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Li Y, Huang R, Ye J, Han X, Meng T, Song D, Yin H. Identification of key eRNAs for intervertebral disc degeneration by integrated multinomial bioinformatics analysis. BMC Musculoskelet Disord 2024; 25:356. [PMID: 38704519 PMCID: PMC11069191 DOI: 10.1186/s12891-024-07438-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 04/12/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND Intervertebral disc degeneration (IVDD) is a common degenerative condition leading to abnormal stress distribution under load, causing intervertebral stenosis, facet joint degeneration, and foraminal stenosis. Very little is known about the molecular mechanism of eRNAs in IVDD. METHODS Gene expression profiles of 38 annulus disc samples composed of 27 less degenerated discs (LDs) and 11 more degenerated discs (MDs) were retrieved from the GEO database. Then, differentially expressed enhancer RNAs (DEeRNAs), differentially expressed target genes (DETGs), and differentially expressed transcription factors (DETFs), hallmark of cancer signalling pathways according to GSVA; the types and quantity of immune cells according to CIBERSORT; and immune gene sets according to ssGSEA were analysed to construct an IVDD-related eRNA network. Then, multidimensional validation was performed to explore the interactions among DEeRNAs, DETFs and DEGs in space. RESULTS A total of 53 components, 14 DETGs, 15 DEeRNAs, 3 DETFs, 5 immune cells, 9 hallmarks, and 7 immune gene sets, were selected to construct the regulatory network. After validation by online multidimensional databases, 21 interactive DEeRNA-DEG-DETF axes related to IVDD exacerbation were identified, among which the C1S-CTNNB1-CHD4 axis was the most significant. CONCLUSION Based upon the results of our study, we theorize that the C1S-CTNNB1-CHD4 axis plays a vital role in IVDD exacerbation. Specifically, C1S recruits CTNNB1 and upregulates the expression of CHD4 in IVDD, and subsequently, CHD4 suppresses glycolysis and activates oxidative phosphorylation, thus generating insoluble collagen fibre deposits and leading to the progression of IVDD. Overall, these DEeRNAs could comprise promising therapeutic targets for IVDD due to their high tissue specificity.
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Affiliation(s)
- Yongai Li
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Runzhi Huang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jianxin Ye
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaying Han
- Department of General Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tong Meng
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Dianwen Song
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Huabin Yin
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Kebede FG, Derks MFL, Dessie T, Hanotte O, Barros CP, Crooijmans RPMA, Komen H, Bastiaansen JWM. Landscape genomics reveals regions associated with adaptive phenotypic and genetic variation in Ethiopian indigenous chickens. BMC Genomics 2024; 25:284. [PMID: 38500079 PMCID: PMC10946127 DOI: 10.1186/s12864-024-10193-6] [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: 10/03/2023] [Accepted: 03/05/2024] [Indexed: 03/20/2024] Open
Abstract
Climate change is a threat to sustainable livestock production and livelihoods in the tropics. It has adverse impacts on feed and water availability, disease prevalence, production, environmental temperature, and biodiversity. Unravelling the drivers of local adaptation and understanding the underlying genetic variation in random mating indigenous livestock populations informs the design of genetic improvement programmes that aim to increase productivity and resilience. In the present study, we combined environmental, genomic, and phenotypic information of Ethiopian indigenous chickens to investigate their environmental adaptability. Through a hybrid sampling strategy, we captured wide biological and ecological variabilities across the country. Our environmental dataset comprised mean values of 34 climatic, vegetation and soil variables collected over a thirty-year period for 260 geolocations. Our biological dataset included whole genome sequences and quantitative measurements (on eight traits) from 513 individuals, representing 26 chicken populations spread along 4 elevational gradients (6-7 populations per gradient). We performed signatures of selection analyses ([Formula: see text] and XP-EHH) to detect footprints of natural selection, and redundancy analyses (RDA) to determine genotype-environment and genotype-phenotype-associations. RDA identified 1909 outlier SNPs linked with six environmental predictors, which have the highest contributions as ecological drivers of adaptive phenotypic variation. The same method detected 2430 outlier SNPs that are associated with five traits. A large overlap has been observed between signatures of selection identified by[Formula: see text]and XP-EHH showing that both methods target similar selective sweep regions. Average genetic differences measured by [Formula: see text] are low between gradients, but XP-EHH signals are the strongest between agroecologies. Genes in the calcium signalling pathway, those associated with the hypoxia-inducible factor (HIF) transcription factors, and sports performance (GALNTL6) are under selection in high-altitude populations. Our study underscores the relevance of landscape genomics as a powerful interdisciplinary approach to dissect adaptive phenotypic and genetic variation in random mating indigenous livestock populations.
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Affiliation(s)
- Fasil Getachew Kebede
- Animal Breeding and Genomics, Wageningen University & Research, Droevendaalsesteeg 1, Wageningen, PB-6708, The Netherlands.
- International Livestock Research Institute, P.O. Box 5689, Addis Ababa, Ethiopia.
| | - Martijn F L Derks
- Animal Breeding and Genomics, Wageningen University & Research, Droevendaalsesteeg 1, Wageningen, PB-6708, The Netherlands
| | - Tadelle Dessie
- International Livestock Research Institute, P.O. Box 5689, Addis Ababa, Ethiopia
| | - Olivier Hanotte
- International Livestock Research Institute, P.O. Box 5689, Addis Ababa, Ethiopia
- School of Life Sciences, The University of Nottingham, Nottingham, NG7 2RD, UK
| | - Carolina Pita Barros
- Animal Breeding and Genomics, Wageningen University & Research, Droevendaalsesteeg 1, Wageningen, PB-6708, The Netherlands
| | - Richard P M A Crooijmans
- Animal Breeding and Genomics, Wageningen University & Research, Droevendaalsesteeg 1, Wageningen, PB-6708, The Netherlands
| | - Hans Komen
- Animal Breeding and Genomics, Wageningen University & Research, Droevendaalsesteeg 1, Wageningen, PB-6708, The Netherlands
| | - John W M Bastiaansen
- Animal Breeding and Genomics, Wageningen University & Research, Droevendaalsesteeg 1, Wageningen, PB-6708, The Netherlands
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Guo Y, Cui J, Liang X, Chen T, Lu C, Peng T. Pancreatic cancer stem cell-derived exosomal miR-210 mediates macrophage M2 polarization and promotes gemcitabine resistance by targeting FGFRL1. Int Immunopharmacol 2024; 127:111407. [PMID: 38134594 DOI: 10.1016/j.intimp.2023.111407] [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: 06/25/2023] [Revised: 11/28/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023]
Abstract
Pancreatic cancer (PC) is a serious threat to human health, with most patients diagnosed at the advanced stages of the disease. Treatment with gemcitabine (GEM) leads to PC GEM resistance. In addition, cancer stem cell (CSC)-derived exosomes play an important role in cancer progression. We aimed to investigate the role and mechanism of action of PC stem cell-derived exosomes in PC drug resistance and progression. CSC-derived exosomes increased the proportion of F4/80+/CD86 + cells and levels of M2 polarization factors. miR-210 is expressed in CSC-derived exosomes. Thus, following co-culture, miR-210 was taken up by macrophages. Transfection or the addition of miR-210 mimics increased the proportion of F4/80+/CD206 + cells and levels of M2 polarization factors. Further, the miR-210 targets inhibited the levels of FGFRL1. The FGFRL1 overexpression plasmid also inhibited miR-210-mediated M2 polarization. After co-culture of THP-M2 cells with PC cells and treatment with GEM, the survival rate, migration rate, and levels of MDR, YB-1, BCRP, p-PI3K, p-AKT, and p-mTOR in PC cells increased. And THP-M2 increased the tumor volume and MDR, YB-1, BCRP, p-PI3K, p-AKT, and p-mTOR levels. Overall, miR-210 from PC stem cell-derived exosome targets and inhibits FGFRL1 to promote macrophage M2 polarization, which activates the p-PI3K/p-AKT/p-mTOR pathway and increases GEM resistance.
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Affiliation(s)
- Yao Guo
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jing Cui
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xueyi Liang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Taoyu Chen
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chong Lu
- Department of thyroid and breast surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Tao Peng
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Blanchard R, Adjei I. Engineering the glioblastoma microenvironment with bioactive nanoparticles for effective immunotherapy. RSC Adv 2023; 13:31411-31425. [PMID: 37901257 PMCID: PMC10603567 DOI: 10.1039/d3ra01153d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 09/27/2023] [Indexed: 10/31/2023] Open
Abstract
While immunotherapies have revolutionized treatment for other cancers, glioblastoma multiforme (GBM) patients have not shown similar positive responses. The limited response to immunotherapies is partly due to the unique challenges associated with the GBM tumor microenvironment (TME), which promotes resistance to immunotherapies, causing many promising therapies to fail. There is, therefore, an urgent need to develop strategies that make the TME immune permissive to promote treatment efficacy. Bioactive nano-delivery systems, in which the nanoparticle, due to its chemical composition, provides the pharmacological function, have recently emerged as an encouraging option for enhancing the efficacy of immunotherapeutics. These systems are designed to overcome immunosuppressive mechanisms in the TME to improve the efficacy of a therapy. This review will discuss different aspects of the TME and how they impede therapy success. Then, we will summarize recent developments in TME-modifying nanotherapeutics and the in vitro models utilized to facilitate these advances.
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Affiliation(s)
- Ryan Blanchard
- Department of Biomedical Engineering, Texas A&M University TX USA
| | - Isaac Adjei
- Department of Biomedical Engineering, Texas A&M University TX USA
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5
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Sadri M, Najafi A, Rahimi A, Behranvand N, Hossein Kazemi M, Khorramdelazad H, Falak R. Hypoxia effects on oncolytic virotherapy in Cancer: Friend or Foe? Int Immunopharmacol 2023; 122:110470. [PMID: 37433246 DOI: 10.1016/j.intimp.2023.110470] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 07/13/2023]
Abstract
Researchers have tried to find novel strategies for cancer treatment in the past decades. Among the utilized methods, administering oncolytic viruses (OVs) alone or combined with other anticancer therapeutic approaches has had promising outcomes, especially in solid tumors. Infecting the tumor cells by these viruses can lead to direct lysis or induction of immune responses. However, the immunosuppressive tumor microenvironment (TME) is considered a significant challenge for oncolytic virotherapy in treating cancer. Based on OV type, hypoxic conditions in the TME can accelerate or repress virus replication. Therefore, genetic manipulation of OVs or other molecular modifications to reduce hypoxia can induce antitumor responses. Moreover, using OVs with tumor lysis capability in the hypoxic TME may be an attractive strategy to overcome the limitations of the therapy. This review summarizes the latest information available in the field of cancer virotherapy and discusses the dual effect of hypoxia on different types of OVs to optimize available related therapeutic methods.
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Affiliation(s)
- Maryam Sadri
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Najafi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Rahimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nafiseh Behranvand
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Kazemi
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
| | - Reza Falak
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
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Miwa S, Yamamoto N, Hayashi K, Takeuchi A, Igarashi K, Taniguchi Y, Morinaga S, Asano Y, Nojima T, Tsuchiya H. Case Report: Unresectable pulmonary metastases of a giant cell tumor of bone treated with denosumab: a case report and review of literature. Front Oncol 2023; 13:1230074. [PMID: 37664037 PMCID: PMC10468596 DOI: 10.3389/fonc.2023.1230074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 07/18/2023] [Indexed: 09/05/2023] Open
Abstract
Giant cell tumors of bone (GCTB) sometimes metastasize to distant organs. In this case report, we present pulmonary metastases of GCTB mimicking malignancies. A 49-year-old man underwent two surgical treatments for a GCTB of the right proximal radius. At the time of the second surgery, no lesions were observed on chest radiography. Three years after surgery, the patient presented with cough and dyspnea, and chest radiography and computed tomography (CT) revealed multiple lung nodules. Positron emission tomography/CT revealed a high accumulation of 18F-fluoro-2-deoxy-D-glucose (18F-FDG) in multiple lesions. Based on the rapid growth and accumulation of 18F-FDG, a metastatic malignant tumor was suspected. CT-guided needle biopsy was performed, and the histology showed proliferation of spindle cells and multinuclear giant cells without malignant changes. Denosumab was administered because multiple lung lesions were unresectable. One month after denosumab treatment, CT showed marked shrinkage of the lesions, and the symptoms significantly improved. Eighteen months after the initial treatment with denosumab, the patient had no symptoms or tumor growth. Although its long-term efficacy and safety remain unclear, denosumab may be a treatment option for patients with unresectable pulmonary GCTB.
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Affiliation(s)
- Shinji Miwa
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Norio Yamamoto
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Katsuhiro Hayashi
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Akihiko Takeuchi
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Kentaro Igarashi
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Yuta Taniguchi
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Sei Morinaga
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Yohei Asano
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Takayuki Nojima
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
- Department of Pathology, Graduate School of Medical Sciences, Kanazawa, Japan
| | - Hiroyuki Tsuchiya
- Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
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Thomas JA, Gireesh Moly AG, Xavier H, Suboj P, Ladha A, Gupta G, Singh SK, Palit P, Babykutty S. Enhancement of immune surveillance in breast cancer by targeting hypoxic tumor endothelium: Can it be an immunological switch point? Front Oncol 2023; 13:1063051. [PMID: 37056346 PMCID: PMC10088512 DOI: 10.3389/fonc.2023.1063051] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 02/17/2023] [Indexed: 03/30/2023] Open
Abstract
Breast cancer ranks second among the causes of cancer-related deaths in women. In spite of the recent advances achieved in the diagnosis and treatment of breast cancer, further study is required to overcome the risk of cancer resistance to treatment and thereby improve the prognosis of individuals with advanced-stage breast cancer. The existence of a hypoxic microenvironment is a well-known event in the development of mutagenesis and rapid proliferation of cancer cells. Tumor cells, purposefully cause local hypoxia in order to induce angiogenesis and growth factors that promote tumor growth and metastatic characteristics, while healthy tissue surrounding the tumor suffers damage or mutate. It has been found that these settings with low oxygen levels cause immunosuppression and a lack of immune surveillance by reducing the activation and recruitment of tumor infiltrating leukocytes (TILs). The immune system is further suppressed by hypoxic tumor endothelium through a variety of ways, which creates an immunosuppressive milieu in the tumor microenvironment. Non responsiveness of tumor endothelium to inflammatory signals or endothelial anergy exclude effector T cells from the tumor milieu. Expression of endothelial specific antigens and immunoinhibitory molecules like Programmed death ligand 1,2 (PDL-1, 2) and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) by tumor endothelium adds fuel to the fire by inhibiting T lymphocytes while promoting regulatory T cells. The hypoxic microenvironment in turn recruits Myeloid Derived Suppressor Cells (MDSCs), Tumor Associated Macrophages (TAMs) and T regulatory cells (Treg). The structure and function of newly generated blood vessels within tumors, on the other hand, are aberrant, lacking the specific organization of normal tissue vasculature. Vascular normalisation may work for a variety of tumour types and show to be an advantageous complement to immunotherapy for improving tumour access. By enhancing immune response in the hypoxic tumor microenvironment, via immune-herbal therapeutic and immune-nutraceuticals based approaches that leverage immunological evasion of tumor, will be briefly reviewed in this article. Whether these tactics may be the game changer for emerging immunological switch point to attenuate the breast cancer growth and prevent metastatic cell division, is the key concern of the current study.
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Affiliation(s)
- Juvin Ann Thomas
- Centre for Tumor Immunology and Microenvironment, Department of Zoology, Mar Ivanios College, Nalanchira, Thiruvananthapuram, Kerala, India
| | - Athira Gireesh Gireesh Moly
- Centre for Tumor Immunology and Microenvironment, Department of Zoology, Mar Ivanios College, Nalanchira, Thiruvananthapuram, Kerala, India
| | - Hima Xavier
- Centre for Tumor Immunology and Microenvironment, Department of Zoology, Mar Ivanios College, Nalanchira, Thiruvananthapuram, Kerala, India
| | - Priya Suboj
- Department of Botany and Biotechnology, St. Xaviers College, Thumba, Thiruvananthapuram, Kerala, India
| | - Amit Ladha
- School of Biosciences, University of Birmingham, Edgbaston, Birmingham, West-Midlands, United Kingdom
| | - Gaurav Gupta
- Department of Immunology, University of Manitoba, Winnipeg, MB, Canada
| | - Santosh Kumar Singh
- Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Partha Palit
- Drug Discovery Research Laboratory, Assam University, Silchar, Department of Pharmaceutical Sciences, Assam, India
| | - Suboj Babykutty
- Centre for Tumor Immunology and Microenvironment, Department of Zoology, Mar Ivanios College, Nalanchira, Thiruvananthapuram, Kerala, India
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Vanmeerbeek I, Govaerts J, Laureano RS, Sprooten J, Naulaerts S, Borras DM, Laoui D, Mazzone M, Van Ginderachter JA, Garg AD. The Interface of Tumour-Associated Macrophages with Dying Cancer Cells in Immuno-Oncology. Cells 2022; 11:3890. [PMID: 36497148 PMCID: PMC9741298 DOI: 10.3390/cells11233890] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/25/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022] Open
Abstract
Tumour-associated macrophages (TAMs) are essential players in the tumour microenvironment (TME) and modulate various pro-tumorigenic functions such as immunosuppression, angiogenesis, cancer cell proliferation, invasion and metastasis, along with resistance to anti-cancer therapies. TAMs also mediate important anti-tumour functions and can clear dying cancer cells via efferocytosis. Thus, not surprisingly, TAMs exhibit heterogeneous activities and functional plasticity depending on the type and context of cancer cell death that they are faced with. This ultimately governs both the pro-tumorigenic and anti-tumorigenic activity of TAMs, making the interface between TAMs and dying cancer cells very important for modulating cancer growth and the efficacy of chemo-radiotherapy or immunotherapy. In this review, we discuss the interface of TAMs with cancer cell death from the perspectives of cell death pathways, TME-driven variations, TAM heterogeneity and cell-death-inducing anti-cancer therapies. We believe that a better understanding of how dying cancer cells influence TAMs can lead to improved combinatorial anti-cancer therapies, especially in combination with TAM-targeting immunotherapies.
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Affiliation(s)
- Isaure Vanmeerbeek
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium
| | - Jannes Govaerts
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium
| | - Raquel S. Laureano
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium
| | - Jenny Sprooten
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium
| | - Stefan Naulaerts
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium
| | - Daniel M. Borras
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium
| | - Damya Laoui
- Laboratory of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, 1050 Brussels, Belgium
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Massimiliano Mazzone
- Laboratory of Tumour Inflammation and Angiogenesis, VIB Center for Cancer Biology, 3000 Leuven, Belgium
- Laboratory of Tumour Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium
| | - Jo A. Van Ginderachter
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050 Brussels, Belgium
- Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, 1050 Brussels, Belgium
| | - Abhishek D. Garg
- Cell Stress & Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium
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Understanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context. Nat Commun 2022; 13:6499. [PMID: 36310236 PMCID: PMC9618579 DOI: 10.1038/s41467-022-34241-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/18/2022] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is a progressive biological condition, leading to organ dysfunction in various clinical settings. Although fibroblasts and macrophages are known as key cellular players for fibrosis development, a comprehensive functional model that considers their interaction in the metabolic/immunologic context of fibrotic tissue has not been set up. Here we show, by transcriptome-based mathematical modeling in an in vitro system that represents macrophage-fibroblast interplay and reflects the functional effects of inflammation, hypoxia and the adaptive immune context, that irreversible fibrosis development is associated with specific combinations of metabolic and inflammatory cues. The in vitro signatures are in good alignment with transcriptomic profiles generated on laser captured glomeruli and cortical tubule-interstitial area, isolated from human transplanted kidneys with advanced stages of glomerulosclerosis and interstitial fibrosis/tubular atrophy, two clinically relevant conditions associated with organ failure in renal allografts. The model we describe here is validated on tissue based quantitative immune-phenotyping of biopsies from transplanted kidneys, demonstrating its feasibility. We conclude that the combination of in vitro and in silico modeling represents a powerful systems medicine approach to dissect fibrosis pathogenesis, applicable to specific pathological conditions, and develop coordinated targeted approaches.
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Comparative Transcriptome Analysis of Organ-Specific Adaptive Responses to Hypoxia Provides Insights to Human Diseases. Genes (Basel) 2022; 13:genes13061096. [PMID: 35741857 PMCID: PMC9222487 DOI: 10.3390/genes13061096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/15/2022] [Accepted: 06/17/2022] [Indexed: 02/01/2023] Open
Abstract
The common carp is a hypoxia-tolerant fish, and the understanding of its ability to live in low-oxygen environments has been applied to human health issues such as cancer and neuron degeneration. Here, we investigated differential gene expression changes during hypoxia in five common carp organs including the brain, the gill, the head kidney, the liver, and the intestine. Based on RNA sequencing, gene expression changes under hypoxic conditions were detected in over 1800 genes in common carp. The analysis of these genes further revealed that all five organs had high expression-specific properties. According to the results of the GO and KEGG, the pathways involved in the adaptation to hypoxia provided information on responses specific to each organ in low oxygen, such as glucose metabolism and energy usage, cholesterol synthesis, cell cycle, circadian rhythm, and dopamine activation. DisGeNET analysis showed that some human diseases such as cancer, diabetes, epilepsy, metabolism diseases, and social ability disorders were related to hypoxia-regulated genes. Our results suggested that common carp undergo various gene regulations in different organs under hypoxic conditions, and integrative bioinformatics may provide some potential targets for advancing disease research.
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11
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Yakupova EI, Maleev GV, Krivtsov AV, Plotnikov EY. Macrophage polarization in hypoxia and ischemia/reperfusion: Insights into the role of energetic metabolism. Exp Biol Med (Maywood) 2022; 247:958-971. [PMID: 35220781 PMCID: PMC9189569 DOI: 10.1177/15353702221080130] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2023] Open
Abstract
Macrophages, the key cells of innate immunity, possess wide phenotypical and functional heterogeneity. In vitro studies showed that microenvironment signals could induce the so-called polarization of macrophages into two phenotypes: classically activated macrophages (M1) or alternatively activated macrophages (M2). Functionally, they are considered as proinflammatory and anti-inflammatory/pro-regenerative, respectively. However, in vivo studies into macrophage states revealed a continuum of phenotypes from M1 to M2 state instead of the clearly distinguished extreme phenotypes. An important role in determining the type of polarization of macrophages is played by energy metabolism, including the activity of oxidative phosphorylation. In this regard, hypoxia and ischemia that affect cellular energetics can modulate macrophage polarization. Here, we overview the data on macrophage polarization during metabolic shift-associated pathologies including ischemia and ischemia/reperfusion in various organs and discuss the role of energy metabolism potentially triggering the macrophage polarization.
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Affiliation(s)
- Elmira I Yakupova
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119234, Russia
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino 142290, Russia
| | - Grigoriy V Maleev
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Russia
| | - Andrei V Krivtsov
- Center for Pediatric Cancer Therapeutics, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Egor Y Plotnikov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119234, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Moscow 117997, Russia
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12
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Tune BXJ, Sim MS, Poh CL, Guad RM, Woon CK, Hazarika I, Das A, Gopinath SCB, Rajan M, Sekar M, Subramaniyan V, Fuloria NK, Fuloria S, Batumalaie K, Wu YS. Matrix Metalloproteinases in Chemoresistance: Regulatory Roles, Molecular Interactions, and Potential Inhibitors. JOURNAL OF ONCOLOGY 2022; 2022:3249766. [PMID: 35586209 PMCID: PMC9110224 DOI: 10.1155/2022/3249766] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 04/11/2022] [Accepted: 04/19/2022] [Indexed: 02/08/2023]
Abstract
Cancer is one of the major causes of death worldwide. Its treatments usually fail when the tumor has become malignant and metastasized. Metastasis is a key source of cancer recurrence, which often leads to resistance towards chemotherapeutic agents. Hence, most cancer-related deaths are linked to the occurrence of chemoresistance. Although chemoresistance can emerge through a multitude of mechanisms, chemoresistance and metastasis share a similar pathway, which is an epithelial-to-mesenchymal transition (EMT). Matrix metalloproteinases (MMPs), a class of zinc and calcium-chelated enzymes, are found to be key players in driving cancer migration and metastasis through EMT induction. The aim of this review is to discuss the regulatory roles and associated molecular mechanisms of specific MMPs in regulating chemoresistance, particularly EMT initiation and resistance to apoptosis. A brief presentation on their potential diagnostic and prognostic values was also deciphered. It also aimed to describe existing MMP inhibitors and the potential of utilizing other strategies to inhibit MMPs to reduce chemoresistance, such as upstream inhibition of MMP expressions and MMP-responsive nanomaterials to deliver drugs as well as epigenetic regulations. Hence, manipulation of MMP expression can be a powerful tool to aid in treating patients with chemo-resistant cancers. However, much still needs to be done to bring the solution from bench to bedside.
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Affiliation(s)
- Bernadette Xin Jie Tune
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Maw Shin Sim
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Chit Laa Poh
- Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor 47500, Malaysia
| | - Rhanye Mac Guad
- Department of Biomedical Science and Therapeutics, Faculty of Medicine and Health Science, Universiti Malaysia Sabah, Kota Kinabalu, 88400 Sabah, Malaysia
| | - Choy Ker Woon
- Department of Anatomy, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, 47000 Selangor, Malaysia
| | - Iswar Hazarika
- Department of Pharmacology, Girijananda Chowdhury Institute of Pharmaceutical Science, Guwahati 781017, India
| | - Anju Das
- Department of Pharmacology, Royal School of Pharmacy, Royal Global University, Guwahati 781035, India
| | - Subash C. B. Gopinath
- Faculty of Chemical Engineering Technology, Universiti Malaysia Perlis (UniMAP), Arau, 02600 Perlis, Malaysia
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis, Kangar, 01000 Perlis, Malaysia
| | - Mariappan Rajan
- Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
| | - Mahendran Sekar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh 30450, Perak, Malaysia
| | - Vetriselvan Subramaniyan
- Department of Pharmacology, School of Medicine, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Selangor 42610, Malaysia
| | | | - Shivkanya Fuloria
- Faculty of Pharmacy, AIMST University, Semeling, Bedong, Kedah 08100, Malaysia
| | - Kalaivani Batumalaie
- Department of Biomedical Sciences, Faculty of Health Sciences, Asia Metropolitan University, 81750 Johor Bahru, Malaysia
| | - Yuan Seng Wu
- Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor 47500, Malaysia
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Selangor 47500, Malaysia
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13
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Zambito G, Mishra G, Schliehe C, Mezzanotte L. Near-Infrared Bioluminescence Imaging of Macrophage Sensors for Cancer Detection In Vivo. Front Bioeng Biotechnol 2022; 10:867164. [PMID: 35615475 PMCID: PMC9124759 DOI: 10.3389/fbioe.2022.867164] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/23/2022] [Indexed: 11/13/2022] Open
Abstract
Melanoma is an aggressive type of skin cancer with a poor prognosis after it gets metastasized. The early detection of malignant melanoma is critical for effective therapy. Because melanoma often resembles moles, routine skin check-up may help for timely identification of suspicious areas. Recently, it has been shown that the interplay of melanoma cells with the immune system can help develop efficient therapeutic strategies. Here, we leveraged engineered macrophages (BMC2) as cell-based sensors for metastatic melanoma. To perform dual-color bioluminescence imaging (BLI) in vivo, macrophages were engineered to express a green click beetle luciferase (CBG2) and a near-infrared fluorescent dye (DiR), and B16F10 melanoma cells were instead engineered to express a near-infrared click beetle luciferase (CBR2). Using real-time in vivo dual-color BLI and near-infrared fluorescence (FL) imaging, we could demonstrate that macrophages were able to sense and substantially accumulate in subcutaneous and metastatic melanoma tissues at 72 h after systemic injections. Together, we showed the potentiality to use optical imaging technologies to track circulating macrophages for the non-invasive detection of metastatic melanoma.
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Affiliation(s)
- Giorgia Zambito
- Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Department of Molecular Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - Gunja Mishra
- Department of Immunology, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - Christopher Schliehe
- Department of Immunology, Erasmus MC University Medical Center, Rotterdam, Netherlands
| | - Laura Mezzanotte
- Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Department of Molecular Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands
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14
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Mudassar F, Shen H, Cook KM, Hau E. Improving the synergistic combination of programmed death‐1/programmed death ligand‐1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment. J Med Imaging Radiat Oncol 2022; 66:560-574. [PMID: 35466515 PMCID: PMC9322583 DOI: 10.1111/1754-9485.13416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 04/05/2022] [Accepted: 04/10/2022] [Indexed: 11/28/2022]
Abstract
Immune checkpoint inhibition with PD‐1/PD‐L1 blockade is a promising area in the field of anti‐cancer therapy. Although clinical data have revealed success of PD‐1/PD‐L1 blockade as monotherapy or in combination with CTLA‐4 or chemotherapy, the combination with radiotherapy could further boost anti‐tumour immunity and enhance clinical outcomes due to the immunostimulatory effects of radiation. However, the synergistic combination of PD‐1/PD‐L1 blockade and radiotherapy can be challenged by the complex nature of the tumour microenvironment (TME), including the presence of tumour hypoxia. Hypoxia is a major barrier to the effectiveness of both radiotherapy and PD‐1/PD‐L1 blockade immunotherapy. Thus, targeting the hypoxic TME is an attractive strategy to enhance the efficacy of the combination. Addition of compounds that directly or indirectly reduce hypoxia, to the combination of PD‐1/PD‐L1 inhibitors and radiotherapy may optimize the success of the combination and improve therapeutic outcomes. In this review, we will discuss the synergistic combination of PD‐1/PD‐L1 blockade and radiotherapy and highlight the role of hypoxic TME in impeding the success of both therapies. In addition, we will address the potential approaches for targeting tumour hypoxia and how exploiting these strategies could benefit the combination of PD‐1/PD‐L1 blockade and radiotherapy.
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Affiliation(s)
- Faiqa Mudassar
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research The Westmead Institute for Medical Research Sydney New South Wales Australia
- Sydney Medical School The University of Sydney Sydney New South Wales Australia
| | - Han Shen
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research The Westmead Institute for Medical Research Sydney New South Wales Australia
- Sydney Medical School The University of Sydney Sydney New South Wales Australia
| | - Kristina M Cook
- Sydney Medical School The University of Sydney Sydney New South Wales Australia
- Charles Perkins Centre The University of Sydney Sydney New South Wales Australia
| | - Eric Hau
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research The Westmead Institute for Medical Research Sydney New South Wales Australia
- Sydney Medical School The University of Sydney Sydney New South Wales Australia
- Department of Radiation Oncology, Crown Princess Mary Cancer Centre Westmead Hospital Sydney New South Wales Australia
- Blacktown Hematology and Cancer Centre Blacktown Hospital Sydney New South Wales Australia
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15
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Onishi H, Nakamura K, Yanai K, Nagai S, Nakayama K, Oyama Y, Fujimura A, Ozono K, Yamasaki A. Cancer therapy that targets the Hedgehog signaling pathway considering the cancer microenvironment (Review). Oncol Rep 2022; 47:93. [DOI: 10.3892/or.2022.8304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 02/25/2022] [Indexed: 11/05/2022] Open
Affiliation(s)
- Hideya Onishi
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Katsuya Nakamura
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Kosuke Yanai
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Shuntaro Nagai
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Kazunori Nakayama
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Yasuhiro Oyama
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Akiko Fujimura
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Keigo Ozono
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Akio Yamasaki
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
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16
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Iscaro A, Jones C, Forbes N, Mughal A, Howard FN, Janabi HA, Demiral S, Perrie Y, Essand M, Weglarz A, Cruz LJ, Lewis CE, Muthana M. Targeting circulating monocytes with CCL2-loaded liposomes armed with an oncolytic adenovirus. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2022; 40:102506. [PMID: 34875352 DOI: 10.1016/j.nano.2021.102506] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 09/17/2021] [Accepted: 11/17/2021] [Indexed: 12/24/2022]
Abstract
Oncolytic viruses (OVs) selectively replicate in and destroy cancer cells resulting in anti-tumor immunity. However, clinical use remains a challenge because of virus clearance upon intravenous delivery. OV packaging using a nanomedicine approach could overcome this. Here we encapsulate an oncolytic adenovirus (Ad[I/PPT-E1A]) into CCL2-coated liposomes in order to exploit recruitment of CCR2-expressing circulating monocytes into tumors. We demonstrate successful encapsulation of Ad[I/PPT-E1A] into CCL2-coated liposomes that were preferentially taken up by CCR2-expressing monocytes. No complex-related toxicities were observed following incubation with prostate tumor cells and the encapsulation did not affect virus oncolytic activity in vitro. Furthermore, intravenous administration of our nanomedicine resulted in a significant reduction in tumor size and pulmonary metastasis in prostate cancer-bearing mice whereby a 1000-fold less virus was needed compared to Ad[I/PPT-E1A] alone. Taken together our data provide an opportunity to target OVs via circulation to inaccessible tumors using liposome-assisted drug delivery.
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Affiliation(s)
- Alessandra Iscaro
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | - Christian Jones
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | - Neil Forbes
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland
| | - Amina Mughal
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | | | - Haider Al Janabi
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | - Secil Demiral
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | - Yvonne Perrie
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, Scotland
| | - Magnus Essand
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Aleksandra Weglarz
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | - Luis J Cruz
- Department of Radiology, Division Translational Nanobiomaterials and Imaging, Leiden University Medical Center, Leiden, The Netherlands
| | - Claire E Lewis
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | - Munitta Muthana
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK.
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17
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Jiang J, Kraneburg U, Dornseifer U, Schilling AF, Hadjipanayi E, Machens HG, Moog P. Hypoxia Preconditioned Serum (HPS)-Hydrogel Can Accelerate Dermal Wound Healing in Mice—An In Vivo Pilot Study. Biomedicines 2022; 10:biomedicines10010176. [PMID: 35052855 PMCID: PMC8773663 DOI: 10.3390/biomedicines10010176] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/10/2022] [Accepted: 01/12/2022] [Indexed: 02/04/2023] Open
Abstract
The ability to use the body’s resources to promote wound repair is increasingly becoming an interesting area of regenerative medicine research. Here, we tested the effect of topical application of blood-derived hypoxia preconditioned serum (HPS) on wound healing in a murine wound model. Alginate hydrogels loaded with two different HPS concentrations (10 and 40%) were applied topically on full-thickness wounds created on the back of immunocompromised mice. We achieved a significant dose-dependent wound area reduction after 5 days in HPS-treated groups compared with no treatment (NT). On average, both HPS-10% and HPS-40% -treated wounds healed 1.4 days faster than NT. Healed tissue samples were investigated on post-operative day 15 (POD 15) by immunohistology and showed an increase in lymphatic vessels (LYVE-1) up to 45% with HPS-40% application, while at this stage, vascularization (CD31) was comparable in the HPS-treated and NT groups. Furthermore, the expression of proliferation marker Ki67 was greater on POD 15 in the NT-group compared to HPS-treated groups, in accordance with the earlier completion of wound healing observed in the latter. Collagen deposition was similar in all groups, indicating lack of scar tissue hypertrophy as a result of HPS-hydrogel treatment. These findings show that topical HPS application is safe and can accelerate dermal wound healing in mice.
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Affiliation(s)
- Jun Jiang
- Experimental Plastic Surgery, Clinic for Plastic, Reconstructive and Hand Surgery, Klinikum Rechts der Isar, Technische Universität München, D-81675 Munich, Germany; (J.J.); (U.K.); (E.H.)
| | - Ursula Kraneburg
- Experimental Plastic Surgery, Clinic for Plastic, Reconstructive and Hand Surgery, Klinikum Rechts der Isar, Technische Universität München, D-81675 Munich, Germany; (J.J.); (U.K.); (E.H.)
| | - Ulf Dornseifer
- Department of Plastic, Reconstructive and Aesthetic Surgery, Isar Klinikum, D-80331 Munich, Germany;
| | - Arndt F. Schilling
- Department of Trauma Surgery, Orthopedics and Plastic Surgery, Universitätsmedizin Göttingen, D-37075 Gottingen, Germany;
| | - Ektoras Hadjipanayi
- Experimental Plastic Surgery, Clinic for Plastic, Reconstructive and Hand Surgery, Klinikum Rechts der Isar, Technische Universität München, D-81675 Munich, Germany; (J.J.); (U.K.); (E.H.)
| | - Hans-Günther Machens
- Experimental Plastic Surgery, Clinic for Plastic, Reconstructive and Hand Surgery, Klinikum Rechts der Isar, Technische Universität München, D-81675 Munich, Germany; (J.J.); (U.K.); (E.H.)
- Correspondence: (H.-G.M.); (P.M.)
| | - Philipp Moog
- Experimental Plastic Surgery, Clinic for Plastic, Reconstructive and Hand Surgery, Klinikum Rechts der Isar, Technische Universität München, D-81675 Munich, Germany; (J.J.); (U.K.); (E.H.)
- Correspondence: (H.-G.M.); (P.M.)
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18
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Aggarwal V, Rathod S, Vashishth K, Upadhyay A. Immune Cell Metabolites as Fuel for Cancer Cells. IMMUNO-ONCOLOGY CROSSTALK AND METABOLISM 2022:153-186. [DOI: 10.1007/978-981-16-6226-3_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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19
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He Z, Zhang S. Tumor-Associated Macrophages and Their Functional Transformation in the Hypoxic Tumor Microenvironment. Front Immunol 2021; 12:741305. [PMID: 34603327 PMCID: PMC8481680 DOI: 10.3389/fimmu.2021.741305] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/01/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor-associated macrophages (TAMs) are some of the most abundant immune cells within tumors and perform a broad repertoire of functions via diverse phenotypes. On the basis of their functional differences in tumor growth, TAMs are usually categorized into two subsets of M1 and M2. It is well established that the tumor microenvironment (TME) is characterized by hypoxia along with tumor progression. TAMs adopt an M1-like pro-inflammatory phenotype at the early phases of oncogenesis and mediate immune response that inhibits tumor growth. As tumors progress, anabatic hypoxia of the TME gradually induces the M2-like functional transformation of TAMs by means of direct effects, metabolic influence, lactic acidosis, angiogenesis, remodeled stroma, and then urges them to participate in immunosuppression, angiogenesis and other tumor-supporting procedure. Therefore, thorough comprehension of internal mechanism of this TAM functional transformation in the hypoxic TME is of the essence, and might provide some novel insights in hypoxic tumor immunotherapeutic strategies.
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Affiliation(s)
- Zicong He
- Department of Radiology, First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Shuixing Zhang
- Department of Radiology, First Affiliated Hospital of Jinan University, Guangzhou, China
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20
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Shin E, Koo JS. Glucose Metabolism and Glucose Transporters in Breast Cancer. Front Cell Dev Biol 2021; 9:728759. [PMID: 34552932 PMCID: PMC8450384 DOI: 10.3389/fcell.2021.728759] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/10/2021] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most common malignancy in women worldwide and is associated with high mortality rates despite the continuously advancing treatment strategies. Glucose is essential for cancer cell metabolism owing to the Warburg effect. During the process of glucose metabolism, various glycolytic metabolites, such as serine and glycine metabolites, are produced and other metabolic pathways, such as the pentose phosphate pathway (PPP), are associated with the process. Glucose is transported into the cell by glucose transporters, such as GLUT. Breast cancer shows high expressions of glucose metabolism-related enzymes and GLUT, which are also related to breast cancer prognosis. Triple negative breast cancer (TNBC), which is a high-grade breast cancer, is especially dependent on glucose metabolism. Breast cancer also harbors various stromal cells such as cancer-associated fibroblasts and immune cells as tumor microenvironment, and there exists a metabolic interaction between these stromal cells and breast cancer cells as explained by the reverse Warburg effect. Breast cancer is heterogeneous, and, consequently, its metabolic status is also diverse, which is especially affected by the molecular subtype, progression stage, and metastatic site. In this review, we will focus on glucose metabolism and glucose transporters in breast cancer, and we will additionally discuss their potential applications as cancer imaging tracers and treatment targets.
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Affiliation(s)
| | - Ja Seung Koo
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
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21
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Zhang Y, Coleman M, Brekken RA. Perspectives on Hypoxia Signaling in Tumor Stroma. Cancers (Basel) 2021; 13:3070. [PMID: 34202979 PMCID: PMC8234221 DOI: 10.3390/cancers13123070] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/11/2021] [Accepted: 06/17/2021] [Indexed: 12/12/2022] Open
Abstract
Hypoxia is a well-known characteristic of solid tumors that contributes to tumor progression and metastasis. Oxygen deprivation due to high demand of proliferating cancer cells and standard of care therapies induce hypoxia. Hypoxia signaling, mainly mediated by the hypoxia-inducible transcription factor (HIF) family, results in tumor cell migration, proliferation, metabolic changes, and resistance to therapy. Additionally, the hypoxic tumor microenvironment impacts multiple cellular and non-cellular compartments in the tumor stroma, including disordered tumor vasculature, homeostasis of ECM. Hypoxia also has a multifaceted and often contradictory influence on immune cell function, which contributes to an immunosuppressive environment. Here, we review the important function of HIF in tumor stromal components and summarize current clinical trials targeting hypoxia. We provide an overview of hypoxia signaling in tumor stroma that might help address some of the challenges associated with hypoxia-targeted therapies.
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Affiliation(s)
- Yuqing Zhang
- Hamon Center for Therapeutic Oncology Research, UT Southwestern, Dallas, TX 75390, USA; (Y.Z.); (M.C.)
- Department of Surgery, UT Southwestern, Dallas, TX 75390, USA
- Cancer Biology Graduate Program, UT Southwestern, Dallas, TX 75390, USA
| | - Morgan Coleman
- Hamon Center for Therapeutic Oncology Research, UT Southwestern, Dallas, TX 75390, USA; (Y.Z.); (M.C.)
- Division of Pediatric Hematology and Oncology, UT Southwestern, Dallas, TX 75390, USA
| | - Rolf A. Brekken
- Hamon Center for Therapeutic Oncology Research, UT Southwestern, Dallas, TX 75390, USA; (Y.Z.); (M.C.)
- Department of Surgery, UT Southwestern, Dallas, TX 75390, USA
- Cancer Biology Graduate Program, UT Southwestern, Dallas, TX 75390, USA
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22
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Fu Z, Mowday AM, Smaill JB, Hermans IF, Patterson AV. Tumour Hypoxia-Mediated Immunosuppression: Mechanisms and Therapeutic Approaches to Improve Cancer Immunotherapy. Cells 2021; 10:1006. [PMID: 33923305 PMCID: PMC8146304 DOI: 10.3390/cells10051006] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/21/2021] [Accepted: 04/23/2021] [Indexed: 01/05/2023] Open
Abstract
The magnitude of the host immune response can be regulated by either stimulatory or inhibitory immune checkpoint molecules. Receptor-ligand binding between inhibitory molecules is often exploited by tumours to suppress anti-tumour immune responses. Immune checkpoint inhibitors that block these inhibitory interactions can relieve T-cells from negative regulation, and have yielded remarkable activity in the clinic. Despite this success, clinical data reveal that durable responses are limited to a minority of patients and malignancies, indicating the presence of underlying resistance mechanisms. Accumulating evidence suggests that tumour hypoxia, a pervasive feature of many solid cancers, is a critical phenomenon involved in suppressing the anti-tumour immune response generated by checkpoint inhibitors. In this review, we discuss the mechanisms associated with hypoxia-mediate immunosuppression and focus on modulating tumour hypoxia as an approach to improve immunotherapy responsiveness.
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Affiliation(s)
- Zhe Fu
- Malaghan Institute of Medical Research, Wellington 6042, New Zealand; (Z.F.); (I.F.H.)
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, University of Auckland, Auckland 1142, New Zealand; (A.M.M.); (J.B.S.)
| | - Alexandra M. Mowday
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, University of Auckland, Auckland 1142, New Zealand; (A.M.M.); (J.B.S.)
- Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland 1142, New Zealand
| | - Jeff B. Smaill
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, University of Auckland, Auckland 1142, New Zealand; (A.M.M.); (J.B.S.)
- Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland 1142, New Zealand
| | - Ian F. Hermans
- Malaghan Institute of Medical Research, Wellington 6042, New Zealand; (Z.F.); (I.F.H.)
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, University of Auckland, Auckland 1142, New Zealand; (A.M.M.); (J.B.S.)
| | - Adam V. Patterson
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, University of Auckland, Auckland 1142, New Zealand; (A.M.M.); (J.B.S.)
- Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland 1142, New Zealand
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23
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Mehta AK, Kadel S, Townsend MG, Oliwa M, Guerriero JL. Macrophage Biology and Mechanisms of Immune Suppression in Breast Cancer. Front Immunol 2021; 12:643771. [PMID: 33968034 PMCID: PMC8102870 DOI: 10.3389/fimmu.2021.643771] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 02/17/2021] [Indexed: 12/14/2022] Open
Abstract
Macrophages are crucial innate immune cells that maintain tissue homeostasis and defend against pathogens; however, their infiltration into tumors has been associated with adverse outcomes. Tumor-associated macrophages (TAMs) represent a significant component of the inflammatory infiltrate in breast tumors, and extensive infiltration of TAMs has been linked to poor prognosis in breast cancer. Here, we detail how TAMs impede a productive tumor immunity cycle by limiting antigen presentation and reducing activation of cytotoxic T lymphocytes (CTLs) while simultaneously supporting tumor cell survival, angiogenesis, and metastasis. There is an urgent need to overcome TAM-mediated immune suppression for durable anti-tumor immunity in breast cancer. To date, failure to fully characterize TAM biology and classify multiple subsets has hindered advancement in therapeutic targeting. In this regard, the complexity of TAMs has recently taken center stage owing to their subset diversity and tightly regulated molecular and metabolic phenotypes. In this review, we reveal major gaps in our knowledge of the functional and phenotypic characterization of TAM subsets associated with breast cancer, before and after treatment. Future work to characterize TAM subsets, location, and crosstalk with neighboring cells will be critical to counteract TAM pro-tumor functions and to identify novel TAM-modulating strategies and combinations that are likely to enhance current therapies and overcome chemo- and immuno-therapy resistance.
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Affiliation(s)
- Anita K Mehta
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States.,Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States
| | - Sapana Kadel
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Madeline G Townsend
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States.,Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States
| | - Madisson Oliwa
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States.,Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States
| | - Jennifer L Guerriero
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States.,Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States
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24
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Wang SS, Gu Q, Liu N, Li J, Liu X. Aerobic exercise attenuates ectopic renal sinus adipose tissue accumulation-related renal hypoxia injury in obese mice. Life Sci 2021; 279:119106. [PMID: 33497740 DOI: 10.1016/j.lfs.2021.119106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/02/2021] [Accepted: 01/03/2021] [Indexed: 12/20/2022]
Abstract
AIMS We explored the effect of aerobic exercise on renal sinus adipose (RSA) accumulation and RSA accumulation-related renal injury in obese mice. MAIN METHODS C57BL/6J male mice (n = 30) were evenly divided into three groups: control group (CON, n = 10), obese group (OB, n = 10; given high-fat diet) and obese + aerobic exercise group (OB + E, n = 10; given HFD and 8 weeks of moderate-intensity exercise training). The body weight and kidney weight were measured after sacrificing. Morphological alterations of adipose and renal tissues were measured on hematoxylin-eosin (HE) stained slides. The macrophages surface markers (F4/80, CD68, CD206, CD163), monocyte chemotactic protein 1 (MCP-1) and hypoxia inducible factor-1α (HIF-1α) were examined by immunohistochemistry assay. Inflammation-related factors (FGF-21, KIM-1, IL-6) were analyzed via serum enzyme-linked immunosorbent assay. KEY FINDINGS We found that aerobic exercise significantly reduced body weight, kidney weight, serum FGF-21 and KIM-1 levels, and ameliorated glomerular hypertrophy and RSA size accumulation in OB + E group compared with OB group. Furthermore, HIF-1α in the RSA and renal tissues was significantly increased in the OB group (P < 0.05), but exercise effectively reduced the expression of HIF-1α and ameliorated renal inflammation by reducing MCP-1 and CD68 expression (both P < 0.05), improving the conversion from M1 (CD68) to M2 (CD206, CD163) macrophages (P < 0.05), and finally alleviating the level of IL-6 (P < 0.01). SIGNIFICANCE Aerobic exercise could reduce RSA accumulation-related adipose hypoxia and macrophage infiltration, and subsequently attenuate the progress of renal injury.
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Affiliation(s)
- Sha-Sha Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Qing Gu
- Department of Endocrinology, Shidong Hospital, Shanghai, China
| | - Nian Liu
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Jingyuan Li
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Xiangyun Liu
- School of Kinesiology, Shanghai University of Sport, Shanghai, China.
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25
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Arianfar E, Shahgordi S, Memarian A. Natural Killer Cell Defects in Breast Cancer: A Key Pathway for Tumor Evasion. Int Rev Immunol 2020; 40:197-216. [PMID: 33258393 DOI: 10.1080/08830185.2020.1845670] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
As the most important innate immune component cancers invader, natural killer (NK) cells have a magnificent role in antitumor immunity without any prior sensitization. Different subsets of NK cells have distinct responses during tumor cell exposure, according to their phenotypes and environments. Their function is induced mainly by the activity of both inhibitory and activating receptors against cancerous cells. Since the immunosuppression in the tumor microenvironment of breast cancer patients has directly deteriorated the phenotype and disturbed the function of NK cells, recruiting compensatory mechanisms indicate promising outcomes for immunotherapeutic approaches. These evidences accentuate the importance of NK cell distinct features in protection against breast tumors. In this review, we discuss the several mechanisms involved in NK cells suppression which consequently promote tumor progression and disease recurrence in patients with breast cancer.
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Affiliation(s)
- Elaheh Arianfar
- Student Research Committee, Faculty of Medicine, Department of Immunology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sanaz Shahgordi
- Student Research Committee, Faculty of Medicine, Department of Immunology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Ali Memarian
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran.,Immunology department, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
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26
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Zhang B, Cheng P. Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy. Mol Cancer 2020; 19:158. [PMID: 33172438 PMCID: PMC7656670 DOI: 10.1186/s12943-020-01275-6] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023] Open
Abstract
As a promising therapeutic strategy, oncolytic virotherapy has shown potent anticancer efficacy in numerous pre-clinical and clinical trials. Oncolytic viruses have the capacity for conditional-replication within carcinoma cells leading to cell death via multiple mechanisms, including direct lysis of neoplasms, induction of immunogenic cell death, and elicitation of innate and adaptive immunity. In addition, these viruses can be engineered to express cytokines or chemokines to alter tumor microenvironments. Combination of oncolytic virotherapy with other antitumor therapeutic modalities, such as chemotherapy and radiation therapy as well as cancer immunotherapy can be used to target a wider range of tumors and promote therapeutic efficacy. In this review, we outline the basic biological characteristics of oncolytic viruses and the underlying mechanisms that support their use as promising antitumor drugs. We also describe the enhanced efficacy attributed to virotherapy combined with other drugs for the treatment of cancer.
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Affiliation(s)
- Bin Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People's South Road, Chengdu, 610041, PR China
| | - Ping Cheng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People's South Road, Chengdu, 610041, PR China.
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27
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Zhang D, Xu X, Ye Q. Metabolism and immunity in breast cancer. Front Med 2020; 15:178-207. [PMID: 33074528 DOI: 10.1007/s11684-020-0793-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 04/17/2020] [Indexed: 12/12/2022]
Abstract
Breast cancer is one of the most common malignancies that seriously threaten women's health. In the process of the malignant transformation of breast cancer, metabolic reprogramming and immune evasion represent the two main fascinating characteristics of cancer and facilitate cancer cell proliferation. Breast cancer cells generate energy through increased glucose metabolism. Lipid metabolism contributes to biological signal pathways and forms cell membranes except energy generation. Amino acids act as basic protein units and metabolic regulators in supporting cell growth. For tumor-associated immunity, poor immunogenicity and heightened immunosuppression cause breast cancer cells to evade the host's immune system. For the past few years, the complex mechanisms of metabolic reprogramming and immune evasion are deeply investigated, and the genes involved in these processes are used as clinical therapeutic targets for breast cancer. Here, we review the recent findings related to abnormal metabolism and immune characteristics, regulatory mechanisms, their links, and relevant therapeutic strategies.
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Affiliation(s)
- Deyu Zhang
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China
| | - Xiaojie Xu
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China.
| | - Qinong Ye
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China.
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28
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Tong Y, Gao WQ, Liu Y. Metabolic heterogeneity in cancer: An overview and therapeutic implications. Biochim Biophys Acta Rev Cancer 2020; 1874:188421. [PMID: 32835766 DOI: 10.1016/j.bbcan.2020.188421] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 08/19/2020] [Accepted: 08/19/2020] [Indexed: 12/13/2022]
Abstract
Recent research on cancer metabolism has revealed that individual tumors have highly heterogeneous metabolic profiles that contribute to the connective metabolic networks within the tumor and its environment. Indeed, tumor-associated cells types, including tumor cells, cancer-associated fibroblasts (CAFs) and immune cells, reprogram their metabolism in many different ways due to diverse genetic backgrounds and complex environmental stimuli. This intratumoral metabolic heterogeneity and the derived metabolic interactions play an instrumental role in cancer progression. Understanding how this heterogeneity occurs may provide promising therapeutic strategies. Here, we review the diverse metabolic profiles of several important cell subpopulations in tumors and their impact on tumor progression and discuss the consequent metabolic interactions as well as the related therapeutic concerns.
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Affiliation(s)
- Yu Tong
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
| | - Yanfeng Liu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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29
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Multidirectional Strategies for Targeted Delivery of Oncolytic Viruses by Tumor Infiltrating Immune Cells. Pharmacol Res 2020; 161:105094. [PMID: 32795509 DOI: 10.1016/j.phrs.2020.105094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 07/18/2020] [Accepted: 07/20/2020] [Indexed: 02/07/2023]
Abstract
Oncolytic virus (OV) immunotherapy has demonstrated to be a promising approach in cancer treatment due to tumor-specific oncolysis. However, their clinical use so far has been largely limited due to the lack of suitable delivery strategies with high efficacy. Direct 'intratumoral' injection is the way to cross the hurdles of systemic toxicity, while providing local effects. Progress in this field has enabled the development of alternative way using 'systemic' oncolytic virotherapy for producing better results. One major potential roadblock to systemic OV delivery is the low virus persistence in the face of hostile immune system. The delivery challenge is even greater when attempting to target the oncolytic viruses into the entire tumor mass, where not all tumor cells are equally exposed to exactly the same microenvironment. The microenvironment of many tumors is known to be massively infiltrated with various types of leucocytes in both primary and metastatic sites. Interestingly, this intratumoral immune cell heterogeneity exhibits a degree of organized distribution inside the tumor bed as evidenced, for example, by the hypoxic tumor microenviroment where predominantly recruits tumor-associated macrophages. Although in vivo OV delivery seems complicated and challenging, recent results are encouraging for decreasing the limitations of systemically administered oncolytic viruses and an improved efficiency of oncolytic viral therapy in targeting cancerous tissues in vitro. Here, we review the latest developments of carrier cell-based oncolytic virus delivery using tumor-infiltrating immune cells with a focus on the main features of each cellular vehicle.
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30
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Stockle J, Romero DA, Amon CH. Optimization of porous stents for endovascular repair of abdominal aortic aneurysms. INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING 2020; 36:e3336. [PMID: 32212322 DOI: 10.1002/cnm.3336] [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: 08/27/2019] [Revised: 01/21/2020] [Accepted: 03/17/2020] [Indexed: 06/10/2023]
Abstract
This study presents a simulation-based methodology to design porous stents to induce suitable hemodynamic environments inside abdominal aortic aneurysm (AAA) sacs. In the proposed methodology, an optimization algorithm iteratively modifies the porosity distribution of the stent and executes a computational fluid dynamics (CFD) simulation to determine the effect of these changes on the hemodynamic conditions inside the aneurysm sac. The optimization iterations proceed until relevant hemodynamic parameters are within ranges prescribed a priori by the user as desirable to control the progression of the AAA. The resulting porosity distribution uniquely describes the porous stent design that can control the hemodynamic environment (eg, shear stress at the aneurysm wall, pressure distribution, residence time), reducing AAA rupture risks and improving treatment efficacy. To demonstrate its potential, the proposed methodology is applied to idealized AAA geometry under steady-state flow conditions, though it may be easily applied to more complex AAA geometries under transient, pulsatile flow conditions. The proposed methodology has the potential to enable the design of a new generation of porous stents tailored to patient-specific geometries and flow conditions, to improve patient outcomes.
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Affiliation(s)
- Juan Stockle
- Escuela de Ingenieria Industrial, Universidad Diego Portales, Santiago, Chile
| | - David A Romero
- Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Cristina H Amon
- Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario, Canada
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
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31
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Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages. Cancers (Basel) 2020; 12:cancers12061411. [PMID: 32486098 PMCID: PMC7352439 DOI: 10.3390/cancers12061411] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/16/2020] [Accepted: 05/17/2020] [Indexed: 12/17/2022] Open
Abstract
Macrophages are key innate immune cells in the tumor microenvironment (TME) that regulate primary tumor growth, vascularization, metastatic spread and tumor response to various types of therapies. The present review highlights the mechanisms of macrophage programming in tumor microenvironments that act on the transcriptional, epigenetic and metabolic levels. We summarize the latest knowledge on the types of transcriptional factors and epigenetic enzymes that control the direction of macrophage functional polarization and their pro- and anti-tumor activities. We also focus on the major types of metabolic programs of macrophages (glycolysis and fatty acid oxidation), and their interaction with cancer cells and complex TME. We have discussed how the regulation of macrophage polarization on the transcriptional, epigenetic and metabolic levels can be used for the efficient therapeutic manipulation of macrophage functions in cancer.
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32
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Raudenska M, Gumulec J, Balvan J, Masarik M. Caveolin-1 in oncogenic metabolic symbiosis. Int J Cancer 2020; 147:1793-1807. [PMID: 32196654 DOI: 10.1002/ijc.32987] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/28/2020] [Accepted: 03/16/2020] [Indexed: 12/18/2022]
Abstract
Metabolic phenotypes of cancer cells are heterogeneous and flexible as a tumor mass is a hurriedly evolving system capable of constant adaptation to oxygen and nutrient availability. The exact type of cancer metabolism arises from the combined effects of factors intrinsic to the cancer cells and factors proposed by the tumor microenvironment. As a result, a condition termed oncogenic metabolic symbiosis in which components of the tumor microenvironment (TME) promote tumor growth often occurs. Understanding how oncogenic metabolic symbiosis emerges and evolves is crucial for perceiving tumorigenesis. The process by which tumor cells reprogram their TME involves many mechanisms, including changes in intercellular communication, alterations in metabolic phenotypes of TME cells, and rearrangement of the extracellular matrix. It is possible that one molecule with a pleiotropic effect such as Caveolin-1 may affect many of these pathways. Here, we discuss the significance of Caveolin-1 in establishing metabolic symbiosis in TME.
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Affiliation(s)
- Martina Raudenska
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Jaromir Gumulec
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czech Republic
| | - Jan Balvan
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czech Republic
| | - Michal Masarik
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
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33
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Innate and Adaptive Immunity Linked to Recognition of Antigens Shared by Neural Crest-Derived Tumors. Cancers (Basel) 2020; 12:cancers12040840. [PMID: 32244473 PMCID: PMC7226441 DOI: 10.3390/cancers12040840] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/21/2020] [Accepted: 03/26/2020] [Indexed: 12/12/2022] Open
Abstract
In the adult, many embryologic processes can be co-opted by during cancer progression. The mechanisms of divisions, migration, and the ability to escape immunity recognition linked to specific embryo antigens are also expressed by malignant cells. In particular, cells derived from neural crests (NC) contribute to the development of multiple cell types including melanocytes, craniofacial cartilage, glia, neurons, peripheral and enteric nervous systems, and the adrenal medulla. This plastic performance is due to an accurate program of gene expression orchestrated with cellular/extracellular signals finalized to regulate long-distance migration, proliferation, differentiation, apoptosis, and survival. During neurulation, prior to initiating their migration, NC cells must undergo an epithelial–mesenchymal transition (EMT) in which they alter their actin cytoskeleton, lose their cell–cell junctions, apicobasal polarity, and acquire a motile phenotype. Similarly, during the development of the tumors derived from neural crests, comprising a heterogeneous group of neoplasms (Neural crest-derived tumors (NCDTs)), a group of genes responsible for the EMT pathway is activated. Here, retracing the molecular pathways performed by pluripotent cells at the boundary between neural and non-neural ectoderm in relation to the natural history of NCDT, points of contact or interposition are highlighted to better explain the intricate interplay between cancer cells and the innate and adaptive immune response.
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34
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Rothe R, Schulze S, Neuber C, Hauser S, Rammelt S, Pietzsch J. Adjuvant drug-assisted bone healing: Part II - Modulation of angiogenesis. Clin Hemorheol Microcirc 2020; 73:409-438. [PMID: 31177206 DOI: 10.3233/ch-199103] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The treatment of critical-size bone defects following complicated fractures, infections or tumor resections is a major challenge. The same applies to fractures in patients with impaired bone healing due to systemic inflammatory and metabolic diseases. Despite considerable progress in development and establishment of new surgical techniques, design of bone graft substitutes and imaging techniques, these scenarios still represent unresolved clinical problems. However, the development of new active substances offers novel potential solutions for these issues. This work discusses therapeutic approaches that influence angiogenesis or hypoxic situations in healing bone and surrounding tissue. In particular, literature on sphingosine-1-phosphate receptor modulators and nitric oxide (NO•) donors, including bi-functional (hybrid) compounds like NO•-releasing cyclooxygenase-2 inhibitors, was critically reviewed with regard to their local and systemic mode of action.
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Affiliation(s)
- Rebecca Rothe
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
| | - Sabine Schulze
- University Center of Orthopaedics and Traumatology (OUC), University Hospital Carl Gustav Carus, Dresden, Germany.,Center for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Christin Neuber
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
| | - Sandra Hauser
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
| | - Stefan Rammelt
- University Center of Orthopaedics and Traumatology (OUC), University Hospital Carl Gustav Carus, Dresden, Germany.,Center for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.,Center for Regenerative Therapies Dresden (CRTD), Tatzberg 4, Dresden, Germany
| | - Jens Pietzsch
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany.,Technische Universität Dresden, School of Science, Faculty of Chemistry and Food Chemistry, Dresden, Germany
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35
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Comparative Evaluation of the Angiogenic Potential of Hypoxia Preconditioned Blood-Derived Secretomes and Platelet-Rich Plasma: An In Vitro Analysis. Biomedicines 2020; 8:biomedicines8010016. [PMID: 31963131 PMCID: PMC7168246 DOI: 10.3390/biomedicines8010016] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 01/08/2020] [Accepted: 01/10/2020] [Indexed: 12/24/2022] Open
Abstract
Blood-derived factor preparations are being clinically employed as tools for promoting tissue repair and regeneration. Here we set out to characterize the in vitro angiogenic potential of two types of frequently used autologous blood-derived secretomes: platelet-rich plasma (PRP) and hypoxia preconditioned plasma (HPP)/serum (HPS). The concentration of key pro-angiogenic (VEGF) and anti-angiogenic (TSP-1, PF-4) protein factors in these secretomes was analyzed via ELISA, while their ability to induce microvessel formation and sprouting was examined in endothelial cell and aortic ring cultures, respectively. We found higher concentrations of VEGF in PRP and HPP/HPS compared to normal plasma and serum. This correlated with improved induction of microvessel formation by PRP and HPP/HPS. HPP had a significantly lower TSP-1 and PF-4 concentration than PRP and HPS. PRP and HPP/HPS appeared to induce similar levels of microvessel sprouting; however, the length of these sprouts was greater in HPP/HPS than in PRP cultures. A bell-shaped angiogenic response profile was observed with increasing HPP/HPS dilutions, with peak values significantly exceeding the PRP response. Our findings demonstrate that optimization of peripheral blood cell-derived angiogenic factor signalling through hypoxic preconditioning offers an improved alternative to simple platelet concentration and release of growth factors pre-stored in platelets.
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36
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Cassim S, Pouyssegur J. Tumor Microenvironment: A Metabolic Player that Shapes the Immune Response. Int J Mol Sci 2019; 21:E157. [PMID: 31881671 PMCID: PMC6982275 DOI: 10.3390/ijms21010157] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 12/04/2019] [Accepted: 12/06/2019] [Indexed: 02/06/2023] Open
Abstract
Immune cells survey and patrol throughout the body and sometimes take residence in niche environments with distinct cellular subtypes and nutrients that may fluctuate from those in which they matured. Rooted in immune cell physiology are metabolic pathways and metabolites that not only deliver substrates and energy for growth and survival, but also instruct effector functions and cell differentiation. Unlike cancer cells, immune cells are not subject to a "Darwinian evolutionary pressure" that would allow them to adapt to developing tumors but are often irrevocably affected to local nutrient deprivation. Thus, immune cells must metabolically adapt to these changing conditions in order to perform their necessary functions. On the other hand, there is now a growing appreciation that metabolic changes occurring in cancer cells can impact on immune cell functionality and contribute to tumor immune evasion, and as such, there is a considerable and growing interest in developing techniques that target metabolism for immunotherapy. In this review, we discuss the metabolic plasticity displayed by innate and adaptive immune cells and highlight how tumor-derived lactate and tumor acidity restrict immunity. To our knowledge, this review outlines the most recent insights on how tumor microenvironment metabolically instructs immune responsiveness.
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Affiliation(s)
- Shamir Cassim
- Department of Medical Biology, Centre Scientifique de Monaco, CSM, 98000 Monaco, Monaco;
| | - Jacques Pouyssegur
- Department of Medical Biology, Centre Scientifique de Monaco, CSM, 98000 Monaco, Monaco;
- University Côte d’Azur, IRCAN, CNRS, Centre A. Lacassagne, 06189 Nice, France
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37
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Ordonez AA, Pokkali S, Sanchez-Bautista J, Klunk MH, Urbanowski ME, Kübler A, Bishai WR, Elkington PT, Jain SK. Matrix Metalloproteinase Inhibition in a Murine Model of Cavitary Tuberculosis Paradoxically Worsens Pathology. J Infect Dis 2019; 219:633-636. [PMID: 29920600 DOI: 10.1093/infdis/jiy373] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 06/15/2018] [Indexed: 12/12/2022] Open
Abstract
Matrix metalloproteinases (MMPs) degrade extracellular matrix and are implicated in tuberculosis pathogenesis and cavitation. In particular, MMP-7 is induced by hypoxia and highly expressed around pulmonary cavities of Mycobacterium tuberculosis-infected C3HeB/FeJ mice. In this study, we evaluated whether administration of cipemastat, an orally available potent inhibitor of MMP-7, could reduce pulmonary cavitation in M. tuberculosis-infected C3HeB/FeJ mice. We demonstrate that, compared with untreated controls, cipemastat treatment paradoxically increases the frequency of cavitation (32% vs 7%; P = .029), immunopathology, and mortality. Further studies are needed to understand the role of MMP inhibitors as adjunctive treatments for pulmonary tuberculosis.
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Affiliation(s)
- Alvaro A Ordonez
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Supriya Pokkali
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Julian Sanchez-Bautista
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mariah H Klunk
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Michael E Urbanowski
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - André Kübler
- Queen's Hospital, Barking, Havering, and Redbridge University Hospital National Health Service Trust, Romford
| | - William R Bishai
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Paul T Elkington
- Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, NIHR Biomedical Research Centre.,Institute of Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Sanjay K Jain
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Sadaghianloo N, Contenti J, Dardik A, Mazure NM. Role of Hypoxia and Metabolism in the Development of Neointimal Hyperplasia in Arteriovenous Fistulas. Int J Mol Sci 2019; 20:ijms20215387. [PMID: 31671790 PMCID: PMC6862436 DOI: 10.3390/ijms20215387] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 10/24/2019] [Accepted: 10/25/2019] [Indexed: 12/11/2022] Open
Abstract
For patients with end-stage renal disease requiring hemodialysis, their vascular access is both their lifeline and their Achilles heel. Despite being recommended as primary vascular access, the arteriovenous fistula (AVF) shows sub-optimal results, with about 50% of patients needing a revision during the year following creation. After the AVF is created, the venous wall must adapt to new environment. While hemodynamic changes are responsible for the adaptation of the extracellular matrix and activation of the endothelium, surgical dissection and mobilization of the vein disrupt the vasa vasorum, causing wall ischemia and oxidative stress. As a consequence, migration and proliferation of vascular cells participate in venous wall thickening by a mechanism of neointimal hyperplasia (NH). When aggressive, NH causes stenosis and AVF dysfunction. In this review we show how hypoxia, metabolism, and flow parameters are intricate mechanisms responsible for the development of NH and stenosis during AVF maturation.
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Affiliation(s)
- Nirvana Sadaghianloo
- Centre de Méditerranéen de Médecine Moléculaire (C3M), Université Côte d'Azur, INSERM U1065, 151 Route de St Antoine de Ginestière, BP2 3194, 06204 Nice CEDEX 03, France.
- Department of Vascular Surgery, Centre Hospitalier Universitaire de Nice, 06000 Nice, France.
| | - Julie Contenti
- Centre de Méditerranéen de Médecine Moléculaire (C3M), Université Côte d'Azur, INSERM U1065, 151 Route de St Antoine de Ginestière, BP2 3194, 06204 Nice CEDEX 03, France.
- Department of Emergency Medicine, Centre Hospitalier Universitaire de Nice, 06000 Nice, France.
| | - Alan Dardik
- Department of Surgery and the Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06520, USA.
- Department of Surgery, VA Connecticut Healthcare Systems, West Haven, CT 06516, USA.
| | - Nathalie M Mazure
- Centre de Méditerranéen de Médecine Moléculaire (C3M), Université Côte d'Azur, INSERM U1065, 151 Route de St Antoine de Ginestière, BP2 3194, 06204 Nice CEDEX 03, France.
- Department of Vascular Surgery, Centre Hospitalier Universitaire de Nice, 06000 Nice, France.
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Subramanian L, Maghajothi S, Singh M, Kesh K, Kalyani A, Sharma S, Khullar M, Victor SM, Swarnakar S, Asthana S, Mullasari AS, Mahapatra NR. A Common Tag Nucleotide Variant in MMP7 Promoter Increases Risk for Hypertension via Enhanced Interactions With CREB (Cyclic AMP Response Element-Binding Protein) Transcription Factor. Hypertension 2019; 74:1448-1459. [PMID: 31656093 DOI: 10.1161/hypertensionaha.119.12960] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
MMP (matrix metalloproteinase)-7-a potent extracellular matrix degrading enzyme-is emerging as a new regulator of cardiovascular diseases. However, potential contributions of MMP7 genetic variations to hypertension remain unknown. In this study, we probed for the association of a tag single-nucleotide polymorphism in the MMP7 promoter (-181A/G; rs11568818) with hypertension in an urban South Indian population (n=1501). The heterozygous AG genotype significantly increased risk for hypertension as compared with the wild-type AA genotype (odds ratio, 1.60 [95% CI, 1.25-2.06]; P=2.4×10-4); AG genotype carriers also displayed significantly higher diastolic blood pressure and mean arterial pressure than wild-type AA individuals. The study was replicated in a North Indian population (n=949) (odds ratio, 1.52 [95% CI, 1.11-2.09]; P=0.01). Transient transfection experiments using MMP7 promoter-luciferase reporter constructs revealed that the variant -181G allele conferred greater promoter activity than the -181A allele. Computational prediction and structure-based conformational and molecular dynamics simulation studies suggested higher binding affinity for the CREB (cyclic AMP response element-binding protein) to the -181G promoter. In corroboration, overexpression/downregulation of CREB and chromatin immunoprecipitation experiments provided convincing evidence for stronger binding of CREB with the -181G promoter. The -181G promoter also displayed enhanced responses to hypoxia and epinephrine treatment. The higher promoter activity of -181G allele translated to increased MMP7 protein level, and MMP7-181AG heterozygous individuals displayed elevated plasma MMP7 levels, which positively correlated with blood pressure. In conclusion, the MMP7 A-181G promoter polymorphism increased MMP7 expression under pathophysiological conditions (hypoxic stress and catecholamine excess) via increased interactions with CREB and enhanced the risk for hypertension in its carriers.
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Affiliation(s)
- Lakshmi Subramanian
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India (L.S., S.M., A.K., N.R.M.)
| | - Sakthisree Maghajothi
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India (L.S., S.M., A.K., N.R.M.)
| | - Mrityunjay Singh
- Drug Discovery Research Center, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India (M.S., S.A.)
| | - Kousik Kesh
- Drug Development Diagnostic and Biotechnology Division, Indian Institute of Chemical Biology, Kolkata, India (K.K., S.SW.)
| | - Ananthamohan Kalyani
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India (L.S., S.M., A.K., N.R.M.)
| | - Saurabh Sharma
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S. Sharma, M.K.)
| | - Madhu Khullar
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India (S. Sharma, M.K.)
| | - Suma M Victor
- Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, India (S.M.V., A.S.M.)
| | - Snehasikta Swarnakar
- Drug Development Diagnostic and Biotechnology Division, Indian Institute of Chemical Biology, Kolkata, India (K.K., S.SW.)
| | - Shailendra Asthana
- Drug Discovery Research Center, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India (M.S., S.A.)
| | - Ajit S Mullasari
- Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, India (S.M.V., A.S.M.)
| | - Nitish R Mahapatra
- From the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India (L.S., S.M., A.K., N.R.M.)
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Gravbrot N, Gilbert-Gard K, Mehta P, Ghotmi Y, Banerjee M, Mazis C, Sundararajan S. Therapeutic Monoclonal Antibodies Targeting Immune Checkpoints for the Treatment of Solid Tumors. Antibodies (Basel) 2019; 8:E51. [PMID: 31640266 PMCID: PMC6963985 DOI: 10.3390/antib8040051] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 10/15/2019] [Accepted: 10/16/2019] [Indexed: 12/23/2022] Open
Abstract
Recently, modulation of immune checkpoints has risen to prominence as a means to treat a number of solid malignancies, given the durable response seen in many patients and improved side effect profile compared to conventional chemotherapeutic agents. Several classes of immune checkpoint modulators have been developed. Here, we review current monoclonal antibodies directed against immune checkpoints that are employed in practice today. We discuss the history, mechanism, indications, and clinical data for each class of therapies. Furthermore, we review the challenges to durable tumor responses that are seen in some patients and discuss possible interventions to circumvent these barriers.
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Affiliation(s)
- Nicholas Gravbrot
- Division of Hematology-Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, AZ 85724, USA.
| | - Kacy Gilbert-Gard
- Division of Hematology-Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, AZ 85724, USA.
| | - Paras Mehta
- Division of Hematology-Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, AZ 85724, USA.
| | - Yarah Ghotmi
- Division of Hematology-Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, AZ 85724, USA.
| | - Madhulika Banerjee
- Division of Hematology-Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, AZ 85724, USA.
| | - Christopher Mazis
- Division of Hematology-Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, AZ 85724, USA.
| | - Srinath Sundararajan
- Division of Hematology-Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, AZ 85724, USA.
- Texas Oncology, Dallas, TX 75251, USA.
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Ke X, Chen C, Song Y, Cai Q, Li J, Tang Y, Han X, Qu W, Chen A, Wang H, Xu G, Liu D. Hypoxia modifies the polarization of macrophages and their inflammatory microenvironment, and inhibits malignant behavior in cancer cells. Oncol Lett 2019; 18:5871-5878. [PMID: 31788060 PMCID: PMC6865149 DOI: 10.3892/ol.2019.10956] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Accepted: 09/06/2019] [Indexed: 12/27/2022] Open
Abstract
Macrophages are a heterogeneous group of phagocytes that play critical roles in inflammation, infection and tumor growth. Macrophages respond to different environmental factors and are thereby polarized into specialized functional subsets. Although hypoxia is an important environmental factor, its impact on human macrophage polarization and subsequent modification of the inflammatory microenvironment have not been fully established. The present study aimed to elucidate the effect of hypoxia exposure on the ability of human macrophages to polarize into the classically activated (pro-inflammatory) M1, and the alternatively activated (anti-inflammatory) M2 phenotypes. The effect on the inflammatory microenvironment and the subsequent modification of A549 lung carcinoma cells was also investigated. The presented data show that hypoxia promoted macrophage polarization towards the M2 phenotype, and modified the inflammatory microenvironment by decreasing the release of proinflammatory cytokines. Modification of the microenvironment by proinflammatory M1 macrophages under hypoxia reversed the inhibition of malignant behaviors within the proinflammatory microenvironment. Furthermore, it was identified p38 signaling (a major contributor to the response to reactive oxygen species generated by hypoxic stress), but not hypoxia-induced factor, as a key regulator of macrophages under hypoxia. Taken together, the data suggest that hypoxia affects the inflammatory microenvironment by modifying the polarization of macrophages, and thus, reversing the inhibitory effects of a proinflammatory microenvironment on the malignant behaviors of several types of cancer cell.
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Affiliation(s)
- Xixian Ke
- Department of Cardiothoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Cheng Chen
- Department of Cardiothoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yongxiang Song
- Department of Cardiothoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Qingyong Cai
- Department of Cardiothoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Jian Li
- Department of Cardiothoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Yang Tang
- Department of Cardiothoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Xu Han
- Department of Cardiothoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Wendong Qu
- Department of Cardiothoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Anping Chen
- Department of Cardiothoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Hui Wang
- Department of Cardiothoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Gang Xu
- Department of Cardiothoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Daxing Liu
- Department of Cardiothoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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Shi SZ, Lee EJ, Lin YJ, Chen L, Zheng HY, He XQ, Peng JY, Noonepalle SK, Shull AY, Pei FC, Deng LB, Tian XL, Deng KY, Shi H, Xin HB. Recruitment of monocytes and epigenetic silencing of intratumoral CYP7B1 primarily contribute to the accumulation of 27-hydroxycholesterol in breast cancer. Am J Cancer Res 2019; 9:2194-2208. [PMID: 31720082 PMCID: PMC6834472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Accepted: 09/28/2019] [Indexed: 06/10/2023] Open
Abstract
Previous studies showed that intratumoral 27-Hydroxycholesterol (27-HC), a metabolite of cholesterol, promotes growth, invasion and migration of breast cancer cells and that tumor-associated macrophages (TAMs) in breast cancers are closely related to tumor growth and metastatic progression. However, the relationship between 27-HC and TAMs in breast cancer remains unclear. In the present study, we observed that CYP27A1, the 27-HC synthesizing enzyme, was expressed in a much higher level in THP1 monocytes and THP1-derived macrophages than in breast cancer cells, and the promoter of CYP7B1, the degrading enzyme for 27-HC, was highly methylated in breast tumor cells. In addition, THP-1 monocytes and murine bone marrow cells were differentiated toward M2 type macrophages after being co-cultured with breast cancer cells or being exposed to exosomes derived from breast cancer cells. M2 type macrophages produced higher amounts of 27-HC than M0 and M1 type macrophages. 27-HC not only stimulated ER+ cancer cell proliferation as reported, but also promoted the recruitment of CCR2- and CCR5-expressing monocytes by inducing macrophages to express multiple chemokines including CCL2, CCL3 and CCL4. Taken together, our data demonstrate that the hypermethylation of CYP7B1 and recruitment of monocytes likely contribute to the accumulation of 27-Hydroxycholesterol in breast cancer and that the interaction of 27-HC with macrophages further promote the development of breast cancer.
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Affiliation(s)
- Shui-Zhen Shi
- The National Engineering Research Center for Bioengineering Drugs and Technologies, Institute of Translational Medicine, Nanchang UniversityNanchang, Jiangxi, China
- College of Life Science, Nanchang UniversityNanchang, Jiangxi, China
| | - Eun-Joon Lee
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta UniversityAugusta, Georgia
- Georgia Cancer Center, Medical College of Georgia, Augusta UniversityAugusta, Georgia
| | - Ying-Jiong Lin
- The National Engineering Research Center for Bioengineering Drugs and Technologies, Institute of Translational Medicine, Nanchang UniversityNanchang, Jiangxi, China
| | - Lu Chen
- The National Engineering Research Center for Bioengineering Drugs and Technologies, Institute of Translational Medicine, Nanchang UniversityNanchang, Jiangxi, China
| | - Huai-Yu Zheng
- The National Engineering Research Center for Bioengineering Drugs and Technologies, Institute of Translational Medicine, Nanchang UniversityNanchang, Jiangxi, China
| | - Xiang-Qin He
- The National Engineering Research Center for Bioengineering Drugs and Technologies, Institute of Translational Medicine, Nanchang UniversityNanchang, Jiangxi, China
- College of Life Science, Nanchang UniversityNanchang, Jiangxi, China
| | - Jing-Yi Peng
- The National Engineering Research Center for Bioengineering Drugs and Technologies, Institute of Translational Medicine, Nanchang UniversityNanchang, Jiangxi, China
| | - Satish K Noonepalle
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta UniversityAugusta, Georgia
- Georgia Cancer Center, Medical College of Georgia, Augusta UniversityAugusta, Georgia
| | - Austin Y Shull
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta UniversityAugusta, Georgia
- Georgia Cancer Center, Medical College of Georgia, Augusta UniversityAugusta, Georgia
| | - Felix C Pei
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta UniversityAugusta, Georgia
| | - Li-Bin Deng
- The National Engineering Research Center for Bioengineering Drugs and Technologies, Institute of Translational Medicine, Nanchang UniversityNanchang, Jiangxi, China
| | - Xiao-Li Tian
- College of Life Science, Nanchang UniversityNanchang, Jiangxi, China
| | - Ke-Yu Deng
- The National Engineering Research Center for Bioengineering Drugs and Technologies, Institute of Translational Medicine, Nanchang UniversityNanchang, Jiangxi, China
| | - Huidong Shi
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta UniversityAugusta, Georgia
- Georgia Cancer Center, Medical College of Georgia, Augusta UniversityAugusta, Georgia
| | - Hong-Bo Xin
- The National Engineering Research Center for Bioengineering Drugs and Technologies, Institute of Translational Medicine, Nanchang UniversityNanchang, Jiangxi, China
- College of Life Science, Nanchang UniversityNanchang, Jiangxi, China
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Emmer A, Abobarin-Adeagbo A, Posa A, Jordan B, Delank KS, Staege MS, Surov A, Zierz S, Kornhuber ME. Myositis in Lewis rats induced by the superantigen Staphylococcal enterotoxin A. Mol Biol Rep 2019; 46:4085-4094. [DOI: 10.1007/s11033-019-04858-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 05/03/2019] [Indexed: 12/18/2022]
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In Vitro Characterization of Hypoxia Preconditioned Serum (HPS)-Fibrin Hydrogels: Basis for an Injectable Biomimetic Tissue Regeneration Therapy. J Funct Biomater 2019; 10:jfb10020022. [PMID: 31086048 PMCID: PMC6616457 DOI: 10.3390/jfb10020022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Revised: 04/26/2019] [Accepted: 05/05/2019] [Indexed: 01/03/2023] Open
Abstract
Blood-derived growth factor preparations have long been employed to improve perfusion and aid tissue repair. Among these, platelet-rich plasma (PRP)-based therapies have seen the widest application, albeit with mixed clinical results to date. Hypoxia-preconditioned blood products present an alternative to PRP, by comprising the complete wound healing factor-cascade, i.e., hypoxia-induced peripheral blood cell signaling, in addition to platelet-derived factors. This study set out to characterize the preparation of hypoxia preconditioned serum (HPS), and assess the utility of HPS–fibrin hydrogels as vehicles for controlled factor delivery. Our findings demonstrate the positive influence of hypoxic incubation on HPS angiogenic potential, and the individual variability of HPS angiogenic factor concentration. HPS–fibrin hydrogels can rapidly retain HPS factor proteins and gradually release them over time, while both functions appear to depend on the fibrin matrix mass. This offers a means of controlling factor retention/release, through adjustment of HPS fibrinogen concentration, thus allowing modulation of cellular angiogenic responses in a growth factor dose-dependent manner. This study provides the first evidence that HPS–fibrin hydrogels could constitute a new generation of autologous/bioactive injectable compositions that provide biochemical and biomaterial signals analogous to those mediating physiological wound healing. This therefore establishes a rational foundation for their application towards biomimetic tissue regeneration.
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45
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Prenen H, Mazzone M. Tumor-associated macrophages: a short compendium. Cell Mol Life Sci 2019; 76:1447-1458. [PMID: 30747250 PMCID: PMC11105658 DOI: 10.1007/s00018-018-2997-3] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 12/10/2018] [Accepted: 12/12/2018] [Indexed: 02/07/2023]
Abstract
Macrophages play an important role in tissue development and homeostasis. They serve as a nexus between adaptive and innate immunity, and employ considerable plasticity. In cancer, they play a pivotal role in chronic inflammation and tumor growth either by directly stimulating the proliferation of cancer cells or by producing angiogenic and lymphangiogenic factors. Although numerous immune cells play an important role in the tumor microenvironment, tumor-associated macrophages (TAMs) are by far the most extensively studied. A better understanding of the role of TAMs in mediating chemo- and radiotherapy resistance and suppressing immunosurveillance has led to numerous strategies targeting TAMs as an anticancer therapy either by targeting them directly or by polarizing TAMs toward a tumoricidal phenotype.
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Affiliation(s)
- Hans Prenen
- Oncology Department, University Hospital Antwerp, Edegem, Belgium.
- Center for Oncological Research, Antwerp University, Edegem, Belgium.
| | - Massimiliano Mazzone
- Lab of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, 3000, Leuven, Belgium.
- Lab of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of oncology, KU Leuven, 3000, Leuven, Belgium.
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Szewczyk G, Maciejewski TM, Szukiewicz D. Current progress in the inflammatory background of angiogenesis in gynecological cancers. Inflamm Res 2019; 68:247-260. [PMID: 30680411 PMCID: PMC6420455 DOI: 10.1007/s00011-019-01215-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 01/10/2019] [Accepted: 01/14/2019] [Indexed: 12/17/2022] Open
Abstract
A tumor growth depends on the potency of the tumor to support itself with nutrients and oxygen. The development of a vascular network within the tumor is key to its survival. The permanent contest between the tumor and its host involves tumor cells on one side and an immunological system and tissue stroma on the other. The angiogenesis is not only a specialty of the tumor, but it also depends on this complex multidirectional interaction. The most common gynecological cancers, cervical, endometrial and ovarian carcinoma are good examples for studying this problem. In this review, we aim to show that an inflammatory response against a tumor can be reverted into an undesirable process leading to the development of a vascular network within the tumor and, subsequently, further growth of the tumor and progression of a disease. Therefore, a key for tumor management should be searched within the immunological system, rather than focused on cell cycle and anti-angiogenic treatment only.
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Affiliation(s)
- Grzegorz Szewczyk
- Chair and Department of General and Experimental Pathology, Medical University of Warsaw, ul. Pawinskiego 3C, 02-106, Warsaw, Poland.
| | - Tomasz M Maciejewski
- Department of Gynecology and Obstetrics, Institute of Mother and Child, ul. Kasprzaka 17A, 01-211, Warsaw, Poland
| | - Dariusz Szukiewicz
- Chair and Department of General and Experimental Pathology, Medical University of Warsaw, ul. Pawinskiego 3C, 02-106, Warsaw, Poland
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Yang M, McKay D, Pollard JW, Lewis CE. Diverse Functions of Macrophages in Different Tumor Microenvironments. Cancer Res 2018; 78:5492-5503. [PMID: 30206177 PMCID: PMC6171744 DOI: 10.1158/0008-5472.can-18-1367] [Citation(s) in RCA: 291] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 06/21/2018] [Accepted: 07/31/2018] [Indexed: 12/13/2022]
Abstract
Tumor-associated macrophages are a major constituent of malignant tumors and are known to stimulate key steps in tumor progression. In our review in this journal in 2006, we postulated that functionally distinct subsets of these cells exist in different areas within solid tumors. Here, we review the many experimental and clinical studies conducted since then to investigate the function(s), regulation, and clinical significance of macrophages in these sites. The latter include three sites of cancer cell invasion, tumor nests, the tumor stroma, and areas close to, or distant from, the tumor vasculature. A more complete understanding of macrophage diversity in tumors could lead to the development of more selective therapies to restore the formidable, anticancer functions of these cells. Cancer Res; 78(19); 5492-503. ©2018 AACR.
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Affiliation(s)
- Ming Yang
- Department of Oncology & Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Daniel McKay
- Department of Oncology & Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Jeffrey W Pollard
- MRC Centre for Reproductive Health, College of Medicine and Veterinary Medicine, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Claire E Lewis
- Department of Oncology & Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom.
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48
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Singer K, Cheng WC, Kreutz M, Ho PC, Siska PJ. Immunometabolism in cancer at a glance. Dis Model Mech 2018; 11:11/8/dmm034272. [PMID: 30076128 PMCID: PMC6124550 DOI: 10.1242/dmm.034272] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The scientific knowledge about tumor metabolism has grown at a fascinating rate in recent decades. We now know that tumors are highly active both in their metabolism of available nutrients and in the secretion of metabolic by-products. However, cancer cells can modulate metabolic pathways and thus adapt to specific nutrients. Unlike tumor cells, immune cells are not subject to a ‘micro-evolution’ that would allow them to adapt to progressing tumors that continuously develop new mechanisms of immune escape. Consequently, immune cells are often irreversibly affected and may allow or even support cancer progression. The mechanisms of how tumors change immune cell function are not sufficiently explored. It is, however, clear that commonly shared features of tumor metabolism, such as local nutrient depletion or production of metabolic ‘waste’ can broadly affect immune cells and contribute to immune evasion. Moreover, immune cells utilize different metabolic programs based on their subtype and function, and these immunometabolic pathways can be modified in the tumor microenvironment. In this review and accompanying poster, we identify and describe the common mechanisms by which tumors metabolically affect the tumor-infiltrating cells of native and adaptive immunity, and discuss how these mechanisms may lead to novel therapeutic opportunities. Summary: This ‘At a Glance’ review and accompanying poster address how tumors can negatively affect immune cells through depletion of critical nutrients or through production of toxic metabolic products.
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Affiliation(s)
- Katrin Singer
- Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Wan-Chen Cheng
- Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, CH-1066 Epalinges, Vaud, Switzerland.,Ludwig Lausanne Branch, CH-1066 Epalinges, Vaud, Switzerland
| | - Marina Kreutz
- Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Ping-Chih Ho
- Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, CH-1066 Epalinges, Vaud, Switzerland.,Ludwig Lausanne Branch, CH-1066 Epalinges, Vaud, Switzerland
| | - Peter J Siska
- Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany
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The Role of Inflammation and Inflammatory Mediators in the Development, Progression, Metastasis, and Chemoresistance of Epithelial Ovarian Cancer. Cancers (Basel) 2018; 10:cancers10080251. [PMID: 30061485 PMCID: PMC6116184 DOI: 10.3390/cancers10080251] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 07/20/2018] [Accepted: 07/24/2018] [Indexed: 12/12/2022] Open
Abstract
Inflammation plays a role in the initiation and development of many types of cancers, including epithelial ovarian cancer (EOC) and high grade serous ovarian cancer (HGSC), a type of EOC. There are connections between EOC and both peritoneal and ovulation-induced inflammation. Additionally, EOCs have an inflammatory component that contributes to their progression. At sites of inflammation, epithelial cells are exposed to increased levels of inflammatory mediators such as reactive oxygen species, cytokines, prostaglandins, and growth factors that contribute to increased cell division, and genetic and epigenetic changes. These exposure-induced changes promote excessive cell proliferation, increased survival, malignant transformation, and cancer development. Furthermore, the pro-inflammatory tumor microenvironment environment (TME) contributes to EOC metastasis and chemoresistance. In this review we will discuss the roles inflammation and inflammatory mediators play in the development, progression, metastasis, and chemoresistance of EOC.
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Saha S, Shalova IN, Biswas SK. Metabolic regulation of macrophage phenotype and function. Immunol Rev 2018; 280:102-111. [PMID: 29027220 DOI: 10.1111/imr.12603] [Citation(s) in RCA: 166] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Studies in the last 20 years have given us a remarkable insight into the functional and phenotypic diversity of macrophages which reflects their integral role in host defence, homeostasis and pathogenesis. Mouse genetics, transcriptomic and epigenetic studies have provided an ontogenic and molecular perspective to the phenotypic diversity of these cells. Recently, metabolic studies have revealed the crucial role of metabolism and metabolites in shaping the phenotype and function of macrophages. Evidence pertaining to this aspect will be reviewed here.
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Affiliation(s)
- Shilpi Saha
- Singapore Immunology Network (SIgN), Agency for Science, Technology & Research (A*STAR), Singapore
| | - Irina N Shalova
- Singapore Immunology Network (SIgN), Agency for Science, Technology & Research (A*STAR), Singapore
| | - Subhra K Biswas
- Singapore Immunology Network (SIgN), Agency for Science, Technology & Research (A*STAR), Singapore
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