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Geltz A, Geltz J, Kasprzak A. Regulation and Function of Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): The Role of the SRIF System in Macrophage Regulation. Int J Mol Sci 2025; 26:5336. [PMID: 40508145 PMCID: PMC12155148 DOI: 10.3390/ijms26115336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2025] [Revised: 05/16/2025] [Accepted: 05/28/2025] [Indexed: 06/16/2025] Open
Abstract
Colorectal cancer (CRC) remains the leading cause of morbidity and mortality for both men and women worldwide. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) of solid tumors, including CRC. These macrophages are found in the pro-inflammatory M1 and anti-inflammatory M2 forms, with the latter increasingly recognized for its tumor-promoting phenotypes. Many signaling molecules and pathways, including AMPK, EGFR, STAT3/6, mTOR, NF-κB, MAPK/ERK, and HIFs, are involved in regulating TAM polarization. Consequently, researchers are investigating several potential predictive and prognostic markers, and novel TAM-based therapeutic targets, especially in combination therapies for CRC. Macrophages of the gastrointestinal tract, including the normal colon and rectum, produce growth hormone-releasing inhibitory peptide/somatostatin (SRIF/SST) and five SST receptors (SSTRs, SST1-5). While the immunosuppressive function of the SRIF system is primarily known for various tissues, its role within CRC-associated TAMs remains underexplored. This review focuses on the following three aspects of TAMs: first, the role of macrophages in the normal colon and rectum within the broader context of macrophage biology; second, the various bioactive factors and signaling pathways associated with TAM function, along with potential strategies targeting TAMs in CRC; and third, the interaction between the SRIF system and macrophages in both normal tissues and the CRC microenvironment.
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Affiliation(s)
- Agnieszka Geltz
- Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecicki Street 6, 60-781 Poznan, Poland;
- Doctoral School, Poznan University of Medical Sciences, Bukowska Street 70, 60-812 Poznan, Poland;
| | - Jakub Geltz
- Doctoral School, Poznan University of Medical Sciences, Bukowska Street 70, 60-812 Poznan, Poland;
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Szpitalna Street 27/33, 60-572 Poznan, Poland
| | - Aldona Kasprzak
- Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecicki Street 6, 60-781 Poznan, Poland;
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Zhou M, Guan B, Liu Y, Gu Q, Chen W, Xie B, Zhou M, Xiang J, Zhao S, Zhao Q, Yan D. Fibrinogen-like 2 in tumor-associated macrophage-derived extracellular vesicles shapes an immunosuppressive microenvironment in colorectal liver metastases by promoting tumor stemness and neutrophil extracellular traps formation. Cancer Lett 2025; 618:217642. [PMID: 40097065 DOI: 10.1016/j.canlet.2025.217642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 03/01/2025] [Accepted: 03/14/2025] [Indexed: 03/19/2025]
Abstract
Investigating the mechanisms underlying the development of an immunosuppressive microenvironment within colorectal liver metastases (CRLM) is important for identifying synergistic targets for immunotherapy. The regulatory role of tumor-associated macrophage-derived extracellular vesicles (TAM-EVs) in the immune microenvironment of CRLM has not yet been fully explored. Here, we found that TAM-EVs shaped the immunosuppressive microenvironment at the invasive front in murine CRLM models, thus dampening anti-PD-1 immunotherapy. This environment is characterized by an increased tumor stemness potential and abundant neutrophil extracellular traps (NETs) formation. Mechanistically, TAM-EVs-derived fibrinogen-like 2 (FGL2) interacts with the FCGR2B receptor in tumor cells, which further activates a p-STAT3/IL-1β positive feedback loop to increase the stemness potential of cancer cells, whereas IL-1β mediates the communication between cancer cells and neutrophils. The use of an anti-IL-1β monoclonal antibody can reduce NETs production and synergize with anti-PD-1 immunotherapy, which offers clinical translational significance for CRLM therapy. The FGL2/p-STAT3/IL-1β loop correlates with an immunosuppressive microenvironment and poor prognosis in human patients with CRLM. Our results revealed the potential of enhancing the efficacy of immunotherapy via the targeted clearance of NETs using anti-IL-1β monoclonal antibodies, which have significant clinical translational value in the treatment of CRLM.
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Affiliation(s)
- Menghua Zhou
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingjie Guan
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Youdong Liu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qi Gu
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiwei Chen
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bowen Xie
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mantang Zhou
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianjun Xiang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Senlin Zhao
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Qian Zhao
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Dongwang Yan
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Jia J, Wang J, Zhang Y, Bai G, Han L, Niu Y. Deep Learning and Radiomic Signatures Associated with Tumor Immune Heterogeneity Predict Microvascular Invasion in Colon Cancer. Acad Radiol 2025:S1076-6332(25)00432-5. [PMID: 40413149 DOI: 10.1016/j.acra.2025.05.006] [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: 03/24/2025] [Revised: 04/28/2025] [Accepted: 05/04/2025] [Indexed: 05/27/2025]
Abstract
RATIONALE AND OBJECTIVES This study aims to develop and validate a deep learning radiomics signature (DLRS) that integrates radiomics and deep learning features for the non-invasive prediction of microvascular invasion (MVI) in patients with colon cancer (CC). Furthermore, the study explores the potential association between DLRS and tumor immune heterogeneity. MATERIALS AND METHODS This study is a multi-center retrospective study that included a total of 1007 patients with colon cancer (CC) from three medical centers and The Cancer Genome Atlas (TCGA-COAD) database. Patients from Medical Centers 1 and 2 were divided into a training cohort (n = 592) and an internal validation cohort (n = 255) in a 7:3 ratio. Medical Center 3 (n = 135) and the TCGA-COAD database (n = 25) were used as external validation cohorts. Radiomics and deep learning features were extracted from contrast-enhanced venous-phase CT images. Feature selection was performed using machine learning algorithms, and three predictive models were developed: a radiomics model, a deep learning (DL) model, and a combined deep learning radiomics (DLR) model. The predictive performance of each model was evaluated using multiple metrics, including the area under the curve (AUC), sensitivity, and specificity. Additionally, differential gene expression analysis was conducted on RNA-seq data from the TCGA-COAD dataset to explore the association between the DLRS and tumor immune heterogeneity within the tumor microenvironment. RESULTS Compared to the standalone radiomics and deep learning models, DLR fusion model demonstrated superior predictive performance. The AUC for the internal validation cohort was 0.883 (95% CI: 0.828-0.937), while the AUC for the external validation cohort reached 0.855 (95% CI: 0.775-0.935). Furthermore, stratifying patients from the TCGA-COAD dataset into high-risk and low-risk groups based on the DLRS revealed significant differences in immune cell infiltration and immune checkpoint expression between the two groups (P < 0.05). CONCLUSION The contrast-enhanced CT-based DLR fusion model developed in this study effectively predicts the MVI status in patients with CC. This model serves as a non-invasive preoperative assessment tool and reveals a potential association between the DLRS and immune heterogeneity within the tumor microenvironment, providing insights to optimize individualized treatment strategies.
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Affiliation(s)
- Jianye Jia
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong'an Road, Xicheng District, Beijing 100050, China (J.J., J.W., Y.N.)
| | - Jiahao Wang
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong'an Road, Xicheng District, Beijing 100050, China (J.J., J.W., Y.N.)
| | - Yongxian Zhang
- Department of Radiology, Beijing Tongren Hospital, Capital Medical University, No.1 DongJiaoMinXiang Street, DongCheng District, Beijing 100730, China (Y.Z.)
| | - Genji Bai
- Department of Medical Imaging Center, The Affiliated Huaian NO.1 People's Hospital of Nanjing Medical University, Huaian 223300, Jiangsu, PR China (G.B.)
| | - Lei Han
- Department of Medical Imaging, Huaian Hospital Affiliated to Xuzhou Medical University, Huaian 223001, Jiangsu, China (L.H.)
| | - Yantao Niu
- Department of Radiology, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong'an Road, Xicheng District, Beijing 100050, China (J.J., J.W., Y.N.).
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Siqin S, Nikitina E, Rahbari M, Ernst C, Krunic D, Birgin E, Tessmer C, Hofmann I, Rahbari N, Bund T. Bovine Meat and Milk Factor (BMMF) Protein Is Expressed in Macrophages Spread Widely over the Mucosa of Colorectal Cancer Patients. Cells 2025; 14:455. [PMID: 40136704 PMCID: PMC11940877 DOI: 10.3390/cells14060455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 02/27/2025] [Accepted: 03/17/2025] [Indexed: 03/27/2025] Open
Abstract
Red meat consumption is considered a risk factor for colorectal cancer (CRC) development and stimulated isolation of plasmid-like DNA molecules from bovine serum and milk, termed bovine meat and milk factors (BMMFs). BMMFs encode a conserved replication protein (Rep). Increased populations of Rep-expressing macrophages have been identified in the peritumor of CRC patients and pre-cancerous tissues when compared to the tissues of healthy individuals. This supports the concept that BMMFs increase cancer risk by indirect carcinogenesis, upon induction of chronic inflammation. However, the spread of Rep+ immune cells in tissues at greater distances from primary tumors has not yet been assessed. Here, we immunohistologically analyzed the presence of Rep+ immune cells in sets of tumor, peritumor and, additionally, distant tissues of CRC patients (n = 13). We identified consistently high numbers of BMMF-positive macrophages in mucosal tissues at distances of as much as 25 cm away from the primary tumors, at levels comparable to peritumors and associated with M2-like macrophage polarization. The broad distribution of BMMFs suggests that BMMF+ macrophages might already exist at stages of pre-cancerous dysplasia or before. Quantification of BMMF tissue expression during colonoscopy might help to preventively stratify individuals at risk of developing polyps/CRC and recommend them for enhanced surveillance and/or changes in dietary lifestyle.
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Affiliation(s)
- Sumen Siqin
- Division of Episomal-Persistent DNA in Cancer- and Chronic Diseases, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Ekaterina Nikitina
- Division of Episomal-Persistent DNA in Cancer- and Chronic Diseases, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Mohammad Rahbari
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, University of Tuebingen, 72076 Tuebingen, Germany
| | - Claudia Ernst
- Division of Episomal-Persistent DNA in Cancer- and Chronic Diseases, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Damir Krunic
- Light Microscopy Facility, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Emrullah Birgin
- Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- Clinic for General and Visceral Surgery, University Hospital Ulm, 89081 Ulm, Germany
| | - Claudia Tessmer
- Core Facility Antibodies, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Ilse Hofmann
- Core Facility Antibodies, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Nuh Rahbari
- Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- Clinic for General and Visceral Surgery, University Hospital Ulm, 89081 Ulm, Germany
| | - Timo Bund
- Division of Episomal-Persistent DNA in Cancer- and Chronic Diseases, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Si Q, Wang Y, Lu W, Liu Z, Song Y, Chen S, Xia S, Li H, Weng P, Jing Y, Yu Q, Zhu F, Zhang X, Huang X, Ni Y. Transferrin receptor uptakes iron from tumor-associated neutrophils to regulate invasion patterns of OSCC. Cancer Immunol Immunother 2025; 74:43. [PMID: 39751915 PMCID: PMC11699170 DOI: 10.1007/s00262-024-03894-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 11/13/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Transferrin receptor (TFRC) uptakes iron-loaded transferrin (TF) to acquire iron and regulates tumor development. Nonetheless, the clinical values and the precise functions of TF-TFRC axis in the development of oral squamous cell carcinoma (OSCC) were still undiscovered, especially the impacts of their regional heterogeneous expression. METHODS Immunohistochemistry (IHC) was used to analyze the expression of TFRC in 106 OSCC patients. Then the prognostic value of TFRC was compared between high and low worst pattern of invasion (WPOI) patients. OSCC cells with low or high expression of TFRC were constructed, and functional experiments were performed to elucidate the effects of TFRC on the migration and proliferation of OSCC cells. Multi-immunofluorescence was applied to stain TF and tumor-associated neutrophils (TANs). The stimulating effects of TF were compared between normal and high TFRC cells in vitro and across different OSCC patients' subgroups in our sample bank and TCGA database. RESULTS Higher TFRC was expressed at invasive tumor front (ITF) in OSCC and correlated with WPOI. Only at ITF in patients with WPOI 4-5, TFRC was a prognostic factor. High TFRC promoted migration and proliferation of cancer cells. Additionally, TANs secreted TF outside. Exogenous TF promoted migration and proliferation of cells with high expression of TFRC. Compared to the TANslowTFRClow OSCC patients, TANshighTFRChigh OSCC patients had poorer clinical outcomes. CONCLUSIONS Higher expression of TFRC at ITF and TANs-TF-TFRC axis promoted OSCC invasion at ITF by facilitating cell migration and proliferation, which may result from increased cellular iron uptake through regulating iron metabolism.
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Affiliation(s)
- Qian Si
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
- Department of Oral Pathology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Yuhan Wang
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Wanqiu Lu
- Central Laboratory, School of Biopharmacy, China Pharmaceutical University, Nanjing, 210023, Jiangsu, China
| | - Zijian Liu
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Yuxian Song
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Sheng Chen
- Department of Oral Pathology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Shu Xia
- Department of Oral Pathology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Huiling Li
- Department of Oral Pathology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Pei Weng
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Yue Jing
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Qiuya Yu
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China
| | - Feng Zhu
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China.
| | - Xiaoxin Zhang
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China.
| | - Xiaofeng Huang
- Department of Oral Pathology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China.
| | - Yanhong Ni
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, China.
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Rajendran D, Oon CE. Navigating therapeutic prospects by modulating autophagy in colorectal cancer. Life Sci 2024; 358:123121. [PMID: 39389340 DOI: 10.1016/j.lfs.2024.123121] [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: 06/13/2024] [Revised: 09/25/2024] [Accepted: 10/05/2024] [Indexed: 10/12/2024]
Abstract
Colorectal cancer (CRC) remains a leading cause of death globally despite the improvements in cancer treatment. Autophagy is an evolutionarily conserved lysosomal-dependent degradation pathway that is critical in maintaining cellular homeostasis. However, in cancer, autophagy may have conflicting functions in preventing early tumour formation versus the maintenance of advanced-stage tumours. Defective autophagy has a broad and dynamic effect not just on cancer cells, but also on the tumour microenvironment which influences tumour progression and response to treatment. To add to the layer of complexity, somatic mutations in CRC including tumour protein p53 (TP53), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), Kirsten rat sarcoma viral oncogene homolog (KRAS), and phosphatase and tensin homolog (PTEN) can render chemoresistance by promoting a pro-survival advantage through autophagy. Recent studies have also reported autophagy-related cell deaths that are distinct from classical autophagy by employing parts of the autophagic machinery, which impacts strategies for autophagy regulation in cancer therapy. This review discusses the molecular processes of autophagy in the evolution of CRC and its role in the tumour microenvironment, as well as prospective therapeutic methods based on autophagy suppression or promotion. It also highlights clinical trials using autophagy modulators for treating CRC, underscoring the importance of autophagy regulation in CRC therapy.
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Affiliation(s)
- Deepa Rajendran
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Gelugor, 11800, Penang, Malaysia.
| | - Chern Ein Oon
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Gelugor, 11800, Penang, Malaysia.
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Yuan W, Zhang J, Chen H, Zhuang Y, Zhou H, Li W, Qiu W, Zhou H. Natural compounds modulate the mechanism of action of tumour-associated macrophages against colorectal cancer: a review. J Cancer Res Clin Oncol 2024; 150:502. [PMID: 39546016 PMCID: PMC11568041 DOI: 10.1007/s00432-024-06022-8] [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: 09/11/2024] [Accepted: 10/28/2024] [Indexed: 11/17/2024]
Abstract
Colorectal cancer (CRC) exhibits a substantial morbidity and mortality rate, with its aetiology and pathogenesis remain elusive. It holds significant importance within the tumour microenvironment (TME) and exerts a crucial regulatory influence on tumorigenesis, progression, and metastasis. TAMs possess the capability to foster CRC pathogenesis, proliferation, invasion, and metastasis, as well as angiogenesis, immune evasion, and tumour resistance. Furthermore, TAMs can mediate the prognosis of CRC. In this paper, we review the mechanisms by which natural compounds target TAMs to exert anti-CRC effects from the perspective of the promotional effects of TAMs on CRC, mainly regulating the polarization of TAMs, reducing the infiltration and recruitment of TAMs, enhancing the phagocytosis of macrophages, and regulating the signalling pathways and cytokines, and discuss the potential value and therapeutic strategies of natural compounds-targeting the TAMs pathway in CRC clinical treatment.
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Affiliation(s)
- Weichen Yuan
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiexiang Zhang
- Urology Centre, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Surgery of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Haibin Chen
- Science and Technology Department, Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yupei Zhuang
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Hongli Zhou
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenting Li
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Wenli Qiu
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Hongguang Zhou
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
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Fan Q, Fu ZW, Xu M, Lv F, Shi JS, Zeng QQ, Xiong DH. Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer. World J Gastrointest Oncol 2024; 16:4064-4079. [DOI: 10.4251/wjgo.v16.i10.4064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 08/03/2024] [Accepted: 08/16/2024] [Indexed: 09/26/2024] Open
Abstract
The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
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Affiliation(s)
- Qi Fan
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Zheng-Wei Fu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Ming Xu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Feng Lv
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Jia-Song Shi
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Qi-Qi Zeng
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - De-Hai Xiong
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
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Dariya B, Girish BP, Merchant N, Srilatha M, Nagaraju GP. Resveratrol: biology, metabolism, and detrimental role on the tumor microenvironment of colorectal cancer. Nutr Rev 2024; 82:1420-1436. [PMID: 37862428 DOI: 10.1093/nutrit/nuad133] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2023] Open
Abstract
A substantial increase in colorectal cancer (CRC)-associated fatalities can be attributed to tumor recurrence and multidrug resistance. Traditional treatment options, including radio- and chemotherapy, also exhibit adverse side effects. Ancient treatment strategies that include phytochemicals like resveratrol are now widely encouraged as an alternative therapeutic option. Resveratrol is the natural polyphenolic stilbene in vegetables and fruits like grapes and apples. It inhibits CRC progression via targeting dysregulated cancer-promoting pathways, including PI3K/Akt/Kras, targeting transcription factors like NF-κB and STAT3, and an immunosuppressive tumor microenvironment. In addition, combination therapies for cancer include resveratrol as an adjuvant to decrease multidrug resistance that develops in CRC cells. The current review discusses the biology of resveratrol and explores different mechanisms of action of resveratrol in inhibiting CRC progression. Further, the detrimental role of resveratrol on the immunosuppressive tumor microenvironment of CRC has been discussed. This review illustrates clinical trials on resveratrol in different cancers, including resveratrol analogs, and their efficiency in promoting CRC inhibition.
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Affiliation(s)
- Begum Dariya
- Center for Drug Design, University of Minnesota, Minneapolis, Minnesota, USA
| | - Bala Prabhakar Girish
- Nanotechnology Laboratory, Institute of Frontier Technology, Acharya N.G. Ranga Agricultural University, Tirupati, Andhra Pradesh, India
| | - Neha Merchant
- Department of Bioscience and Biotechnology, Banasthali Vidyapith, Banasthali, Rajasthan, India
| | - Mundla Srilatha
- Department of Biotechnology, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
| | - Ganji Purnachandra Nagaraju
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, Alabama, USA
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Urbaniec-Stompór J, Michalak M, Godlewski J. Correlating Ultrastructural Changes in the Invasion Area of Colorectal Cancer with CT and MRI Imaging. Int J Mol Sci 2024; 25:9905. [PMID: 39337393 PMCID: PMC11432200 DOI: 10.3390/ijms25189905] [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: 07/23/2024] [Revised: 09/09/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
The cancer invasion of the large intestine, a destructive process that begins within the mucous membrane, causes cancer cells to gradually erode specific layers of the intestinal wall. The normal tissues of the intestine are progressively replaced by a tumour mass, leading to the impairment of the large intestine's proper morphology and function. At the ultrastructural level, the disintegration of the extracellular matrix (ECM) by cancer cells triggers the activation of inflammatory cells (macrophages) and connective tissue cells (myofibroblasts) in this area. This accumulation and the functional interactions between these cells form the tumour microenvironment (TM). The constant modulation of cancer cells and cancer-associated fibroblasts (CAFs) creates a specific milieu akin to non-healing wounds, which induces colon cancer cell proliferation and promotes their survival. This review focuses on the processes occurring at the "front of cancer invasion", with a particular focus on the role of the desmoplastic reaction in neoplasm development. It then correlates the findings from the microscopic observation of the cancer's ultrastructure with the potential of modern radiological imaging, such as computer tomography (CT) and magnetic resonance imaging (MRI), which visualizes the tumour, its boundaries, and the tissue reactions in the large intestine.
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Affiliation(s)
- Joanna Urbaniec-Stompór
- Department of Diagnostic Imaging, Clinical Hospital of the Ministry of Internal Affairs and Administration with the Warmia-Mazury Oncology Centre, 10228 Olsztyn, Poland
| | - Maciej Michalak
- Department of Diagnostic Imaging, Clinical Hospital of the Ministry of Internal Affairs and Administration with the Warmia-Mazury Oncology Centre, 10228 Olsztyn, Poland
- Department of Oncology, Faculty of Medical Sciences, University of Warmia and Mazury, 10228 Olsztyn, Poland
| | - Janusz Godlewski
- Department of Human Histology and Embryology, Faculty of Medical Sciences, University of Warmia and Mazury, 10082 Olsztyn, Poland
- Clinical Surgical Oncology Department, Clinical Hospital of the Ministry of Internal Affairs and Administration with the Warmia-Mazury Oncology Centre, 10228 Olsztyn, Poland
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11
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Muijlwijk T, Nijenhuis DNLM, Ganzevles SH, Ekhlas F, Ballesteros-Merino C, Peferoen LAN, Bloemena E, Fox BA, Poell JB, Leemans CR, Brakenhoff RH, van de Ven R. Immune cell topography of head and neck cancer. J Immunother Cancer 2024; 12:e009550. [PMID: 39053947 DOI: 10.1136/jitc-2024-009550] [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] [Accepted: 07/13/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Approximately 50% of head and neck squamous cell carcinomas (HNSCC) recur after treatment with curative intent. Immune checkpoint inhibitors are treatment options for recurrent/metastatic HNSCC; however, less than 20% of patients respond. To increase this response rate, it is fundamental to increase our understanding of the spatial tumor immune microenvironment (TIME). METHODS In total, 53 HNSCC specimens were included. Using a seven-color multiplex immunohistochemistry panel we identified tumor cells, CD163+macrophages, B cells, CD8+T cells, CD4+T helper cells and regulatory T cells (Tregs) in treatment-naive surgical resection specimens (n=29) and biopsies (n=18). To further characterize tumor-infiltrating CD8+T cells, we stained surgical resection specimens (n=12) with a five-color tumor-resident panel including CD103, Ki67, CD8 and pan-cytokeratin. Secretome analysis was performed on matched tumor suspensions (n=11) to measure protein levels. RESULTS Based on CD8+T cell infiltrates, we identified four different immunotypes: fully infiltrated, stroma-restricted, immune-excluded, and immune-desert. We found higher cytokine levels in fully infiltrated tumors compared with other immunotypes. While the highest immune infiltrates were observed in the invasive margin for all immune cells, CD163+macrophages and Tregs had the highest tendency to infiltrate the tumor center. Within the tumor center, especially B cells stayed at the tumor stroma, whereas CD163+macrophages, followed by T cells, were more often localized within tumor fields. Also, B cells were found further away from other cells and often formed aggregates while T cells and CD163+macrophages tended to be more closely located to each other. Across resection specimens from various anatomical sites within the head and neck, oral cavity tumors exhibited the highest densities of Tregs. Moreover, the distance from B cells and T cells to tumor cells was shortest in oral cavity squamous cell carcinoma (OCSCC), suggesting more interaction between lymphocytes and tumor cells. Also, the fraction of T cells within 10 µm of CD163+macrophages was lowest in OCSCC, indicating fewer myeloid/T-cell suppressive interactions in OCSCC. CONCLUSIONS We comprehensively described the TIME of HNSCC using a unique data set of resection specimens. We discovered that the composition, as well as the relative localization of immune cells in the TIME, differed in distinct anatomical sites of the head and neck.
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Affiliation(s)
- Tara Muijlwijk
- Otolaryngology / Head and Neck Surgery, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
- Cancer Biology and Immunology, Cancer Centre Amsterdam, Amsterdam, The Netherlands
- Cancer Immunology, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands
| | - Dennis N L M Nijenhuis
- Otolaryngology / Head and Neck Surgery, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
- Cancer Biology and Immunology, Cancer Centre Amsterdam, Amsterdam, The Netherlands
- Cancer Immunology, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands
| | - Sonja H Ganzevles
- Otolaryngology / Head and Neck Surgery, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
- Cancer Biology and Immunology, Cancer Centre Amsterdam, Amsterdam, The Netherlands
- Cancer Immunology, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands
| | - Fatima Ekhlas
- Otolaryngology / Head and Neck Surgery, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
- Cancer Biology and Immunology, Cancer Centre Amsterdam, Amsterdam, The Netherlands
- Cancer Immunology, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands
| | - Carmen Ballesteros-Merino
- Molecular and Tumor Immunology Laboratory, Providence Cancer Institute, Robert W. Franz Research Center at the Earle A. Chiles Research Institute, Portland, Oregon, USA
| | - Laura A N Peferoen
- Cancer Biology and Immunology, Cancer Centre Amsterdam, Amsterdam, The Netherlands
- Pathology, Amsterdam UMC - Locatie VUMC, Amsterdam, The Netherlands
- Maxillofacial Surgery/ Oral Pathology, Academic Center for Dentistry, Amsterdam, The Netherlands
| | - Elisabeth Bloemena
- Cancer Biology and Immunology, Cancer Centre Amsterdam, Amsterdam, The Netherlands
- Pathology, Amsterdam UMC - Locatie VUMC, Amsterdam, The Netherlands
- Maxillofacial Surgery/ Oral Pathology, Academic Center for Dentistry, Amsterdam, The Netherlands
| | - Bernard A Fox
- Molecular and Tumor Immunology Laboratory, Providence Cancer Institute, Robert W. Franz Research Center at the Earle A. Chiles Research Institute, Portland, Oregon, USA
| | - Jos B Poell
- Otolaryngology / Head and Neck Surgery, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
- Cancer Biology and Immunology, Cancer Centre Amsterdam, Amsterdam, The Netherlands
| | - C René Leemans
- Otolaryngology / Head and Neck Surgery, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
- Cancer Biology and Immunology, Cancer Centre Amsterdam, Amsterdam, The Netherlands
| | - Ruud H Brakenhoff
- Otolaryngology / Head and Neck Surgery, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
- Cancer Biology and Immunology, Cancer Centre Amsterdam, Amsterdam, The Netherlands
| | - Rieneke van de Ven
- Otolaryngology / Head and Neck Surgery, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
- Cancer Biology and Immunology, Cancer Centre Amsterdam, Amsterdam, The Netherlands
- Cancer Immunology, Amsterdam Institute for Immunology and Infectious Diseases, Amsterdam, The Netherlands
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12
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Liu W, Kuang T, Liu L, Deng W. The role of innate immune cells in the colorectal cancer tumor microenvironment and advances in anti-tumor therapy research. Front Immunol 2024; 15:1407449. [PMID: 39100676 PMCID: PMC11294098 DOI: 10.3389/fimmu.2024.1407449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 06/25/2024] [Indexed: 08/06/2024] Open
Abstract
Innate immune cells in the colorectal cancer microenvironment mainly include macrophages, neutrophils, natural killer cells, dendritic cells and bone marrow-derived suppressor cells. They play a pivotal role in tumor initiation and progression through the secretion of diverse cytokines, chemokines, and other factors that govern these processes. Colorectal cancer is a common malignancy of the gastrointestinal tract, and understanding the role of innate immune cells in the microenvironment of CRC may help to improve therapeutic approaches to CRC and increase the good prognosis. In this review, we comprehensively explore the pivotal role of innate immune cells in the initiation and progression of colorectal cancer (CRC), alongside an extensive evaluation of the current landscape of innate immune cell-based immunotherapies, thereby offering valuable insights for future research strategies and clinical trials.
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Affiliation(s)
| | | | | | - Wenhong Deng
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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13
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Coulton A, Murai J, Qian D, Thakkar K, Lewis CE, Litchfield K. Using a pan-cancer atlas to investigate tumour associated macrophages as regulators of immunotherapy response. Nat Commun 2024; 15:5665. [PMID: 38969631 PMCID: PMC11226649 DOI: 10.1038/s41467-024-49885-8] [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: 02/27/2023] [Accepted: 06/24/2024] [Indexed: 07/07/2024] Open
Abstract
The paradigm for macrophage characterization has evolved from the simple M1/M2 dichotomy to a more complex model that encompasses the broad spectrum of macrophage phenotypic diversity, due to differences in ontogeny and/or local stimuli. We currently lack an in-depth pan-cancer single cell RNA-seq (scRNAseq) atlas of tumour-associated macrophages (TAMs) that fully captures this complexity. In addition, an increased understanding of macrophage diversity could help to explain the variable responses of cancer patients to immunotherapy. Our atlas includes well established macrophage subsets as well as a number of additional ones. We associate macrophage composition with tumour phenotype and show macrophage subsets can vary between primary and metastatic tumours growing in sites like the liver. We also examine macrophage-T cell functional cross talk and identify two subsets of TAMs associated with T cell activation. Analysis of TAM signatures in a large cohort of immune checkpoint inhibitor-treated patients (CPI1000 + ) identify multiple TAM subsets associated with response, including the presence of a subset of TAMs that upregulate collagen-related genes. Finally, we demonstrate the utility of our data as a resource and reference atlas for mapping of novel macrophage datasets using projection. Overall, these advances represent an important step in both macrophage classification and overcoming resistance to immunotherapies in cancer.
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Affiliation(s)
- Alexander Coulton
- The Tumour Immunogenomics and Immunosurveillance (TIGI) Lab, UCL Cancer Institute, London, WC1E 6DD, UK
| | - Jun Murai
- The Tumour Immunogenomics and Immunosurveillance (TIGI) Lab, UCL Cancer Institute, London, WC1E 6DD, UK
| | - Danwen Qian
- The Tumour Immunogenomics and Immunosurveillance (TIGI) Lab, UCL Cancer Institute, London, WC1E 6DD, UK
| | - Krupa Thakkar
- The Tumour Immunogenomics and Immunosurveillance (TIGI) Lab, UCL Cancer Institute, London, WC1E 6DD, UK
| | - Claire E Lewis
- Department of Oncology and Metabolism, University of Sheffield Medical School, Beech Hill Road, Sheffield, Yorkshire, S10 2RX, UK.
| | - Kevin Litchfield
- The Tumour Immunogenomics and Immunosurveillance (TIGI) Lab, UCL Cancer Institute, London, WC1E 6DD, UK.
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14
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Baş Y, Yilmaz B, Acar SF, Karadağ İ. Programmed Cell Death Ligand 1 Expression in CD163 + Tumor-associated Macrophages in Cancer Gland Rupture Microenvironment. Appl Immunohistochem Mol Morphol 2024; 32:176-182. [PMID: 38314768 DOI: 10.1097/pai.0000000000001186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 01/15/2024] [Indexed: 02/07/2024]
Abstract
In this study, we aimed to examine the relationship among cancer gland rupture microenvironment, programmed cell death ligand 1 (PD-L1) expression in CD163 + tumor-associated macrophages (TAMs), and prognosis in colon adenocarcinoma. A total of 122 patients were diagnosed with colon adenocarcinoma between 2010 and 2019. PD-L1 + (clone 22C3) "macrophage scores" in the microenvironment of cancer gland rupture were calculated. The effects of these variables on prognosis were statistically analyzed. CD163 + TAMs were denser in the cancer gland rupture microenvironment. PD-L1 + TAMs were observed in the tumor periphery, and there was a significant difference between the rates of PD-L1 expression in TAMs and survival time (log-rank = 10.46, P = 0.015), clinical stage 2 ( P = 0.038), and primary tumor 3 and primary tumor 4 cases ( P = 0.004, P = 0.013). The risk of mortality was 4.070 times higher in patients with a PD-L1 expression rate of ≥1% in CD163 + TAMs. High PD-L1 expression in CD163 + TAMs is associated with poor overall survival. Therefore, blocking PD-L1 in CD163 + TAMs can be used as a target for immunotherapy.
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Affiliation(s)
- Yilmaz Baş
- Department of Pathology, Faculty of Medicine
| | | | | | - İbrahim Karadağ
- Department of Oncology, Erol Olçok Education and Research Hospital, Hitit University, Çorum, Turkey
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15
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Lou E, Xiu J, Baca Y, Saeed A, Prakash A, Gholami S, Subramanian S, Starr TK, Fontana E, Pandey R, Lenz HJ, Shields AF, Nabhan C, Oberley M, Seeber A, El-Deiry W. Differential landscape of immune evasion in oncogenic RAS-driven primary and metastatic colorectal cancers. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200786. [PMID: 38596288 PMCID: PMC10963927 DOI: 10.1016/j.omton.2024.200786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 02/26/2024] [Accepted: 02/26/2024] [Indexed: 04/11/2024]
Abstract
Oncogenic drivers such as KRAS extensively modulate the tumor inflammatory microenvironment (TIME) of colorectal cancer (CRC). The influence of KRAS on modulating immune cell composition remains unclear. The objective of this study was to identify signatures of infiltrative immune cells and distinctive patterns that differ between RAS wild-type (WT) and oncogenic mutant (MT) CRC that explain immune evasion in MT tumors. A total of 7,801 CRC specimens were analyzed using next-generation DNA sequencing, whole-exome sequencing, and/or whole transcriptome sequencing. Deficiency of mismatch repair (dMMR)/microsatellite instability (MSI) and tumor mutation burden (TMB) were also assessed. KRAS mutations were present in 48% of CRC, similarly distributed in patients younger than vs. 50 years and older. In microsatellite stable (MSS) KRAS MT tumors, composition of the TIME included higher neutrophil infiltration and lower infiltration of B cells. MSI-H/dMMR was significantly more prevalent in RAS WT (9.1%) than in KRAS MT (2.9%) CRC. In MSS CRC, TMB-high cases were significantly higher in RAS MT (3.1%) than in RAS WT (2.1%) tumors. KRAS and NRAS mutations are associated with increased neutrophil infiltration, with codon-specific differences. These results demonstrate significant differences in the TIME of RAS mutant CRC that match previous reports of immunoevasive characteristics of such tumors.
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Affiliation(s)
- Emil Lou
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | | | | | - Anwaar Saeed
- University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Ajay Prakash
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | | | | | - Timothy K. Starr
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Minnesota, Minneapolis, MN, USA
| | - Elisa Fontana
- Drug Development Unit, Sarah Cannon Research Institute UK, Marylebone, London, UK
| | - Ritu Pandey
- Arizona Cancer Center, Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Anthony F. Shields
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | | | | | - Andreas Seeber
- Department of Internal Medicine V (Hematology and Oncology), Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
| | - Wafik El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Legorreta Cancer Center, Brown University, Providence, RI, USA
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16
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Alzamami A. Implications of single-cell immune landscape of tumor microenvironment for the colorectal cancer diagnostics and therapy. Med Oncol 2023; 40:352. [PMID: 37950801 DOI: 10.1007/s12032-023-02226-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 10/18/2023] [Indexed: 11/13/2023]
Abstract
Colorectal cancer (CRC) originates from the polyps lining the colon and is among the most common types of cancer. With the increasing popularity of single-cell sequencing technologies, researchers have been able to better understand the immune landscape of colorectal cancer, by analyzing their expression and interactions in detail with the tumor microenvironment (TME) at single-cell level. Since the tumor-immune cell interactions play a critical part in the advancement as well as treatment response in colorectal cancer, the release of inhibitory factors such as T cells are important for recognizing and destroying cancer cells. Such information is vital to identify immunotherapeutic targets for cure and monitoring response to treatments. Therefore, a comprehensive single-cell studies-based overview of key immunogenic agents regulating the TME of CRC is provided in this review. Tumor-associated macrophages can promote tumor growth and resistance to treatment by releasing factors that inhibit the function of other immune cells. Additionally, colorectal cancer cells can express programmed cell death protein 1 and its ligand, which can also inhibit T-cell function. Researchers have found that certain types of immune cells, prominently T cells, natural killer, and dendritic cells, can have a positive impact on the prognosis of colorectal cancer patients. Treatments like immune checkpoint inhibitors and CAR-T therapies that help to release the inhibitory signals from the cancer cells allow the immune cells to function more effectively.
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Affiliation(s)
- Ahmad Alzamami
- Clinical Laboratory Science Department, College of Applied Medical Sciences, Shaqra University, 11961, Al-Quwayiyah, Saudi Arabia.
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17
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Li H, Pan L, Guo J, Lao J, Wei M, Huang F. Integration of single-cell and bulk RNA sequencing to establish a prognostic signature based on tumor-associated macrophages in colorectal cancer. BMC Gastroenterol 2023; 23:385. [PMID: 37950156 PMCID: PMC10638776 DOI: 10.1186/s12876-023-03035-4] [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: 08/16/2023] [Accepted: 11/07/2023] [Indexed: 11/12/2023] Open
Abstract
Several studies have shown significant involvement of tumor-associated macrophages (TAMs) in the tumor microenvironment and cancer progression. However, no data on reliable TAM-related biomarkers are available for predicting the prognosis of patients with colorectal cancer (CRC). We analyzed the clinical data and gene expression profiles of patients with CRC from databases. The single-cell transcriptomic data was applied to identify M2-like TAM-related differentially expressed genes. Univariate Cox and least absolute shrinkage and selection operator regression analyses were used to determine the prognostic signature genes. Then, seven key genes were screened to develop the prognostic signature. In the training and external validation cohorts, the overall survival (OS) of patients in the high-risk group was significantly shorter compared to the low-risk group. Consequently, we created a nomogram that could accurately and reliably predict the prognosis of patient with CRC. A significant correlation was observed between the patient's prognosis, clinical features, sensitivity to anticancer drugs, TME, and risk scores. Moreover, risk score was strongly related to the response to immunotherapy in patients from GSE91061, GSE78220, and GSE60331 cohorts. Finally, high expression of HSPA1A, SERPINA1, CXCL1, and low expression of DNASE1L3 were found in human CRC tissue and normal tissue by using qRT-PCR. In conclusion, the M2-like TAM-related prognostic signature could predict the survival, prognosis, and response of patients with CRC to immunotherapy, which sheds light on the role of TAMs in CRCs and enhances our understanding of TAMs.
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Affiliation(s)
- Hua Li
- Department of Anorectal Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi Province, China
| | - Lujuan Pan
- Gastroenterology Department, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi Province, China
| | - Junyu Guo
- Department of Anorectal Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi Province, China
| | - JianLe Lao
- Department of Cardiothoracic Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi Province, China
| | - Mingwei Wei
- Department of Anorectal Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi Province, China
| | - Fuda Huang
- Department of Anorectal Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi Province, China.
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18
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Tamari H, Kitadai Y, Takigawa H, Yuge R, Urabe Y, Shimamoto F, Oka S. Investigating the Role of Tumor-Infiltrating Lymphocytes as Predictors of Lymph Node Metastasis in Deep Submucosal Invasive Colorectal Cancer: A Retrospective Cross-Sectional Study. Cancers (Basel) 2023; 15:5238. [PMID: 37958412 PMCID: PMC10649548 DOI: 10.3390/cancers15215238] [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: 08/18/2023] [Revised: 09/25/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
The role of tumor-infiltrating T cells (TILs) in colorectal cancer (CRC) and their significance in early-stage CRC remain unknown. We investigated the role of TILs in early-stage CRC, particularly in deep submucosal invasive (T1b) CRC. Sixty patients with CRC (20 each with intramucosal [IM group], submucosal invasive [SM group], and advanced cancer [AD group]) were randomly selected. We examined changes in TILs with tumor invasion and the relationship between TILs and LN metastasis risk. Eighty-four patients with T1b CRC who underwent initial surgical resection with LN dissection or additional surgical resection with LN dissection after endoscopic resection were then selected. TIL phenotype and number were evaluated using triple immunofluorescence for CD4, CD8, and Foxp3. All subtypes were more numerous according to the degree of CRC invasion and more abundant at the invasive front of the tumor (IF) than in the center of the tumor (CT) in the SM and AD groups. The increased Foxp3 cells at the IF and high ratios of Foxp3/CD4 and Foxp3/CD8 positively correlated with LN metastasis. In conclusion, tumor invasion positively correlated with the number of TILs in CRC. The number and ratio of Foxp3 cells at the IF may predict LN metastasis in T1b CRC.
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Affiliation(s)
- Hirosato Tamari
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (H.T.); (R.Y.); (S.O.)
| | - Yasuhiko Kitadai
- Department of Health Sciences, Faculty of Human Culture and Science, Prefectural University of Hiroshima, Hiroshima 734-8558, Japan
| | - Hidehiko Takigawa
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (H.T.); (R.Y.); (S.O.)
| | - Ryo Yuge
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (H.T.); (R.Y.); (S.O.)
| | - Yuji Urabe
- Department of Gastrointestinal Endoscopy and Medicine, Hiroshima University Hospital, Hiroshima 734-8551, Japan;
| | - Fumio Shimamoto
- Faculty of Health Sciences, Hiroshima Cosmopolitan University, Hiroshima 734-0014, Japan;
| | - Shiro Oka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-8551, Japan; (H.T.); (H.T.); (R.Y.); (S.O.)
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19
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Zhao Y, Lu X, Huang H, Yao Y, Liu H, Sun Y. Dendrobium officinale polysaccharide Converts M2 into M1 Subtype Macrophage Polarization via the STAT6/PPAR-r and JAGGED1/NOTCH1 Signaling Pathways to Inhibit Gastric Cancer. Molecules 2023; 28:7062. [PMID: 37894541 PMCID: PMC10609635 DOI: 10.3390/molecules28207062] [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: 09/11/2023] [Revised: 09/29/2023] [Accepted: 10/07/2023] [Indexed: 10/29/2023] Open
Abstract
Dendrobium officinale polysaccharide (DOP) has shown various biological activities. However, the ability of DOP to participate in immune regulation during anti-gastric cancer treatment has remained unclear. In this study, the in vitro results showed that DOP has the potential to polarize THP-1 macrophages from the M2 to the M1 phenotype, downregulate the STAT6/PPAR-r signaling pathway and the protein expression of their down-targeted ARG1 and TGM2, and further decrease the main protein and mRNA expression in the JAGGED1/NOTCH1 signaling pathway. DOP suppressed the migration of gastric cancer cells by decreasing the protein expression of N-cadherin and Vimentin and increasing E-cadherin. In addition, CM-DOP promoted the apoptosis of gastric cancer cells by upregulating Caspase-3 and increasing the ratio of Bax/Bcl-2. In vivo, DOP effectively inhibited the growth of tumors and the expression of Ki-67. In summary, these findings demonstrated that DOP converted the polarization of M2 subtype macrophages into M1 subtypes via the STAT6/PPAR-r and JAGGED1/NOTCH1 signaling pathways in order to reduce apoptosis and prevent migration, thus indicating the potential of DOP as an adjuvant tumor therapy in preclinical and clinical trials.
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Affiliation(s)
- Yi Zhao
- Research Center for Differentiation and Development of Basic Theory of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; (Y.Z.); (X.L.); (H.H.); (Y.Y.)
| | - Xuefeng Lu
- Research Center for Differentiation and Development of Basic Theory of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; (Y.Z.); (X.L.); (H.H.); (Y.Y.)
| | - Hongxia Huang
- Research Center for Differentiation and Development of Basic Theory of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; (Y.Z.); (X.L.); (H.H.); (Y.Y.)
| | - Yao Yao
- Research Center for Differentiation and Development of Basic Theory of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; (Y.Z.); (X.L.); (H.H.); (Y.Y.)
| | - Hongning Liu
- Research Center for Differentiation and Development of Basic Theory of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China; (Y.Z.); (X.L.); (H.H.); (Y.Y.)
| | - Youzhi Sun
- School of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
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20
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Wang Y, Wang R, Li B, Huang Z, Zhao S, Chen S, Lan T, Ren S, Wu F, Tan J, Li J. Cancer-associated fibroblasts in the invasive tumour front promote the metastasis of oral squamous cell carcinoma through MFAP5 upregulation. Gene 2023:147504. [PMID: 37217152 DOI: 10.1016/j.gene.2023.147504] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/26/2023] [Accepted: 05/19/2023] [Indexed: 05/24/2023]
Abstract
Cancer-associated fibroblasts (CAFs) are widely involved in the development and progression of tumours. As a direct junction between tumour and normal host tissue, the tumour invasive front can remodel host tissue to generate a microenvironment more suitable for tumour invasion. However, whether CAFs derived from the invasive front (CAFs-F) have a greater ability to promote tumour invasion than CAFs derived from the superficial tumour (CAFs-S) is unclear. In this study, we characterized primary CAFs from different spatial locations of tumours. We demonstrated that CAFs-F had an increased ability to promote oral squamous cell carcinoma (OSCC) proliferation and invasion in vitro and significantly enhanced tumour growth in vivo compared to CAFs-S. Mechanistically, transcriptome profiling analysis revealed that the expression of MFAP5, encoding microfibril associated protein 5, was dramatically increased in CAFs-F compared to CAFs-S, which further confirmed that the MFAP5 protein level was elevated in head and neck squamous cell carcinoma (HNSCC) and that this increase was correlated with poor survival. Genetic ablation of MFAP5 impaired the preinvasive capabilities of CAFs-F. Together, our findings demonstrated that CAFs-F had a greater ability to promote tumour invasion than CAFs-S and that MFAP5 might be involved in this process.
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Affiliation(s)
- Yujia Wang
- Department of Oral and Maxillofacial Surgery, Department of General Dentistry, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University. 107 Yanjiang West Road, Guangzhou 510120, China
| | - Ruixin Wang
- Department of Oral and Maxillofacial Surgery, Department of General Dentistry, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University. 107 Yanjiang West Road, Guangzhou 510120, China
| | - Bowen Li
- Department of Oral and Maxillofacial Surgery, Department of General Dentistry, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University. 107 Yanjiang West Road, Guangzhou 510120, China
| | - Zhuoshan Huang
- Department of Oral and Maxillofacial Surgery, Department of General Dentistry, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University. 107 Yanjiang West Road, Guangzhou 510120, China
| | - Sufeng Zhao
- Nanjing Stomatological Hospital, Medical School of Nanjing University. 30 Zhongyang Road, Nanjing 210000, China
| | - Suling Chen
- Department of Oral and Maxillofacial Surgery, Department of General Dentistry, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University. 107 Yanjiang West Road, Guangzhou 510120, China
| | - Tianjun Lan
- Department of Oral and Maxillofacial Surgery, Department of General Dentistry, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University. 107 Yanjiang West Road, Guangzhou 510120, China
| | - Siqi Ren
- Department of Oral and Maxillofacial Surgery, Department of General Dentistry, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University. 107 Yanjiang West Road, Guangzhou 510120, China
| | - Fan Wu
- Department of Oral and Maxillofacial Surgery, Department of General Dentistry, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University. 107 Yanjiang West Road, Guangzhou 510120, China
| | - Jing Tan
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
| | - Jinsong Li
- Department of Oral and Maxillofacial Surgery, Department of General Dentistry, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University. 107 Yanjiang West Road, Guangzhou 510120, China.
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21
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Li L, Tian Y. The role of metabolic reprogramming of tumor-associated macrophages in shaping the immunosuppressive tumor microenvironment. Biomed Pharmacother 2023; 161:114504. [PMID: 37002579 DOI: 10.1016/j.biopha.2023.114504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/04/2023] [Accepted: 03/07/2023] [Indexed: 03/15/2023] Open
Abstract
Macrophages are potent immune effector cells in innate immunity and exert dual-effects in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) make up a significant portion of TME immune cells. Similar to M1/M2 macrophages, TAMs are also highly plastic, and their functions are regulated by cytokines, chemokines and other factors in the TME. The metabolic changes in TAMs are significantly associated with polarization towards a protumour or antitumour phenotype. The metabolites generated via TAM metabolic reprogramming in turn promote tumor progression and immune tolerance. In this review, we explore the metabolic reprogramming of TAMs in terms of energy, amino acid and fatty acid metabolism and the potential roles of these changes in immune suppression.
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Affiliation(s)
- Lunxu Li
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yu Tian
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China.
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22
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Tan S, Yang Y, Yang W, Han Y, Huang L, Yang R, Hu Z, Tao Y, Liu L, Li Y, Oyang L, Lin J, Peng Q, Jiang X, Xu X, Xia L, Peng M, Wu N, Tang Y, Cao D, Liao Q, Zhou Y. Exosomal cargos-mediated metabolic reprogramming in tumor microenvironment. J Exp Clin Cancer Res 2023; 42:59. [PMID: 36899389 PMCID: PMC9999652 DOI: 10.1186/s13046-023-02634-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 02/28/2023] [Indexed: 03/12/2023] Open
Abstract
Metabolic reprogramming is one of the hallmarks of cancer. As nutrients are scarce in the tumor microenvironment (TME), tumor cells adopt multiple metabolic adaptations to meet their growth requirements. Metabolic reprogramming is not only present in tumor cells, but exosomal cargos mediates intercellular communication between tumor cells and non-tumor cells in the TME, inducing metabolic remodeling to create an outpost of microvascular enrichment and immune escape. Here, we highlight the composition and characteristics of TME, meanwhile summarize the components of exosomal cargos and their corresponding sorting mode. Functionally, these exosomal cargos-mediated metabolic reprogramming improves the "soil" for tumor growth and metastasis. Moreover, we discuss the abnormal tumor metabolism targeted by exosomal cargos and its potential antitumor therapy. In conclusion, this review updates the current role of exosomal cargos in TME metabolic reprogramming and enriches the future application scenarios of exosomes.
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Affiliation(s)
- Shiming Tan
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yiqing Yang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Wenjuan Yang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yaqian Han
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Lisheng Huang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.,University of South China, Hengyang, 421001, Hunan, China
| | - Ruiqian Yang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.,University of South China, Hengyang, 421001, Hunan, China
| | - Zifan Hu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.,University of South China, Hengyang, 421001, Hunan, China
| | - Yi Tao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.,University of South China, Hengyang, 421001, Hunan, China
| | - Lin Liu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yun Li
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Linda Oyang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Jinguan Lin
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Qiu Peng
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Xianjie Jiang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Xuemeng Xu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Longzheng Xia
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Mingjing Peng
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Nayiyuan Wu
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yanyan Tang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Deliang Cao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.
| | - Qianjin Liao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China. .,Hunan Key Laboratory of Translational Radiation Oncology, 283 Tongzipo Road, Changsha, 410013, Hunan, China.
| | - Yujuan Zhou
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China. .,Hunan Key Laboratory of Translational Radiation Oncology, 283 Tongzipo Road, Changsha, 410013, Hunan, China.
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23
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A zebrafish HCT116 xenograft model to predict anandamide outcomes on colorectal cancer. Cell Death Dis 2022; 13:1069. [PMID: 36564370 PMCID: PMC9789132 DOI: 10.1038/s41419-022-05523-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 12/08/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022]
Abstract
Colon cancer is one of the leading causes of death worldwide. In recent years, cannabinoids have been extensively studied for their potential anticancer effects and symptom management. Several in vitro studies reported anandamide's (AEA) ability to block cancer cell proliferation and migration, but evidence from in vivo studies is still lacking. Thus, in this study, the effects of AEA exposure in zebrafish embryos transplanted with HCT116 cells were evaluated. Totally, 48 hpf xenografts were exposed to 10 nM AEA, 10 nM AM251, one of the cannabinoid 1 receptor (CB1) antagonist/inverse agonists, and to AEA + AM251, to verify the specific effect of AEA treatment. AEA efficacy was evaluated by confocal microscopy, which demonstrated that these xenografts presented a smaller tumor size, reduced tumor angiogenesis, and lacked micrometastasis formation. To gain deeper evidence into AEA action, microscopic observations were completed by molecular analyses. RNA seq performed on zebrafish transcriptome reported the downregulation of genes involved in cell proliferation, angiogenesis, and the immune system. Conversely, HCT116 cell transcripts resulted not affected by AEA treatment. In vitro HCT116 culture, in fact, confirmed that AEA exposure did not affect cell proliferation and viability, thus suggesting that the reduced tumor size mainly depends on direct effects on the fish rather than on the transplanted cancer cells. AEA reduced cell proliferation and tumor angiogenesis, as suggested by socs3 and pcnp mRNAs and Vegfc protein levels, and exerted anti-inflammatory activity, as indicated by the reduction of il-11a, mhc1uba, and csf3b mRNA. Of note, are the results obtained in groups exposed to AM251, which presence nullifies AEA's beneficial effects. In conclusion, this study promotes the efficacy of AEA in personalized cancer therapy, as suggested by its ability to drive tumor growth and metastasis, and strongly supports the use of zebrafish xenograft as an emerging model platform for cancer studies.
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24
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Przygodzka P, Soboska K, Sochacka E, Pacholczyk M, Braun M, Kassassir H, Papiewska-Pająk I, Kielbik M, Boncela J. Neuromedin U secreted by colorectal cancer cells promotes a tumour-supporting microenvironment. Cell Commun Signal 2022; 20:193. [PMID: 36482448 PMCID: PMC9733105 DOI: 10.1186/s12964-022-01003-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 11/04/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Neuromedin U (NMU) was identified as one of the hub genes closely related to colorectal cancer (CRC) progression and was recently shown to be a motility inducer in CRC cells. Its autocrine signalling through specific receptors increases cancer cell migration and invasiveness. Because of insufficient knowledge concerning NMU accessibility and action in the tumour microenvironment, its role in CRC remains poorly understood and its potential as a therapeutic target is still difficult to define. METHODS NMU expression in CRC tissue was detected by IHC. Data from The Cancer Genome Atlas were used to analyse gene expression in CRC. mRNA and protein expression was detected by real-time PCR, immunoblotting or immunofluorescence staining and analysed using confocal microscopy or flow cytometry. Proteome Profiler was used to detect changes in the profiles of cytokines released by cells constituting tumour microenvironment after NMU treatment. NMU receptor activity was monitored by detecting ERK1/2 activation. Transwell cell migration, wound healing assay and microtube formation assay were used to evaluate the effects of NMU on the migration of cancer cells, human macrophages and endothelial cells. RESULTS Our current study showed increased NMU levels in human CRC when compared to normal adjacent tissue. We detected a correlation between high NMUR1 expression and shorter overall survival of patients with CRC. We identified NMUR1 expression on macrophages, endothelial cells, platelets, and NMUR1 presence in platelet microparticles. We confirmed ERK1/2 activation by treatment of macrophages and endothelial cells with NMU, which induced pro-metastatic phenotypes of analysed cells and changed their secretome. Finally, we showed that NMU-stimulated macrophages increased the migratory potential of CRC cells. CONCLUSIONS We propose that NMU is involved in the modulation and promotion of the pro-metastatic tumour microenvironment in CRC through the activation of cancer cells and other tumour niche cells, macrophages and endothelial cells. Video abstract.
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Affiliation(s)
- Patrycja Przygodzka
- grid.413454.30000 0001 1958 0162Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Kamila Soboska
- grid.413454.30000 0001 1958 0162Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland ,grid.10789.370000 0000 9730 2769Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
| | - Ewelina Sochacka
- grid.413454.30000 0001 1958 0162Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland ,grid.10789.370000 0000 9730 2769Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
| | - Marcin Pacholczyk
- grid.6979.10000 0001 2335 3149Department of Systems Biology and Engineering, Silesian University of Technology, Akademicka 16, 44-100 Gliwice, Poland
| | - Marcin Braun
- grid.8267.b0000 0001 2165 3025Department of Pathology, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland
| | - Hassan Kassassir
- grid.413454.30000 0001 1958 0162Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Izabela Papiewska-Pająk
- grid.413454.30000 0001 1958 0162Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Michal Kielbik
- grid.413454.30000 0001 1958 0162Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
| | - Joanna Boncela
- grid.413454.30000 0001 1958 0162Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232 Lodz, Poland
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25
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EMR1/ADGRE1 Expression in Cancer Cells Upregulated by Tumor-Associated Macrophages Is Related to Poor Prognosis in Colorectal Cancer. Biomedicines 2022; 10:biomedicines10123121. [PMID: 36551877 PMCID: PMC9775542 DOI: 10.3390/biomedicines10123121] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
EMR1, a member of the adhesion G protein-coupled receptor family (ADGRE1), is a macrophage marker that is abnormally expressed in cancer cells. However, its clinical significance in colorectal cancer (CRC) is not well-known. In this investigation, EMR1 expression in tumor cells (EMR1-TC) was found in 91 (22.8%) of the 399 CRC samples tested by immunohistochemical staining and showed a significant relationship with lymph node metastasis. Furthermore, EMR1-TC was significantly associated with CD68+ CD163+ tumor-associated macrophages (TAMs), and CRC with a high combined EMR1-TC+CD68+CD163+ score showed worse recurrence-free survival prognosis. In an in vitro co-culture assay of colon cancer cells with myeloid cells, we found that EMR1 expression significantly upregulated in cancer cells was induced by macrophages. In addition, there was increased expression of M2 markers (CD163 and interleukin-6 & 10) in myeloid portion, while that of M1 markers (CD86 and iNOS) remained unchanged. Accordingly, upon treatment with M2 macrophage polarization inhibitors (O-ATP, trametinib, bardoxolone methyl), EMR1 expression reduced significantly, along with M2 markers (CD163 and interleukin-6 & 10). In conclusion, EMR1-TC was a high-risk factor for lymph node metastasis and correlated with poor recurrence free survival, particularly in patients with TAM-rich CRC. Furthermore, EMR1 expression in colon cancer cells may be related to M2 macrophage polarization and vice versa.
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26
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Jing F, Liu X, Chen X, Wu F, Gao Q. Tailoring biomaterials and applications targeting tumor-associated macrophages in cancers. Front Immunol 2022; 13:1049164. [PMID: 36439188 PMCID: PMC9691967 DOI: 10.3389/fimmu.2022.1049164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 10/25/2022] [Indexed: 04/04/2024] Open
Abstract
Tumor-associated macrophages (TAMs) play a critical role in supporting tumor growth and metastasis, taming host immunosurveillance, and augmenting therapeutic resistance. As the current treatment paradigms for cancers are generally insufficient to exterminate cancer cells, anti-cancer therapeutic strategies targeting TAMs have been developed. Since TAMs are highly heterogeneous and the pro-tumoral functions are mediated by phenotypes with canonical surface markers, TAM-associated materials exert anti-tumor functions by either inhibiting polarization to the pro-tumoral phenotype or decreasing the abundance of TAMs. Furthermore, TAMs in association with the immunosuppressive tumor microenvironment (TME) and tumor immunity have been extensively exploited in mounting evidence, and could act as carriers or accessory cells of anti-tumor biomaterials. Recently, a variety of TAM-based materials with the capacity to target and eliminate cancer cells have been increasingly developed for basic research and clinical practice. As various TAM-based biomaterials, including antibodies, nanoparticles, RNAs, etc., have been shown to have potential anti-tumor effects reversing the TME, in this review, we systematically summarize the current studies to fully interpret the specific properties and various effects of TAM-related biomaterials, highlighting the potential clinical applications of targeting the crosstalk among TAMs, tumor cells, and immune cells in anti-cancer therapy.
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Affiliation(s)
- Fangqi Jing
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiaowei Liu
- State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, China
| | - Xiaoxuan Chen
- Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Fanglong Wu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Frontier Innovation Center for Dental Medicine Plus, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Qinghong Gao
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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He Y, Han Y, Fan AH, Li D, Wang B, Ji K, Wang X, Zhao X, Lu Y. Multi-perspective comparison of the immune microenvironment of primary colorectal cancer and liver metastases. Lab Invest 2022; 20:454. [PMID: 36195882 PMCID: PMC9533561 DOI: 10.1186/s12967-022-03667-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 09/25/2022] [Indexed: 11/10/2022]
Abstract
BACKGROUND Liver metastases are a major contributor to the poor immunotherapy response in colorectal cancer patients. However, the distinctions in the immune microenvironment between primary tumors and liver metastases are poorly characterized. The goal of this study was to compare the expression profile of multiple immune cells to further analyze the similarities and differences between the microenvironments of liver metastases and the primary tumor. METHODS Tissues from 17 patients with colorectal cancer who underwent resection of primary and liver metastases was analyzed using multispectral immunofluorescence. The expression of multiple immune cells (CD8, Foxp3, CD68, CD163, CD20, CD11c, CD66b, CD56, PD-L1, INF-γ, Ki67 and VEGFR-2) in the tumor center (TC), tumor invasive front (< 150 µm from the tumor center, TF) and peritumoral region (≥ 150 µm from the tumor center, PT) was evaluated via comparison. The expression of CD68 and CD163 in different regions was further analyzed based on the cell colocalization method. In addition, different immune phenotypes were studied and compared according to the degree of CD8 infiltration. RESULTS The expression trends of 12 markers in the TF and TC regions were basically the same in the primary tumor and liver metastasis lesions. However, in comparison of the TF and PT regions, the expression trends were not identical between primary and liver metastases, especially CD163, which was more highly expressed in the PT region relative to the TF region. In the contrast of different space distribution, the expression of CD163 was higher in liver metastases than in the primary foci. Further analysis of CD68 and CD163 via colocalization revealed that the distribution of macrophages in liver metastases was significantly different from that in the primary foci, with CD68-CD163+ macrophages predominating in liver metastases. In addition, among the three immunophenotypes, CD163 expression was highest in the immune rejection phenotype. CONCLUSIONS The immune cells found in the primary tumors of colorectal cancer differed from those in liver metastases in terms of their spatial distribution. More immunosuppressive cells were present in the liver metastases, with the most pronounced differential distribution found for macrophages. CD68-CD163+ macrophages may be associated with intrahepatic immunosuppression and weak immunotherapeutic effects.
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Affiliation(s)
- Yangsong He
- Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Yanan Han
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - A-Hui Fan
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Danxiu Li
- Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Boda Wang
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Kun Ji
- Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China
| | - Xin Wang
- Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.
| | - Xiaodi Zhao
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Yuanyuan Lu
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
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Zheng SM, Chen H, Sha WH, Chen XF, Yin JB, Zhu XB, Zheng ZW, Ma J. Oxidized low-density lipoprotein stimulates CD206 positive macrophages upregulating CD44 and CD133 expression in colorectal cancer with high-fat diet. World J Gastroenterol 2022; 28:4993-5006. [PMID: 36160648 PMCID: PMC9494932 DOI: 10.3748/wjg.v28.i34.4993] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/15/2022] [Accepted: 08/22/2022] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND Oxidized low-density lipoprotein (ox-LDL), which is abnormally increased in the serum of colorectal cancer (CRC) patients consuming a high-fat diet (HFD), may be one of the risk factors for the development of CRC. Ox-LDL exerts a regulatory effect on macrophages and may influence CRC through the tumor microenvironment. The role of ox-LDL in CRC remains unclear.
AIM To investigate the role of ox-LDL through macrophages in HFD associated CRC.
METHODS The expression of ox-LDL and CD206 was detected in colorectal tissues of CRC patients with hyperlipidemia and HFD-fed mice by immunofluorescence. We stimulated the macrophages with 20 μg/mL ox-LDL and assessed the expression levels of CD206 and the cytokines by cell fluorescence and quantitative polymerase chain reaction. We further knocked down LOX-1, the surface receptor of ox-LDL, to confirm the function of ox-LDL in macrophages. Then, LoVo cells were co-cultured with the stimulated macrophages to analyze the CD44 and CD133 expression by western blot.
RESULTS The expression of ox-LDL and the CD206 was significantly increased in the stroma of colorectal tissues of CRC patients with hyperlipidemia, and also upregulated in the HFD-fed mice. Moreover, an increased level of CD206 and decreased level of inducible nitric oxide synthase were observed in macrophages after ox-LDL continuous stimulation. Such effects were inhibited when the surface receptor LOX-1 was knocked down in macrophages. Ox-LDL could induce CD206+ macrophages, which resulted in high expression of CD44 and CD133 in co-cultured LoVo cells.
CONCLUSION Ox-LDL stimulates CD206+ macrophages to upregulate CD44 and CD133 expression in HFD related CRC.
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Affiliation(s)
- Shi-Min Zheng
- Department of Gastroenterology and Hepatology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
- Medical College, Shantou University, Shantou 515041, Guangdong Province, China
| | - Hao Chen
- Department of Gastroenterology and Hepatology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
| | - Wei-Hong Sha
- Department of Gastroenterology and Hepatology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
- Medical College, Shantou University, Shantou 515041, Guangdong Province, China
- Medical College, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xiao-Fen Chen
- Department of Gastroenterology and Hepatology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
- Medical College, Shantou University, Shantou 515041, Guangdong Province, China
| | - Jian-Bin Yin
- Medical College, Southern Medical University, Guangzhou 510515, Guangdong Province, China
- Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, Guangdong Province, China
| | - Xiao-Bo Zhu
- Department of Gastroenterology and Hepatology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
| | - Zhong-Wen Zheng
- Department of Gastroenterology and Hepatology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
| | - Juan Ma
- Department of Gastroenterology and Hepatology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
- Medical College, Shantou University, Shantou 515041, Guangdong Province, China
- Medical College, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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Ryu HS, Lee JL, Kim CW, Yoon YS, Park IJ, Lim SB, Yu CS, Kim JH, Kim JC. Correlative Significance of Tumor Regression Grade and ypT Category in Patients Undergoing Preoperative Chemoradiotherapy for Locally Advanced Rectal Cancer. Clin Colorectal Cancer 2022; 21:212-219. [PMID: 35300935 DOI: 10.1016/j.clcc.2022.02.001] [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: 12/09/2021] [Revised: 01/28/2022] [Accepted: 02/07/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND In patients with locally advanced rectal cancer, the treatment response to preoperative chemoradiotherapy (PRCRT) varies, and the ypT stage may change as a result of tumor shrinkage. The purpose of this study was to evaluate the correlative significance and determine the prognostic value of tumor regression grade and ypT category staging systems. MATERIALS AND METHODS This retrospective observational study was conducted in a tertiary center. A total of 1240 patients with rectal cancer who underwent curative resection after PRCRT between January 2007 and December 2016 were consecutively included. RESULTS A significant association was found between the American Joint Committee on Cancer/College of American Pathology tumor regression grading system and ypT category, indicating a potential correlation between worse tumor regression grade and more advanced T stage (Cramer's V = 0.255, P < .001). The ypT stage and tumor regression grade were independent predictors of each other (P < .001). The good response group (tumor regression grades 0-1) had significantly higher 5-year disease-free survival (85.5% vs. 68.2%, P < .001) and overall survival (92.1% vs. 81.0%, P < .001) rates than the poor response group (tumor regression grades 2-3). However, the ypT and ypN categories were the most important independent prognostic factors for disease-free and overall survival. CONCLUSIONS Tumor regression grade and ypT category were significantly correlated. Although tumor regression grade alone is not definitive, it is closely related to the ypT stage and impacts oncologic outcomes. These findings should be taken into consideration when stratifying the prognosis of patients undergoing PRCRT.
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Affiliation(s)
- Hyo Seon Ryu
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jong Lyul Lee
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chan Wook Kim
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yong Sik Yoon
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - In Ja Park
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seok-Byung Lim
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chang Sik Yu
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ji Hun Kim
- Department of Pathology, Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea
| | - Jin Cheon Kim
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Identification of a Prognostic Transcriptome Signature for Hepatocellular Carcinoma with Lymph Node Metastasis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7291406. [PMID: 35847584 PMCID: PMC9279092 DOI: 10.1155/2022/7291406] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 05/12/2022] [Accepted: 05/31/2022] [Indexed: 11/17/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, and the prognosis of HCC patients with lymph node metastasis (LNM) is poor. However, robust biomarkers for predicting the prognosis of HCC LNM are still lacking. This study used weighted gene coexpression network analysis of GSE28248 (N = 80) microarray data to identify gene modules associated with HCC LNM and validated in GSE40367 dataset (N = 18). The prognosis-related genes in the HCC LNM module were further screened based on the prognostic curves of 371 HCC samples from TCGA. We finally developed a prognostic signature, PSG-30, as a prognostic-related biomarker in HCC LNM. The HCC subtypes identified by PSG-30-based consensus clustering analysis showed significant differences in prognosis, clinicopathological stage, m6A modification, ferroptosis activation, and immune characteristics. In addition, RAD54B was selected by regression model as an independent risk factor affecting the prognosis of HCC patients with LNM, and its expression was significantly positively correlated with tumor mutational burden and microsatellite instability in high-risk subtypes. Patients with high RAD54B expression had a better prognosis in the immune checkpoint inhibitor-treated cohorts but had a poor prognosis in the HCC sorafenib-treated group. The association of high RAD54B expression with LNM in breast cancer (BRCA) and cholangiocarcinoma and its prognostic effect in BRCA LNM cases suggest the value of RAD54B at the pancancer level. In conclusion, PSG-30 can effectively identify HCC LNM population with poor prognosis, and high-risk patients with high RAD54B expression may be more suitable for immunotherapy.
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Manzoor S, Muhammad JS, Maghazachi AA, Hamid Q. Autophagy: A Versatile Player in the Progression of Colorectal Cancer and Drug Resistance. Front Oncol 2022; 12:924290. [PMID: 35912261 PMCID: PMC9329589 DOI: 10.3389/fonc.2022.924290] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is among the topmost malignancies for both genders. Despite the high incidence rate and advances in diagnostic tools, treatment in many cases is still ineffective. Most cancerous lesions in CRC begin as benign, followed by the development of invasive forms and metastases. The development of CRC has been linked to defects in autophagy, which plays both a pro-and anti-tumor role and is mainly context-dependent. Autophagy suppression could enhance apoptosis via p53 activation, or autophagy also promotes tumor progression by maintaining tumor growth and increasing resistance to chemotherapy. Autophagy promotes the invasion and metastasis of CRC cells via increased epithelial-mesenchymal transition (EMT). Moreover, dysbiosis of gut microbiota upregulated autophagy and metastasis markers. Autophagy responses may also modulate the tumor microenvironment (TME) via regulating the differentiation process of several innate immune cells. Treatments that promote tumor cell death by stimulating or inhibiting autophagy could be beneficial if used as an adjunct treatment, but the precise role of various autophagy-modulating drugs in CRC patients is needed to be explored. In this article, we present an overview of the autophagy process and its role in the pathogenesis and therapeutic resistance of CRC. Also, we focused on the current understanding of the role of the EMT and TME, including its relation to gut microbiota and immune cells, in autophagic manipulation of CRC. We believe that there is a potential link between autophagy, TME, EMT, and drug resistance, suggesting that further studies are needed to explore this aspect.
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Affiliation(s)
- Shaista Manzoor
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Azzam A. Maghazachi
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Qutayba Hamid
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
- Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montreal, QC, Canada
- *Correspondence: Qutayba Hamid,
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32
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Helicobacter pylori promotes gastric cancer progression through the tumor microenvironment. Appl Microbiol Biotechnol 2022; 106:4375-4385. [PMID: 35723694 DOI: 10.1007/s00253-022-12011-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 05/26/2022] [Accepted: 06/01/2022] [Indexed: 02/05/2023]
Abstract
Gastric cancer (GC) is a leading type of cancer. Although immunotherapy has yielded important recent progress in the treatment of GC, the prognosis remains poor due to drug resistance and frequent recurrence and metastasis. There are multiple known risk factors for GC, and infection with Helicobacter pylori is one of the most significant. The mechanisms underlying the associations of H. pylori and GC remain unclear, but it is well known that infection can alter the tumor microenvironment (TME). The TME and the tumor itself constitute a complete ecosystem, and the TME plays critical roles in tumor progression, metastasis, and drug resistance. H. pylori infection can act synergistically with the TME to cause DNA damage and abnormal expression of multiple genes and activation of signaling pathways. It also modulates the host immune system in ways that enhance the proliferation and metastasis of tumor cells, promote epithelial-mesenchymal transition, inhibit apoptosis, and provide energy support for tumor growth. This review elaborates myriad ways that H. pylori infections promote the occurrence and progression of GC by influencing the TME, providing new directions for immunotherapy treatments for this important disease. KEY POINTS: • H. pylori infections cause DNA damage and affect the repair of the TME to DNA damage. • H. pylori infections regulate oncogenes or activate the oncogenic signaling pathways. • H. pylori infections modulate the immune system within the TME.
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Wei R, Zhou Y, Li C, Rychahou P, Zhang S, Titlow WB, Bauman G, Wu Y, Liu J, Wang C, Weiss HL, Evers BM, Wang Q. Ketogenesis Attenuates KLF5-Dependent Production of CXCL12 to Overcome the Immunosuppressive Tumor Microenvironment in Colorectal Cancer. Cancer Res 2022; 82:1575-1588. [PMID: 35247887 DOI: 10.1158/0008-5472.can-21-2778] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/21/2021] [Accepted: 02/04/2022] [Indexed: 11/16/2022]
Abstract
The dynamic composition of the tumor microenvironment (TME) can markedly alter the response to targeted therapies for colorectal cancer. Cancer-associated fibroblasts (CAF) are major components of TMEs that can direct and induce infiltration of immunosuppressive cells through secreted cytokines such as CXCL12. Ketogenic diets (KD) can inhibit tumor growth and enhance the anticancer effects of immune checkpoint blockade. However, the role of ketogenesis on the immunosuppressive TME is not known. Here, we show that decreased ketogenesis is a signature of colorectal cancer and that an increase in ketogenesis using a KD decreases CXCL12 production in tumors, serum, liver, and lungs. Moreover, increasing ketogenesis by overexpression of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) or treatment with the ketone body β-hydroxybutyrate markedly decreased expression of KLF5, which binds the CXCL12 promoter and induces CXCL12 expression in CAFs. KD decreased intratumoral accumulation of immunosuppressive cells, increased infiltration of natural killer and cytotoxic T cells, and enhanced the anticancer effects of PD-1 blockade in murine-derived colorectal cancer. Furthermore, increasing ketogenesis inhibited colorectal cancer migration, invasion, and metastasis in vitro and in vivo. Overall, ketogenesis is downregulated in the colorectal cancer TME, and increased ketogenesis represses KLF5-dependent CXCL12 expression to improve the immunosuppressive TME, which leads to the enhanced efficacy of immunotherapy and reduced metastasis. Importantly, this work demonstrates that downregulation of de novo ketogenesis in the TME is a critical step in colorectal cancer progression. SIGNIFICANCE This study identifies ketogenesis as a critical regulator of the tumor microenvironment in colorectal cancer and suggests the potential for ketogenic diets as a metabolic strategy to overcome immunosuppression and prolong survival. See related commentary by Montrose and Galluzzi, p. 1464.
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Affiliation(s)
- Ruozheng Wei
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| | - Yuning Zhou
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| | - Chang Li
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| | - Piotr Rychahou
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky
- Department of Surgery, University of Kentucky, Lexington, Kentucky
| | - Shulin Zhang
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky
| | - William B Titlow
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky
| | - Greg Bauman
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
| | - Yuanyuan Wu
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| | - Jinpeng Liu
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| | - Chi Wang
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| | - Heidi L Weiss
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| | - B Mark Evers
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky
- Department of Surgery, University of Kentucky, Lexington, Kentucky
| | - Qingding Wang
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky
- Department of Surgery, University of Kentucky, Lexington, Kentucky
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Stage I-IV Colorectal Cancer Prognosis Can Be Predicted by Type and Number of Intratumoral Macrophages and CLEVER-1 + Vessel Density. Cancers (Basel) 2021; 13:cancers13235988. [PMID: 34885098 PMCID: PMC8656733 DOI: 10.3390/cancers13235988] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/20/2021] [Accepted: 11/24/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Tumor-associated macrophages can either promote or prevent cancer growth depending on factors such as macrophage polarization status, tumor type, and disease stage. Macrophages and vessels interact with each other, and the number of lymphatic vessels also affects cancer survival. CLEVER-1 is a protein expressed both on immunosuppressive M2 macrophages and lymphatic vessels. The aim of this study was to validate our previous results regarding the prognostic role of CLEVER-1+ macrophages, CD68+ macrophages, and CLEVER-1+ lymphatic vessels in stage I–IV colorectal cancer. The results indicate that the prognostic role of tumor-associated macrophages and lymphatic vessels changes during disease progression. The findings resemble our earlier results, but are not completely equal, which may be due to the different types of tumor samples used in the two studies (whole section vs. tissue microarray). Abstract Macrophages, which are key players in the tumor microenvironment and affect the prognosis of many cancers, interact with lymphatic vessels in tumor tissue. However, the prognostic role of tumor-associated macrophages (TAM) and lymphatic vessels in human colorectal cancer (CRC) remains controversial. We investigated the prognostic role of CD68+ and CLEVER-1+ (common lymphatic endothelial and vascular endothelial receptor 1) TAMs in addition to CLEVER-1+ lymphatic vessels in 498 stage I–IV CRC patients. The molecular markers were detected by immunohistochemical (IHC) analysis. The results showed that, in early stage I CRC and in young patients (age below median, ≤67.4 years), a high number of CD68+ and CLEVER-1+ TAMs was associated with longer disease-specific survival (DSS). In early stage I CRC, high intratumoral CLEVER-1+ lymphatic vessel density (LVD) predicted a favorable prognosis, whereas the opposite pattern was observed in stage II CRC. The highest density of CLEVER-1+ lymphatic vessels was found in metastatic disease. The combination of intratumoral CLEVER-1+ lymphatic vesselhigh + CD68+ TAMlow was associated with poor DSS in stage I–IV rectal cancer. The present results indicate that the prognostic significance of intratumoral macrophages and CLEVER-1+ lymphatic vessels differs according to disease stage, reflecting the dynamic changes occurring in the tumor microenvironment during disease progression.
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Shin HC, Seo I, Jeong H, Byun SJ, Kim S, Bae SU, Kwon SY, Lee HW. Prognostic Impact of Tumor-Associated Macrophages on Long-Term Oncologic Outcomes in Colorectal Cancer. Life (Basel) 2021; 11:1240. [PMID: 34833118 PMCID: PMC8618174 DOI: 10.3390/life11111240] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/07/2021] [Accepted: 11/09/2021] [Indexed: 12/26/2022] Open
Abstract
This study evaluated the correlation between tumor-associated macrophages (TAMs) and long-term oncologic outcomes in colorectal cancer (CRC). We evaluated TAMs based on the expression of CD68, CD11c, and CD163 as optimal markers via immunohistochemistry in 148 patients with CRC who underwent surgical resection between September 1999 and August 2004. A high proportion of CD68-positive macrophages were associated with the occurrence of distant metastasis. A low proportion of CD11c-positive macrophages were associated with unfavorable overall survival (OS) and disease-free survival. CD11c-positive macrophages were found to act as independent prognostic factors for OS. An analysis of our long-term data indicated that TAMs are significantly associated with OS and prognosis in CRC.
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Affiliation(s)
- Hyeong Chan Shin
- Department of Pathology, Keimyung University School of Medicine, Dongsan Hospital, Daegu 42601, Korea; (H.C.S.); (H.J.); (S.Y.K.)
| | - Incheol Seo
- Department of Microbiology, Dongguk University College of Medicine, Gyeongju 38067, Korea;
| | - Hasong Jeong
- Department of Pathology, Keimyung University School of Medicine, Dongsan Hospital, Daegu 42601, Korea; (H.C.S.); (H.J.); (S.Y.K.)
| | - Sang Jun Byun
- Department of Radiation Oncology, Keimyung University School of Medicine, Dongsan Hospital, Daegu 42601, Korea;
| | - Shin Kim
- Department of Immunology, Keimyung University School of Medicine, Daegu 42601, Korea;
| | - Sung Uk Bae
- Department of Surgery, Keimyung University School of Medicine, Dongsan Hospital, Daegu 42601, Korea;
| | - Sun Young Kwon
- Department of Pathology, Keimyung University School of Medicine, Dongsan Hospital, Daegu 42601, Korea; (H.C.S.); (H.J.); (S.Y.K.)
| | - Hye Won Lee
- Department of Pathology, Keimyung University School of Medicine, Dongsan Hospital, Daegu 42601, Korea; (H.C.S.); (H.J.); (S.Y.K.)
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Tumour microenvironment: a non-negligible driver for epithelial-mesenchymal transition in colorectal cancer. Expert Rev Mol Med 2021; 23:e16. [PMID: 34758892 DOI: 10.1017/erm.2021.13] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cancer remains the leading cause of death worldwide, and metastasis is still the major cause of treatment failure for cancer patients. Epithelial-mesenchymal transition (EMT) has been shown to play a critical role in the metastasis cascade of epithelium-derived carcinoma. Tumour microenvironment (TME) refers to the local tissue environment in which tumour cells produce and live, including not only tumour cells themselves, but also fibroblasts, immune and inflammatory cells, glial cells and other cells around them, as well as intercellular stroma, micro vessels and infiltrated biomolecules from the nearby areas, which has been proved to widely participate in the occurrence and progress of cancer. Emerging and accumulating studies indicate that, on one hand, mesenchymal cells in TME can establish 'crosstalk' with tumour cells to regulate their EMT programme; on the other, EMT-tumour cells can create a favourable environment for their own growth via educating stromal cells. Recently, our group has conducted a series of studies on the interaction between tumour-associated macrophages (TAMs) and colorectal cancer (CRC) cells in TME, confirming that the interaction between TAMs and CRC cells mediated by cytokines or exosomes can jointly promote the metastasis of CRC by regulating the EMT process of tumour cells and the M2-type polarisation process of TAMs. Herein, we present an overview to describe the current knowledge about EMT in cancer, summarise the important role of TME in EMT, and provide an update on the mechanisms of TME-induced EMT in CRC, aiming to provide new ideas for understanding and resisting tumour metastasis.
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37
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Callejas BE, Blyth GAD, Jendzjowsky N, Wang A, Babbar A, Koro K, Wilson RJA, Kelly MM, Cobo ER, McKay DM. Interleukin-4 Programmed Macrophages Suppress Colitis and Do Not Enhance Infectious-Colitis, Inflammation-Associated Colon Cancer or Airway Hypersensitivity. Front Immunol 2021; 12:744738. [PMID: 34691050 PMCID: PMC8527087 DOI: 10.3389/fimmu.2021.744738] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 09/15/2021] [Indexed: 01/09/2023] Open
Abstract
The murine interleukin-4 treated macrophage (MIL4) exerts anti-inflammatory and pro-healing effects and has been shown to reduce the severity of chemical-induced colitis. Positing M(IL4) transfer as an anti-inflammatory therapy, the possibility of side-effects must be considered. Consequently, bone marrow-derived M(IL4)s were administered via intraperitoneal injection to mice concomitant with Citrobacter rodentium infection (infections colitis), azoxymethane/dextran sodium sulphate (AOM/DSS) treatment [a model of colorectal cancer (CRC)], or ovalbumin sensitization (airway inflammation). The impact of M(IL4) treatment on C. rodentium infectivity, colon histopathology, tumor number and size and tissue-specific inflammation was examined in these models. The anti-colitic effect of the M(IL4)s were confirmed in the di-nitrobenzene sulphonic acid model of colitis and the lumen-to-blood movement of 4kDa FITC-dextran and bacterial translocation to the spleen and liver was also improved by M(IL4) treatment. Analysis of the other models of disease, that represent comorbidities that can occur in human inflammatory bowel disease (IBD), revealed that M(IL4) treatment did not exaggerate the severity of any of the conditions. Rather, there was reduction in the size (but not number) of polyps in the colon of AOM/DSS-mice and reduced infectivity and inflammation in C. rodentium-infected mice in M(IL4)-treated mice. Thus, while any new therapy can have unforeseen side effects, our data confirm and extend the anti-colitic capacity of murine M(IL4)s and indicate that systemic delivery of one million M(IL4)s did not exaggerate disease in models of colonic or airways inflammation or colonic tumorigenesis.
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Affiliation(s)
- Blanca E Callejas
- Gastrointestinal Research Group, Inflammation Research Network and Host-Parasite Interaction Group, Department of Physiology and Pharmacology, Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Graham A D Blyth
- Department of Microbiology, Immunology and Infectious Disease, Cumming School of Medicine, University of Calgary and Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Nicholas Jendzjowsky
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Arthur Wang
- Gastrointestinal Research Group, Inflammation Research Network and Host-Parasite Interaction Group, Department of Physiology and Pharmacology, Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Anshu Babbar
- Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Konstantin Koro
- Department of Pathology and Laboratory Medicine, Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Richard J A Wilson
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Margaret M Kelly
- Department of Pathology and Laboratory Medicine, Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Eduardo R Cobo
- Production Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Derek M McKay
- Gastrointestinal Research Group, Inflammation Research Network and Host-Parasite Interaction Group, Department of Physiology and Pharmacology, Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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38
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Galbraith NJ, Wood C, Steele CW. Targeting Metastatic Colorectal Cancer with Immune Oncological Therapies. Cancers (Basel) 2021; 13:3566. [PMID: 34298779 PMCID: PMC8307556 DOI: 10.3390/cancers13143566] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/08/2021] [Accepted: 07/11/2021] [Indexed: 02/07/2023] Open
Abstract
Metastatic colorectal cancer carries poor prognosis, and current therapeutic regimes convey limited improvements in survival and high rates of detrimental side effects in patients that may not stand to benefit. Immunotherapy has revolutionised cancer treatment by restoring antitumoural mechanisms. However, the efficacy in metastatic colorectal cancer, is limited. A literature search was performed using Pubmed (Medline), Web of Knowledge, and Embase. Search terms included combinations of immunotherapy and metastatic colorectal cancer, primarily focusing on clinical trials in humans. Analysis of these studies included status of MMR/MSS, presence of combination strategies, and disease control rate and median overall survival. Evidence shows that immune checkpoint inhibitors, such as anti-PD1 and anti-PD-L1, show efficacy in less than 10% of patients with microsatellite stable, MMR proficient colorectal cancer. In the small subset of patients with microsatellite unstable, MMR deficient cancers, response rates were 40-50%. Combination strategies with immunotherapy are under investigation but have not yet restored antitumoural mechanisms to permit durable disease regression. Immunotherapy provides the potential to offer additional strategies to established chemotherapeutic regimes in metastatic colorectal cancer. Further research needs to establish which adjuncts to immune checkpoint inhibition can unpick resistance, and better predict which patients are likely to respond to individualised therapies to not just improve response rates but to temper unwarranted side effects.
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Affiliation(s)
- Norman J. Galbraith
- Academic Department of Surgery, University of Glasgow, Level 2 New Lister Building, Glasgow Royal Infirmary, 10-16 Alexandra Parade, Glasgow G31 2ER, UK; (C.W.); (C.W.S.)
| | - Colin Wood
- Academic Department of Surgery, University of Glasgow, Level 2 New Lister Building, Glasgow Royal Infirmary, 10-16 Alexandra Parade, Glasgow G31 2ER, UK; (C.W.); (C.W.S.)
| | - Colin W. Steele
- Academic Department of Surgery, University of Glasgow, Level 2 New Lister Building, Glasgow Royal Infirmary, 10-16 Alexandra Parade, Glasgow G31 2ER, UK; (C.W.); (C.W.S.)
- Institute of Cancer Sciences, Beatson Institute, Garscube Campus, Switchback Road, Bearsden G61 1BD, UK
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Inagaki K, Kunisho S, Takigawa H, Yuge R, Oka S, Tanaka S, Shimamoto F, Chayama K, Kitadai Y. Role of tumor-associated macrophages at the invasive front in human colorectal cancer progression. Cancer Sci 2021; 112:2692-2704. [PMID: 33964093 PMCID: PMC8253270 DOI: 10.1111/cas.14940] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/30/2021] [Accepted: 04/30/2021] [Indexed: 12/15/2022] Open
Abstract
Macrophages are an essential component of antitumor activity; however, the role of tumor‐associated macrophages (TAMs) in colorectal cancer (CRC) remains controversial. Here, we elucidated the role of TAMs in CRC progression, especially at the early stage. We assessed the TAM number, phenotype, and distribution in 53 patients with colorectal neoplasia, including intramucosal neoplasia, submucosal invasive colorectal cancer (SM‐CRC), and advanced cancer, using double immunofluorescence for CD68 and CD163. Next, we focused on the invasive front in SM‐CRC and association between TAMs and clinicopathological features including lymph node metastasis, which were evaluated in 87 SM‐CRC clinical specimens. The number of M2 macrophages increased with tumor progression and dynamic changes were observed with respect to the number and phenotype of TAMs at the invasive front, especially at the stage of submucosal invasion. A high M2 macrophage count at the invasive front was correlated with lymphovascular invasion, low histological differentiation, and lymph node metastasis; a low M1 macrophage count at the invasive front was correlated with lymph node metastasis. Furthermore, receiver operating characteristic curve analysis revealed that the M2/M1 ratio was a better predictor of the risk of lymph node metastasis than the pan‐, M1, or M2 macrophage counts at the invasive front. These results suggested that TAMs at the invasive front might play a role in CRC progression, especially at the early stages. Therefore, evaluating the TAM phenotype, number, and distribution may be a potential predictor of metastasis, including lymph node metastasis, and TAMs may be a potential CRC therapeutic target.
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Affiliation(s)
- Katsuaki Inagaki
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Minami-ku, Hiroshima, Japan
| | - Shoma Kunisho
- Department of Health Sciences, Faculty of Human Culture and Science, Prefectural University of Hiroshima, Minami-ku, Hiroshima, Japan
| | - Hidehiko Takigawa
- Department of Endoscopy, Hiroshima University Hospital, Minami-ku, Hiroshima, Japan
| | - Ryo Yuge
- Department of Endoscopy, Hiroshima University Hospital, Minami-ku, Hiroshima, Japan
| | - Shiro Oka
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Minami-ku, Hiroshima, Japan
| | - Shinji Tanaka
- Department of Endoscopy, Hiroshima University Hospital, Minami-ku, Hiroshima, Japan
| | - Fumio Shimamoto
- Faculty of Health Sciences, Hiroshima Shudo University, Asaminami-ku, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Minami-ku, Hiroshima, Japan
| | - Yasuhiko Kitadai
- Department of Health Sciences, Faculty of Human Culture and Science, Prefectural University of Hiroshima, Minami-ku, Hiroshima, Japan
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