM. Complement System in Cutaneous Squamous Cell Carcinoma. Int J Mol Sci 2019; 20:ijms20143550. [PMID: 31331124 PMCID: PMC6678994 DOI: 10.3390/ijms20143550] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 07/16/2019] [Accepted: 07/17/2019] [Indexed: 12/16/2022] Open
Abstract
Epidermal keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer with high mortality rates in the advanced stage. Chronic inflammation is a recognized risk factor for cSCC progression and the complement system, as a part of innate immunity, belongs to the microenvironment of tumors. The complement system is a double-edged sword in cancer, since complement activation is involved in anti-tumor cytotoxicity and immune responses, but it also promotes cancer progression directly and indirectly. Recently, the role of several complement components and inhibitors in the regulation of progression of cSCC has been shown. In this review, we will discuss the role of complement system components and inhibitors as biomarkers and potential new targets for therapeutic intervention in cSCC.
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Affiliation(s)
- Pilvi Riihilä
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520 Turku, Finland
- The Western Cancer Centre of the Cancer Center Finland (FICAN West), University of Turku and Turku University Hospital, Kiinamyllynkatu 10, FI-20520 Turku, Finland
| | - Liisa Nissinen
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520 Turku, Finland
- The Western Cancer Centre of the Cancer Center Finland (FICAN West), University of Turku and Turku University Hospital, Kiinamyllynkatu 10, FI-20520 Turku, Finland
| | - Jaakko Knuutila
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520 Turku, Finland
- The Western Cancer Centre of the Cancer Center Finland (FICAN West), University of Turku and Turku University Hospital, Kiinamyllynkatu 10, FI-20520 Turku, Finland
| | - Pegah Rahmati Nezhad
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520 Turku, Finland
- The Western Cancer Centre of the Cancer Center Finland (FICAN West), University of Turku and Turku University Hospital, Kiinamyllynkatu 10, FI-20520 Turku, Finland
| | - Kristina Viiklepp
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520 Turku, Finland
- The Western Cancer Centre of the Cancer Center Finland (FICAN West), University of Turku and Turku University Hospital, Kiinamyllynkatu 10, FI-20520 Turku, Finland
| | - Veli-Matti Kähäri
- Department of Dermatology, University of Turku and Turku University Hospital, Hämeentie 11 TE6, FI-20520 Turku, Finland.
- The Western Cancer Centre of the Cancer Center Finland (FICAN West), University of Turku and Turku University Hospital, Kiinamyllynkatu 10, FI-20520 Turku, Finland.
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