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1
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Sato Y. The Role of Tregs in the Tumor Microenvironment. Biomedicines 2025; 13:1173. [PMID: 40427000 DOI: 10.3390/biomedicines13051173] [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: 03/29/2025] [Revised: 05/06/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
The tumor microenvironment (TME) is a unique ecosystem that surrounds tumor tissues. The TME is composed of extracellular matrix, immune cells, blood vessels, stromal cells, and fibroblasts. These environments enhance cancer development, progression, and metastasis. Recent success in immune checkpoint blockade also supports the importance of the TME and immune cells residing in the tumor niche. Although the TME can be identified in almost all cancer types, the role of the TME may not be similar among different cancer types. Regulatory T cells (Tregs) play a pivotal role in immune homeostasis and are frequently found in the TME. Owing to their suppressive function, Tregs are often considered unfavorable factors that allow the immune escape of cancer cells. However, the presence of Tregs is not always linked to an unfavorable phenotype, which can be explained by the heterogeneity and plasticity of Tregs. In this review, the current understanding of the role of Tregs in TME is addressed for each cancer cell type. Moreover, recently a therapeutic approach targeting Tregs infiltrating in the TME has been developed including drug antibody conjugate, immunotoxin, and FOXP3 inhibiting peptide. Thus, understanding the role of Tregs in the TME may lead to the development of novel therapies that directly target the TME.
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Affiliation(s)
- Yohei Sato
- Laboratory of Immune Cell Therapy, Project Research Unit, The Jikei University School of Medicine, Tokyo 105-8461, Japan
- Core Research Facilities, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo 105-8461, Japan
- Immunology and Allergy Research Unit, Division of Otorhinolaryngology Head & Neck Surgery, Faculty of Medicine, University of Fukui, Fukui 910-1193, Japan
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2
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Yu H, Yang R, Li M, Li D, Xu Y. The role of Treg cells in colorectal cancer and the immunotherapy targeting Treg cells. Front Immunol 2025; 16:1574327. [PMID: 40308582 PMCID: PMC12040624 DOI: 10.3389/fimmu.2025.1574327] [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: 02/10/2025] [Accepted: 03/28/2025] [Indexed: 05/02/2025] Open
Abstract
Colorectal cancer (CRC) is among the most prevalent and lethal cancers globally, accounting for approximately 10% of all cancer cases and deaths. Regulatory T (Treg) cells, which accumulate in CRC tissue, suppress anti-tumor immune responses and facilitate tumor progression. This review discusses Treg cell origins and functions, along with the mechanisms by which Tregs influence CRC development. In addition, we highlight therapeutic strategies targeting Tregs-such as immune checkpoint inhibitors and combinatorial approaches-to enhance effector T cell responses. A deeper understanding of Treg-mediated immunosuppression in CRC may inform the design of more effective immunotherapies and precision medicine strategies.
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Affiliation(s)
- Hanqing Yu
- Department of General Surgery, The Sixth People’s Hospital of Huizhou, Huizhou, China
| | - Ruiliang Yang
- Department of General Surgery, The Sixth People’s Hospital of Huizhou, Huizhou, China
| | - Meixiang Li
- Department of General Surgery, The Sixth People’s Hospital of Huizhou, Huizhou, China
| | - Dan Li
- Department of Internal Medicine, The Sixth People’s Hospital of Huizhou, Huizhou, China
| | - Yuanqing Xu
- Department of General Surgery, The Sixth People’s Hospital of Huizhou, Huizhou, China
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3
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Sun Y, Wei L, Liu H, Zong G, Xia Z, Li X, Yin Z, Huang D, Zhang Y. Deficiency of myeloid discoidin domain receptor 2 aggravates melanoma lung and bone metastasis. Invest New Drugs 2025; 43:50-59. [PMID: 39725777 DOI: 10.1007/s10637-024-01496-2] [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: 11/12/2024] [Accepted: 12/19/2024] [Indexed: 12/28/2024]
Abstract
Melanoma, one of the most prevalent cancers worldwide, frequently metastasizes to the lung and bones. Tumor-associated macrophages play essential roles in melanoma metastasis but the underlying mechanism remains obscure. We previously demonstrated that specific knockout of Ddr2, a receptor tyrosine kinase, exacerbates systemic inflammation via modulating macrophage repolarization. To investigate whether myeloid Ddr2 regulates melanoma growth and metastasis, we injected B16BL6 melanoma cells into Ddr2LysM (cKO) mice via subcutaneous neck, tail vein, and left ventricle, respectively. We found that the growth of melanoma cells in cKO mice was significantly retarded, as demonstrated by the subcutaneous transplantation tumor model. Unexpectedly, the melanoma metastasis to the lung or bone was significantly stimulated in cKO mice, indicating the complicated role of Ddr2 in macrophages in melanoma development. Furthermore, Ddr2 in macrophages regulated the migration of B16BL6 cells in the co-culture system. Bioinformatics analysis showed that Ddr2 expression correlates with improved prognostic outcomes in melanoma, and high expression of Ddr2 is protective in melanoma metastasis. Our results enrich the current knowledge of Ddr2 in tumor biology and indicate that more consideration should be taken when applying Ddr2 inhibition as a melanoma treatment strategy.
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Affiliation(s)
- Yue Sun
- Department of Orthopaedics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Liangliang Wei
- Honghui Hospital, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Hao Liu
- Department of Orthopaedics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Gaoyang Zong
- Department of Orthopaedics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Zhihao Xia
- Honghui Hospital, Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Xiangyang Li
- Department of Orthopaedics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Zhanhai Yin
- Department of Orthopaedics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Dageng Huang
- Honghui Hospital, Xi'an Jiaotong University, Xi'an, People's Republic of China.
| | - Yan Zhang
- Department of Orthopaedics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
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Singer M, Valerin J, Zhang Z, Zhang Z, Dayyani F, Yaghmai V, Choi A, Imagawa D, Abi-Jaoudeh N. Promising Cellular Immunotherapy for Colorectal Cancer Using Classical Dendritic Cells and Natural Killer T Cells. Cells 2025; 14:166. [PMID: 39936958 PMCID: PMC11817869 DOI: 10.3390/cells14030166] [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: 12/30/2024] [Revised: 01/15/2025] [Accepted: 01/20/2025] [Indexed: 02/13/2025] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality around the world. Despite advances in surgery, chemotherapy, and targeted therapies, the prognosis for patients with metastatic or advanced CRC remains poor. Immunotherapies comprising immune checkpoint inhibitors showed disappointing responses in metastatic CRC (mCRC). However, cellular immunotherapy, specifically using classical dendritic cells (cDCs), may hold unique promise in immune recognition for CRC antigens. cDCs are substantial players in immune recognition and are instrumental in orchestrating innate and adaptive immune responses by processing and presenting tumor antigens to effector cells. Natural killer T (NKT) cells are insufficiently studied but unique effector cells because of their ability to bridge innate and adaptive immune reactions and the crosstalk with dendritic cells in cancer. This review explores the therapeutic potential of using both cDCs and NKT cells as a synergistic therapy in CRC, focusing on their biological roles, strategies for harnessing their capabilities, clinical applications, and the challenges within the tumor microenvironment. Both cDCs and NKT cells can be used as a new effective approach for cell-based therapies in cancers to provide a new hope for CRC patients that are challenging to treat.
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Affiliation(s)
- Mahmoud Singer
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA
| | - Jennifer Valerin
- Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697, USA (A.C.)
| | - Zhuoli Zhang
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA
| | - Zigeng Zhang
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA
| | - Farshid Dayyani
- Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697, USA (A.C.)
| | - Vahid Yaghmai
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA
| | - April Choi
- Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697, USA (A.C.)
| | - David Imagawa
- Department of Surgery, University of California Irvine, Orange, CA 92697, USA
| | - Nadine Abi-Jaoudeh
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA
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Padilha A, Jones E, Cutting S, Godkin A, Gallimore A, Parry L. Regulatory T Cells Play a Role in Determining the Tumourigenicity of the Intestinal Stem Cell Niche. GASTRO HEP ADVANCES 2024; 4:100559. [PMID: 39877864 PMCID: PMC11773477 DOI: 10.1016/j.gastha.2024.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 09/23/2024] [Indexed: 01/31/2025]
Affiliation(s)
- Ana Padilha
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, UK
| | - Emma Jones
- Systems Immunity University Research Institute/Division of Infection and Immunity, School of Medicine, Cardiff, UK
| | - Scott Cutting
- Systems Immunity University Research Institute/Division of Infection and Immunity, School of Medicine, Cardiff, UK
| | - Andrew Godkin
- Systems Immunity University Research Institute/Division of Infection and Immunity, School of Medicine, Cardiff, UK
| | - Awen Gallimore
- Systems Immunity University Research Institute/Division of Infection and Immunity, School of Medicine, Cardiff, UK
| | - Lee Parry
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, UK
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Aruquipa MPS, Donadio MS, Peixoto RD. Liver metastasis and resistance to immunotherapy in microsatellite stable colorectal cancer. A literature review. Ecancermedicalscience 2024; 18:1771. [PMID: 39430087 PMCID: PMC11489097 DOI: 10.3332/ecancer.2024.1771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Indexed: 10/22/2024] Open
Abstract
Background Microsatellite stable (MSS) metastatic colorectal cancer (CRC) remains predominantly managed with chemotherapy. The use of immunotherapy, whether alone or in combination with other systemic or local treatments, displays limited success, especially in the context of active liver metastases (LM). The mechanisms responsible for this resistance are not fully understood. Methods We conducted a comprehensive search across electronic databases such as Medline, PubMed, Google Scholar and ScienceDirect. This search targeted translational studies evaluating the liver tumour immune microenvironment and immune tolerance mechanisms in CRC with LM and prospective studies that assessed immunotherapy either as a standalone treatment or in combination with other systemic or local therapies for patients diagnosed with MSS CRC. Our primary objectives included elucidating the mechanisms of resistance originating from LM in a non-systematic literature review and presenting a summary of the outcomes observed in prospective trials utilising immune checkpoint inhibitors (ICIs), with a focus on the presence of LM. Findings There were 16 prospective trials evaluating immunotherapy for metastatic CRC comprising 1,713 patients. Response rates to immunotherapy inpatients with colorectal liver metastases (CRLM) varied from 0% to 23%. Overall, reduced or null responses to immunotherapy in the presence of liver metastasis in comparison to patients without liver involvement were observed. Conclusion Studies consistently show the resistance derived from classical ICI, both alone and in combination with other systemic treatments in patients with CRLM. The design of upcoming trials using immunotherapy should consider LM as a stratification factor or contemplate excluding patients with liver involvement.
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Affiliation(s)
| | - Mauro S Donadio
- Gastrointestinal Oncology Department, Oncoclinicas, São Paulo 04513-100, Brazil
- https://orcid.org/0000-0002-4705-4802
| | - Renata D Peixoto
- BC Cancer Agency, Vancouver, BC V5Z 4E6, Canada
- https://orcid.org/0000-0003-0053-7951
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Chen Q, Shen M, Yan M, Han X, Mu S, Li Y, Li L, Wang Y, Li S, Li T, Wang Y, Wang W, Wei Z, Hu C, Jin A. Targeting tumor-infiltrating CCR8 + regulatory T cells induces antitumor immunity through functional restoration of CD4 + T convs and CD8 + T cells in colorectal cancer. J Transl Med 2024; 22:709. [PMID: 39080766 PMCID: PMC11290082 DOI: 10.1186/s12967-024-05518-8] [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: 05/12/2024] [Accepted: 07/18/2024] [Indexed: 08/02/2024] Open
Abstract
BACKGROUND Chemokine (C-C motif) receptor 8 (CCR8) is a chemokine receptor selectively expressed on tumor-infiltrating regulatory T cells (Tregs). Strong immunosuppression mediated by CCR8+ Tregs observed in breast and lung malignancies suggest for their functional significance in cancer therapy. To date, detailed characterization of tumor-infiltrating CCR8+ Tregs cells in colorectal cancer (CRC) is limited. METHODS To study the presence and functional involvement of CCR8+ Tregs in CRC, we analyzed the proportions of CCR8-expressing T cells in different T cell subsets in tumor and adjacent normal tissues and peripheral blood mononuclear cells (PBMCs) from CRC patients by Flow cytometry. Also, we compared the distribution of CCR8+ T cells in malignant tissues and peripheral lymphoid organs from a subcutaneous CRC murine model. Bioinformatic analysis was performed to address the significance of CCR8 expression levels in CRC prognosis, immune regulatory gene expression profiles and potential molecular mechanisms associated with CCR8+ Tregs in CRC tumors. Further, we administrated an anti-CCR8 monoclonal antibody to CT26 tumor-bearing mice and examined the antitumor activity of CCR8-targeted therapy both in vivo and in an ex vivo confirmative model. RESULTS Here, we showed that Tregs was predominantly presented in the tumors of CRC patients (13.4 ± 5.8, p < 0.0001) and the CRC subcutaneous murine model (35.0 ± 2.6, p < 0.0001). CCR8 was found to be preferentially expressed on these tumor-infiltrating Tregs (CRC patients: 63.6 ± 16.0, p < 0.0001; CRC murine model: 65.3 ± 9.5, p < 0.0001), which correlated with poor survival. We found that majority of the CCR8+ Tregs expressed activation markers and exhibited strong suppressive functions. Treatment with anti-CCR8 antibody hampered the growth of subcutaneous CRC tumor through effectively restoring the anti-tumor immunity of CD4+ conventional T cells (CD4+ Tconvs) and CD8+ T cells, which was confirmed in the ex vivo examinations. CONCLUSIONS Collectively, these findings illustrate the importance of CCR8+ Tregs for an immunosuppressive microenvironment in CRC tumors by functional inhibition of CD4+ Tconvs and CD8+ T cells, and suggest for the applicable value of CCR8-targeted therapy for CRC.
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Affiliation(s)
- Qian Chen
- Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400010, China
- Chongqing Key Laboratory of Tumor Immune Regulation and Immune Intervention, Chongqing Medical University, Chongqing, 400010, China
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Meiying Shen
- Chongqing Key Laboratory of Tumor Immune Regulation and Immune Intervention, Chongqing Medical University, Chongqing, 400010, China
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Min Yan
- Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400010, China
- Chongqing Key Laboratory of Tumor Immune Regulation and Immune Intervention, Chongqing Medical University, Chongqing, 400010, China
| | - Xiaojian Han
- Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400010, China
- Chongqing Key Laboratory of Tumor Immune Regulation and Immune Intervention, Chongqing Medical University, Chongqing, 400010, China
| | - Song Mu
- Department of Colorectal Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, Guizhou, China
| | - Ya Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Luo Li
- Chongqing Key Laboratory of Tumor Immune Regulation and Immune Intervention, Chongqing Medical University, Chongqing, 400010, China
- Department of Clinical Laboratory, Women and Children's Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Yingming Wang
- Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400010, China
- Chongqing Key Laboratory of Tumor Immune Regulation and Immune Intervention, Chongqing Medical University, Chongqing, 400010, China
| | - Shenglong Li
- School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400010, China
| | - Tingting Li
- Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400010, China
- Chongqing Key Laboratory of Tumor Immune Regulation and Immune Intervention, Chongqing Medical University, Chongqing, 400010, China
| | - Yingying Wang
- Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400010, China
- Chongqing Key Laboratory of Tumor Immune Regulation and Immune Intervention, Chongqing Medical University, Chongqing, 400010, China
| | - Wang Wang
- Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400010, China
- Chongqing Key Laboratory of Tumor Immune Regulation and Immune Intervention, Chongqing Medical University, Chongqing, 400010, China
| | - Zhengqiang Wei
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Chao Hu
- Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400010, China.
- Chongqing Key Laboratory of Tumor Immune Regulation and Immune Intervention, Chongqing Medical University, Chongqing, 400010, China.
| | - Aishun Jin
- Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400010, China.
- Chongqing Key Laboratory of Tumor Immune Regulation and Immune Intervention, Chongqing Medical University, Chongqing, 400010, China.
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8
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González A, Fullaondo A, Odriozola A. Microbiota-associated mechanisms in colorectal cancer. ADVANCES IN GENETICS 2024; 112:123-205. [PMID: 39396836 DOI: 10.1016/bs.adgen.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, ranking third in terms of incidence and second as a cause of cancer-related death. There is growing scientific evidence that the gut microbiota plays a key role in the initiation and development of CRC. Specific bacterial species and complex microbial communities contribute directly to CRC pathogenesis by promoting the neoplastic transformation of intestinal epithelial cells or indirectly through their interaction with the host immune system. As a result, a protumoural and immunosuppressive environment is created conducive to CRC development. On the other hand, certain bacteria in the gut microbiota contribute to protection against CRC. In this chapter, we analysed the relationship of the gut microbiota to CRC and the associations identified with specific bacteria. Microbiota plays a key role in CRC through various mechanisms, such as increased intestinal permeability, inflammation and immune system dysregulation, biofilm formation, genotoxin production, virulence factors and oxidative stress. Exploring the interaction between gut microbiota and tumourigenesis is essential for developing innovative therapeutic approaches in the fight against CRC.
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Affiliation(s)
- Adriana González
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain.
| | - Asier Fullaondo
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | - Adrian Odriozola
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
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Ouyang J, Hu S, Zhu Q, Li C, Kang T, Xie W, Wang Y, Li Y, Lu Y, Qi J, Xia M, Chen J, Yang Y, Sun Y, Gao T, Ye L, Liang Q, Pan Y, Zhu C. RANKL/RANK signaling recruits Tregs via the CCL20-CCR6 pathway and promotes stemness and metastasis in colorectal cancer. Cell Death Dis 2024; 15:437. [PMID: 38902257 PMCID: PMC11190233 DOI: 10.1038/s41419-024-06806-3] [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: 01/16/2024] [Revised: 05/24/2024] [Accepted: 06/03/2024] [Indexed: 06/22/2024]
Abstract
TNF receptor superfamily member 11a (TNFRSF11a, RANK) and its ligand TNF superfamily member 11 (TNFRSF11, RANKL) are overexpressed in many malignancies. However, the clinical importance of RANKL/RANK in colorectal cancer (CRC) is mainly unknown. We examined CRC samples and found that RANKL/RANK was elevated in CRC tissues compared with nearby normal tissues. A higher RANKL/RANK expression was associated with a worse survival rate. Furthermore, RANKL was mostly produced by regulatory T cells (Tregs), which were able to promote CRC advancement. Overexpression of RANK or addition of RANKL significantly increased the stemness and migration of CRC cells. Furthermore, RANKL/RANK signaling stimulated C-C motif chemokine ligand 20 (CCL20) production by CRC cells, leading to Treg recruitment and boosting tumor stemness and malignant progression. This recruitment process was accomplished by CCL20-CCR6 interaction, demonstrating a connection between CRC cells and immune cells. These findings suggest an important role of RANKL/RANK in CRC progression, offering a potential target for CRC prevention and therapy.
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Affiliation(s)
- Jing Ouyang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Shuang Hu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Qingqing Zhu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Chenxin Li
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Tingting Kang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Wenlin Xie
- Pathological Diagnostic Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Yun Wang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Yan Li
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Yingsi Lu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Junhua Qi
- Department of Clinical Medical Laboratory, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Ming Xia
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Jinrun Chen
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Yingqian Yang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
| | - Yazhou Sun
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
- Clinical Big Data Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Tianshun Gao
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China
- Clinical Big Data Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China
| | - Liping Ye
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China.
| | - Qian Liang
- Department of Spine Surgery, The First Affiliated Hospital of Shenzhen University, The Shenzhen Second People's Hospital, Shenzhen, China.
| | - Yihang Pan
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China.
| | - Chengming Zhu
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, 518107, Guangdong, China.
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10
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Burgos-Molina AM, Téllez Santana T, Redondo M, Bravo Romero MJ. The Crucial Role of Inflammation and the Immune System in Colorectal Cancer Carcinogenesis: A Comprehensive Perspective. Int J Mol Sci 2024; 25:6188. [PMID: 38892375 PMCID: PMC11172443 DOI: 10.3390/ijms25116188] [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: 05/04/2024] [Revised: 05/30/2024] [Accepted: 05/31/2024] [Indexed: 06/21/2024] Open
Abstract
Chronic inflammation drives the growth of colorectal cancer through the dysregulation of molecular pathways within the immune system. Infiltration of immune cells, such as macrophages, into tumoral regions results in the release of proinflammatory cytokines (IL-6; IL-17; TNF-α), fostering tumor proliferation, survival, and invasion. Tumors employ various mechanisms to evade immune surveillance, effectively 'cloaking' themselves from detection and subsequent attack. A comprehensive understanding of these intricate molecular interactions is paramount for advancing novel strategies aimed at modulating the immune response against cancer.
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Affiliation(s)
- Antonio Manuel Burgos-Molina
- Surgery, Biochemistry and Immunology Department, School of Medicine, University of Malaga, 29010 Málaga, Spain; (A.M.B.-M.); (T.T.S.); (M.J.B.R.)
| | - Teresa Téllez Santana
- Surgery, Biochemistry and Immunology Department, School of Medicine, University of Malaga, 29010 Málaga, Spain; (A.M.B.-M.); (T.T.S.); (M.J.B.R.)
- Research Network on Chronic Diseases, Primary Care, and Health Promotion (RICAPPS), Carlos III Health Institute (Instituto de Salud Carlos III), Av. de Monforte de Lemos, 5, 28029 Madrid, Spain
- Málaga Biomedical Research Institute (Instituto de Investigación Biomédica de Málaga, IBIMA), Calle Doctor Miguel Díaz Recio, 28, 29010 Málaga, Spain
| | - Maximino Redondo
- Surgery, Biochemistry and Immunology Department, School of Medicine, University of Malaga, 29010 Málaga, Spain; (A.M.B.-M.); (T.T.S.); (M.J.B.R.)
- Research Network on Chronic Diseases, Primary Care, and Health Promotion (RICAPPS), Carlos III Health Institute (Instituto de Salud Carlos III), Av. de Monforte de Lemos, 5, 28029 Madrid, Spain
- Málaga Biomedical Research Institute (Instituto de Investigación Biomédica de Málaga, IBIMA), Calle Doctor Miguel Díaz Recio, 28, 29010 Málaga, Spain
- Research Unit, Hospital Costa del Sol, Autovía A-7, km 187, 29603 Marbella, Spain
| | - María José Bravo Romero
- Surgery, Biochemistry and Immunology Department, School of Medicine, University of Malaga, 29010 Málaga, Spain; (A.M.B.-M.); (T.T.S.); (M.J.B.R.)
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11
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Mitra A, Kumar A, Amdare NP, Pathak R. Current Landscape of Cancer Immunotherapy: Harnessing the Immune Arsenal to Overcome Immune Evasion. BIOLOGY 2024; 13:307. [PMID: 38785789 PMCID: PMC11118874 DOI: 10.3390/biology13050307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 04/24/2024] [Accepted: 04/24/2024] [Indexed: 05/25/2024]
Abstract
Cancer immune evasion represents a leading hallmark of cancer, posing a significant obstacle to the development of successful anticancer therapies. However, the landscape of cancer treatment has significantly evolved, transitioning into the era of immunotherapy from conventional methods such as surgical resection, radiotherapy, chemotherapy, and targeted drug therapy. Immunotherapy has emerged as a pivotal component in cancer treatment, harnessing the body's immune system to combat cancer and offering improved prognostic outcomes for numerous patients. The remarkable success of immunotherapy has spurred significant efforts to enhance the clinical efficacy of existing agents and strategies. Several immunotherapeutic approaches have received approval for targeted cancer treatments, while others are currently in preclinical and clinical trials. This review explores recent progress in unraveling the mechanisms of cancer immune evasion and evaluates the clinical effectiveness of diverse immunotherapy strategies, including cancer vaccines, adoptive cell therapy, and antibody-based treatments. It encompasses both established treatments and those currently under investigation, providing a comprehensive overview of efforts to combat cancer through immunological approaches. Additionally, the article emphasizes the current developments, limitations, and challenges in cancer immunotherapy. Furthermore, by integrating analyses of cancer immunotherapy resistance mechanisms and exploring combination strategies and personalized approaches, it offers valuable insights crucial for the development of novel anticancer immunotherapeutic strategies.
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Affiliation(s)
- Ankita Mitra
- Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA
| | - Anoop Kumar
- Molecular Diagnostic Laboratory, National Institute of Biologicals, Noida 201309, Uttar Pradesh, India
| | - Nitin P. Amdare
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
| | - Rajiv Pathak
- Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
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12
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Sharma S, Singh N, Turk AA, Wan I, Guttikonda A, Dong JL, Zhang X, Opyrchal M. Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions. World J Gastroenterol 2024; 30:1815-1835. [PMID: 38659481 PMCID: PMC11036501 DOI: 10.3748/wjg.v30.i13.1815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/22/2024] [Accepted: 03/13/2024] [Indexed: 04/03/2024] Open
Abstract
Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.
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Affiliation(s)
- Samantha Sharma
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Naresh Singh
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Anita Ahmed Turk
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Isabella Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Akshay Guttikonda
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Julia Lily Dong
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Xinna Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Mateusz Opyrchal
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
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13
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He R, Huang S, Lu J, Su L, Gao X, Chi H. Unveiling the immune symphony: decoding colorectal cancer metastasis through immune interactions. Front Immunol 2024; 15:1362709. [PMID: 38415252 PMCID: PMC10897008 DOI: 10.3389/fimmu.2024.1362709] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 01/29/2024] [Indexed: 02/29/2024] Open
Abstract
Colorectal cancer (CRC), known for its high metastatic potential, remains a leading cause of cancer-related death. This review emphasizes the critical role of immune responses in CRC metastasis, focusing on the interaction between immune cells and tumor microenvironment. We explore how immune cells, through cytokines, chemokines, and growth factors, contribute to the CRC metastasis cascade, underlining the tumor microenvironment's role in shaping immune responses. The review addresses CRC's immune evasion tactics, especially the upregulation of checkpoint inhibitors like PD-1 and CTLA-4, highlighting their potential as therapeutic targets. We also examine advanced immunotherapies, including checkpoint inhibitors and immune cell transplantation, to modify immune responses and enhance treatment outcomes in CRC metastasis. Overall, our analysis offers insights into the interplay between immune molecules and the tumor environment, crucial for developing new treatments to control CRC metastasis and improve patient prognosis, with a specific focus on overcoming immune evasion, a key aspect of this special issue.
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Affiliation(s)
- Ru He
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Shangke Huang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jiaan Lu
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Lanqian Su
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Xinrui Gao
- Department of Oncology, Yongchuan Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Hao Chi
- Clinical Medical College, Southwest Medical University, Luzhou, China
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14
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Luo H, Luo J, Ding N, Zhang T, He Y. BICDL1 Predicts Poor Prognosis and is Correlated with Methylation and Immune Infiltration in Colorectal Cancer. Pharmgenomics Pers Med 2023; 16:1109-1126. [PMID: 38149287 PMCID: PMC10750784 DOI: 10.2147/pgpm.s424209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 12/11/2023] [Indexed: 12/28/2023] Open
Abstract
Background Bicaudal-D (BICD) Family Like Cargo Adaptor 1 (BICDL1) is an essential component of the molecular mechanism during neuronal development. However, BICDL1 has not been reported in cancer. Using bioinformatics analysis, we systematically evaluated the potential role of BICDL1 in CRC. Methods Colorectal cancer (CRC) and normal tissue samples were retrieved from the Gene Expression Omnibus (GEO), Genotype-Tissue Expression (GTEx), and Cancer Genome Atlas (TCGA) databases. Kaplan-Meier (K-M) analysis, nomogram, COX analysis, and receiver operating characteristic (ROC) curves were used to evaluate the prognostic power. Correlation analysis was also conducted to explore the correlation between mRNA expression and the methylation level of BICDL1 using cBioPortal, and the correlation between immune infiltration and BICDL1. RT-qPCR and Western blot assays were performed to analyze BICDL1 expression level between human colorectal cancer cell lines and normal colonic epithelial cells. Results BICDL1 had a higher expression in CRC tissues than in normal tissues (p < 0.001) in TCGA and GES 74602 datasets. Kaplan-Meier survival analysis revealed that patients with high BICDL1 expression had lower overall survival (OS) (1.53, 95% confidence interval: 1.07-2.17, p=0.019). The ROC curves demonstrated that BICDL1 has high specificity and efficiency in diagnosis (AUC=0.919, CI: 0.895-0.943). The expression level of BICDL1 was significantly correlated with the infiltrating levels of Treg (R=0.146, p <0.001), TFH (R=0.080, p=0.043), NK CD56bright cells (R=0.149, p <0.001), aDC (R=0.095, p=0.016), and T helper cell infiltration (R=-0.084, p=0.034). The correlation between BICDL1 expression and methylation levels was negative (R2=0.134, p <0.001), and CRC patients had lower methylation levels than normal people (p=0.036). BICDL1 mRNA and its protein expression levels in CRC cell lines (SW620) was markedly increased compared with that of normal colonic epithelial cells (NCM460) (p < 0.001). Conclusion BICDL1 may be a potential biomarker for evaluating immune infiltration levels and prognosis of CRC.
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Affiliation(s)
- Hongbiao Luo
- Graduate School, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China
- Department of Anorectal Surgery, Chenzhou NO. 1 People’s Hospital, Chenzhou, Hunan, 423000, People’s Republic of China
| | - Ji Luo
- Hunan Key Laboratory of Chinese Medicine on Oncology, Affiliated Hospital of Hunan Academy of Chinese Medicine, Changsha, Hunan, 410006, People’s Republic of China
| | - Ning Ding
- Graduate School, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China
| | - Tao Zhang
- Graduate School, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China
| | - Yongheng He
- Graduate School, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China
- Department of Anorectal Surgery, Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, Hunan, 410006, People’s Republic of China
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15
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Brouwer NP, Webbink L, Haddad TS, Rutgers N, van Vliet S, Wood CS, Jansen PW, Lafarge MW, de Wilt JH, Hugen N, Simmer F, Jamieson NB, Tauriello DV, Kölzer VH, Vermeulen M, Nagtegaal ID. Transcriptomics and proteomics reveal distinct biology for lymph node metastases and tumour deposits in colorectal cancer. J Pathol 2023; 261:401-412. [PMID: 37792663 DOI: 10.1002/path.6196] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/12/2023] [Accepted: 08/02/2023] [Indexed: 10/06/2023]
Abstract
Both lymph node metastases (LNMs) and tumour deposits (TDs) are included in colorectal cancer (CRC) staging, although knowledge regarding their biological background is lacking. This study aimed to compare the biology of these prognostic features, which is essential for a better understanding of their role in CRC spread. Spatially resolved transcriptomic analysis using digital spatial profiling was performed on TDs and LNMs from 10 CRC patients using 1,388 RNA targets, for the tumour cells and tumour microenvironment. Shotgun proteomics identified 5,578 proteins in 12 different patients. Differences in RNA and protein expression were analysed, and spatial deconvolution was performed. Image-based consensus molecular subtype (imCMS) analysis was performed on all TDs and LNMs included in the study. Transcriptome and proteome profiles identified distinct clusters for TDs and LNMs in both the tumour and tumour microenvironment segment, with upregulation of matrix remodelling, cell adhesion/motility, and epithelial-mesenchymal transition (EMT) in TDs (all p < 0.05). Spatial deconvolution showed a significantly increased abundance of fibroblasts, macrophages, and regulatory T-cells (p < 0.05) in TDs. Consistent with a higher fibroblast and EMT component, imCMS classified 62% of TDs as poor prognosis subtype CMS4 compared to 36% of LNMs (p < 0.05). Compared to LNMs, TDs have a more invasive state involving a distinct tumour microenvironment and upregulation of EMT, which are reflected in a more frequent histological classification of TDs as CMS4. These results emphasise the heterogeneity of locoregional spread and the fact that TDs should merit more attention both in future research and during staging. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Nelleke Pm Brouwer
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Loth Webbink
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Tariq S Haddad
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Natasja Rutgers
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Shannon van Vliet
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Colin S Wood
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, UK
- Academic Unit of Surgery, Glasgow Royal Infirmary, University of Glasgow, UK
| | - Pascal Wtc Jansen
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, The Netherlands
| | - Maxime W Lafarge
- Department of Pathology and Molecular Pathology, University and University Hospital of Zürich, Zürich, Switzerland
| | - Johannes Hw de Wilt
- Department of Surgery, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Niek Hugen
- Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Femke Simmer
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Nigel B Jamieson
- Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, UK
- Academic Unit of Surgery, Glasgow Royal Infirmary, University of Glasgow, UK
| | - Daniele Vf Tauriello
- Department of Medical Biosciences, Research Institute for Medical Innovation, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Viktor H Kölzer
- Department of Pathology and Molecular Pathology, University and University Hospital of Zürich, Zürich, Switzerland
| | - Michiel Vermeulen
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, The Netherlands
- The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
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16
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Piroozkhah M, Gholinezhad Y, Piroozkhah M, Shams E, Nazemalhosseini-Mojarad E. The molecular mechanism of actions and clinical utilities of tumor infiltrating lymphocytes in gastrointestinal cancers: a comprehensive review and future prospects toward personalized medicine. Front Immunol 2023; 14:1298891. [PMID: 38077386 PMCID: PMC10704251 DOI: 10.3389/fimmu.2023.1298891] [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: 09/22/2023] [Accepted: 11/13/2023] [Indexed: 12/18/2023] Open
Abstract
Gastrointestinal (GI) cancers remain a significant global health burden, accounting for a substantial number of cases and deaths. Regrettably, the inadequacy of dependable biomarkers hinders the precise forecasting of patient prognosis and the selection of appropriate therapeutic sequencing for individuals with GI cancers, leading to suboptimal outcomes for numerous patients. The intricate interplay between tumor-infiltrating lymphocytes (TILs) and the tumor immune microenvironment (TIME) has been shown to be a pivotal determinant of response to anti-cancer therapy and consequential clinical outcomes across a multitude of cancer types. Therefore, the assessment of TILs has garnered global interest as a promising prognostic biomarker in oncology, with the potential to improve clinical decision-making substantially. Moreover, recent discoveries in immunotherapy have progressively changed the landscape of cancer treatment and significantly prolonged the survival of patients with advanced cancers. Nonetheless, the response rate remains constrained within solid tumor sufferers, even when TIL landscapes appear comparable, which calls for the development of our understanding of cellular and molecular cross-talk between TIME and tumor. Hence, this comprehensive review encapsulates the extant literature elucidating the TILs' underlying molecular pathogenesis, prognostic significance, and their relevance in the realm of immunotherapy for patients afflicted by GI tract cancers. Within this review, we demonstrate that the type, density, and spatial distribution of distinct TIL subpopulations carries pivotal implications for the prediction of anti-cancer treatment responses and patient survival. Furthermore, this review underscores the indispensable role of TILs in modulating therapeutic responses within distinct molecular subtypes, such as those characterized by microsatellite stability or programmed cell death ligand-1 expression in GI tract cancers. The review concludes by outlining future directions in TIL-based personalized medicine, including integrating TIL-based approaches into existing treatment regimens and developing novel therapeutic strategies that exploit the unique properties of TILs and their potential as a promising avenue for personalized cancer treatment.
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Affiliation(s)
- Moein Piroozkhah
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yasaman Gholinezhad
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobin Piroozkhah
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Elahe Shams
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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17
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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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18
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McDonald SJ, Bullard BM, VanderVeen BN, Cardaci TD, Huss AR, Fan D, Hofseth LJ, Murphy EA. Panaxynol alleviates colorectal cancer in a murine model via suppressing macrophages and inflammation. Am J Physiol Gastrointest Liver Physiol 2023; 325:G318-G333. [PMID: 37489869 PMCID: PMC10642997 DOI: 10.1152/ajpgi.00119.2023] [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: 06/12/2023] [Revised: 07/17/2023] [Accepted: 07/24/2023] [Indexed: 07/26/2023]
Abstract
Currently available colorectal cancer (CRC) therapies have limited efficacy and severe adverse effects that may be overcome with the alternative use of natural compounds. We previously reported that panaxynol (PA), a bioactive component in American ginseng, possesses anticancer properties in vitro and suppresses murine colitis through its proapoptotic and anti-inflammatory properties. Because colitis is a predisposing factor of CRC and inflammation is a major driver of CRC, we sought to evaluate the therapeutic potential of PA in CRC. Azoxymethane-dextran sodium sulfate (AOM/DSS) mice (C57BL/6) were administered 2.5 mg/kg PA or vehicle 3 times/wk via oral gavage over 12 wk. PA improved clinical symptoms (P ≤ 0.05) and reduced tumorigenesis (P ≤ 0.05). This improvement may be reflective of PA's restorative effect on intestinal barrier function; PA upregulated the expression of essential tight junction and mucin genes (P ≤ 0.05) and increased the abundance of mucin-producing goblet cells (P ≤ 0.05). Given that macrophages play a substantial role in the pathogenesis of CRC and that we previously demonstrated that PA targets macrophages in colitis, we next assessed macrophages. We show that PA reduces the relative abundance of colonic macrophages within the lamina propria (P ≤ 0.05), and this was consistent with a reduction in the expression of important markers of macrophages and inflammation (P ≤ 0.05). We further confirmed PA's inhibitory effects on macrophages in vitro under CRC conditions (P ≤ 0.05). These results suggest that PA is a promising therapeutic compound to treat CRC and improve clinical symptoms given its ability to inhibit macrophages and modulate the inflammatory environment in the colon.NEW & NOTEWORTHY We report that panaxynol (PA) reduces colorectal cancer (CRC) by improving the colonic and tumor environment. Specifically, we demonstrate that PA improves crypt morphology, upregulates crucial tight junction and mucin genes, and promotes the abundance of mucin-producing goblet cells. Furthermore, PA reduces macrophages and associated inflammation, important drivers of CRC, in the colonic environment. This present study provides novel insights into the potential of PA as a therapeutic agent to ameliorate CRC tumorigenesis.
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Affiliation(s)
- Sierra J McDonald
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, United States
| | - Brooke M Bullard
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, United States
| | - Brandon N VanderVeen
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, United States
| | - Thomas D Cardaci
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, United States
| | - Alexander R Huss
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, United States
| | - Daping Fan
- Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina, United States
| | - Lorne J Hofseth
- Department of Drug Discovery and Biomedical Sciences, University of South Carolina College of Pharmacy, Columbia, South Carolina, United States
| | - E Angela Murphy
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, United States
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Kubick N, Paszkiewicz J, Bieńkowska I, Ławiński M, Horbańczuk JO, Sacharczuk M, Mickael ME. Investigation of Mutated in Colorectal Cancer (MCC) Gene Family Evolution History Indicates a Putative Role in Th17/Treg Differentiation. Int J Mol Sci 2023; 24:11940. [PMID: 37569317 PMCID: PMC10418881 DOI: 10.3390/ijms241511940] [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: 04/13/2023] [Revised: 07/14/2023] [Accepted: 07/21/2023] [Indexed: 08/13/2023] Open
Abstract
The MCC family of genes plays a role in colorectal cancer development through various immunological pathways, including the Th17/Treg axis. We have previously shown that MCC1 but not MCC2 plays a role in Treg differentiation. Our understanding of the genetic divergence patterns and evolutionary history of the MCC family in relation to its function, in general, and the Th17/Treg axis, in particular, remains incomplete. In this investigation, we explored 12 species' genomes to study the phylogenetic origin, structure, and functional specificity of this family. In vertebrates, both MCC1 and MCC2 homologs have been discovered, while invertebrates have a single MCC homolog. We found MCC homologs as early as Cnidarians and Trichoplax, suggesting that the MCC family first appeared 741 million years ago (Ma), whereas MCC divergence into the MCC1 and MCC2 families occurred at 540 Ma. In general, we did not detect significant positive selection regulating MCC evolution. Our investigation, based on MCC1 structural similarity, suggests that they may play a role in the evolutionary changes in Tregs' emergence towards complexity, including the ability to utilize calcium for differentiation through the use of the EFH calcium-binding domain. We also found that the motif NPSTGE was highly conserved in MCC1, but not in MCC2. The NPSTGE motif binds KEAP1 with high affinity, suggesting an Nrf2-mediated function for MCC1. In the case of MCC2, we found that the "modifier of rudimentary" motif is highly conserved. This motif contributes to the regulation of alternative splicing. Overall, our study sheds light on how the evolution of the MCC family is connected to its function in regulating the Th17/Treg axis.
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Affiliation(s)
- Norwin Kubick
- Department of Biology, Institute of Plant Science and Microbiology, Univeristy of Hamburg, Ohnhorststr. 18, 22609 Hamburg, Germany;
| | - Justyna Paszkiewicz
- Department of Health, John Paul II University of Applied Sciences in Biala Podlaska, Sidorska 95/97, 21-500 Biała Podlaska, Poland;
| | - Irmina Bieńkowska
- Institute of Animal Biotechnology and Genetics, Polish Academy of Science, Postępu 36A, 05-552 Jastrzębiec, Poland; (I.B.); (M.Ł.); (J.O.H.)
| | - Michał Ławiński
- Institute of Animal Biotechnology and Genetics, Polish Academy of Science, Postępu 36A, 05-552 Jastrzębiec, Poland; (I.B.); (M.Ł.); (J.O.H.)
- Department of General Surgery, Gastroenterology and Oncology, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Jarosław Olav Horbańczuk
- Institute of Animal Biotechnology and Genetics, Polish Academy of Science, Postępu 36A, 05-552 Jastrzębiec, Poland; (I.B.); (M.Ł.); (J.O.H.)
| | - Mariusz Sacharczuk
- Institute of Animal Biotechnology and Genetics, Polish Academy of Science, Postępu 36A, 05-552 Jastrzębiec, Poland; (I.B.); (M.Ł.); (J.O.H.)
- Department of Pharmacodynamics, Faculty of Pharmacy, Medical University of Warsaw, l Banacha 1, 02-697 Warsaw, Poland
| | - Michel Edwar Mickael
- Institute of Animal Biotechnology and Genetics, Polish Academy of Science, Postępu 36A, 05-552 Jastrzębiec, Poland; (I.B.); (M.Ł.); (J.O.H.)
- PM Research Center, Väpnaregatan 22, 58649 Linköping, Sweden
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Zheng Z, Wieder T, Mauerer B, Schäfer L, Kesselring R, Braumüller H. T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment. Int J Mol Sci 2023; 24:11673. [PMID: 37511431 PMCID: PMC10380781 DOI: 10.3390/ijms241411673] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Therapeutic options for metastatic colorectal cancer (mCRC) are very limited, and the prognosis using combination therapy with a chemotherapeutic drug and a targeted agent, e.g., epidermal growth factor receptor or tyrosine kinase, remains poor. Therefore, mCRC is associated with a poor median overall survival (mOS) of only 25-30 months. Current immunotherapies with checkpoint inhibitor blockade (ICB) have led to a substantial change in the treatment of several cancers, such as melanoma and non-small cell lung cancer. In CRC, ICB has only limited effects, except in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, which comprise about 15% of sporadic CRC patients and about 4% of patients with metastatic CRC. The vast majority of sporadic CRCs are microsatellite-stable (MSS) tumors with low levels of infiltrating immune cells, in which immunotherapy has no clinical benefit so far. Immunotherapy with checkpoint inhibitors requires the presence of infiltrating T cells into the tumor microenvironment (TME). This makes T cells the most important effector cells in the TME, as evidenced by the establishment of the immunoscore-a method to estimate the prognosis of CRC patients. The microenvironment of a tumor contains several types of T cells that are anti-tumorigenic, such as CD8+ T cells or pro-tumorigenic, such as regulatory T cells (Tregs) or T helper 17 (Th17) cells. However, even CD8+ T cells show marked heterogeneity, e.g., they can become exhausted, enter a state of hyporesponsiveness or become dysfunctional and express high levels of checkpoint molecules, the targets for ICB. To kill cancer cells, CD8+ T cells need the recognition of the MHC class I, which is often downregulated on colorectal cancer cells. In this case, a population of unconventional T cells with a γδ T cell receptor can overcome the limitations of the conventional CD8+ T cells with an αβT cell receptor. γδ T cells recognize antigens in an MHC-independent manner, thus acting as a bridge between innate and adaptive immunity. Here, we discuss the effects of different T cell subsets in colorectal cancer with a special emphasis on γδ T cells and the possibility of using them in CAR-T cell therapy. We explain T cell exclusion in microsatellite-stable colorectal cancer and the possibilities to overcome this exclusion to enable immunotherapy even in these "cold" tumors.
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Affiliation(s)
- Ziwen Zheng
- Department of General and Visceral Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Thomas Wieder
- Department of Vegetative and Clinical Physiology, Institute of Physiology, Eberhard Karls University Tübingen, 72074 Tübingen, Germany
| | - Bernhard Mauerer
- Department of General and Visceral Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK) Partner Site Freiburg, 79106 Freiburg, Germany
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Luisa Schäfer
- Department of General and Visceral Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Rebecca Kesselring
- Department of General and Visceral Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK) Partner Site Freiburg, 79106 Freiburg, Germany
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Heidi Braumüller
- Department of General and Visceral Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
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Lucarini V, Nardozi D, Angiolini V, Benvenuto M, Focaccetti C, Carrano R, Besharat ZM, Bei R, Masuelli L. Tumor Microenvironment Remodeling in Gastrointestinal Cancer: Role of miRNAs as Biomarkers of Tumor Invasion. Biomedicines 2023; 11:1761. [PMID: 37371856 DOI: 10.3390/biomedicines11061761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/13/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
Gastrointestinal (GI) cancers are the most frequent neoplasm, responsible for half of all cancer-related deaths. Metastasis is the leading cause of death from GI cancer; thus, studying the processes that regulate cancer cell migration is of paramount importance for the development of new therapeutic strategies. In this review, we summarize the mechanisms adopted by cancer cells to promote cell migration and the subsequent metastasis formation by highlighting the key role that tumor microenvironment components play in deregulating cellular pathways involved in these processes. We, therefore, provide an overview of the role of different microRNAs in promoting tumor metastasis and their role as potential biomarkers for the prognosis, monitoring, and diagnosis of GI cancer patients. Finally, we relate the possible use of nutraceuticals as a new strategy for targeting numerous microRNAs and different pathways involved in GI tumor invasiveness.
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Affiliation(s)
- Valeria Lucarini
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161 Rome, Italy
| | - Daniela Nardozi
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Valentina Angiolini
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161 Rome, Italy
| | - Monica Benvenuto
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
- Departmental Faculty of Medicine and Surgery, Saint Camillus International University of Health and Medical Sciences, via di Sant'Alessandro 8, 00131 Rome, Italy
| | - Chiara Focaccetti
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Raffaele Carrano
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Zein Mersini Besharat
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161 Rome, Italy
| | - Roberto Bei
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Laura Masuelli
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161 Rome, Italy
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22
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Wu Z, Fang ZX, Hou YY, Wu BX, Deng Y, Wu HT, Liu J. Exosomes in metastasis of colorectal cancers: Friends or foes? World J Gastrointest Oncol 2023; 15:731-756. [PMID: 37275444 PMCID: PMC10237026 DOI: 10.4251/wjgo.v15.i5.731] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/07/2023] [Accepted: 04/04/2023] [Indexed: 05/12/2023] Open
Abstract
Colorectal cancer (CRC), the third most common type of cancer worldwide, threaten human health and quality of life. With multidisciplinary, including surgery, chemotherapy and/or radiotherapy, patients with an early diagnosis of CRC can have a good prognosis. However, metastasis in CRC patients is the main risk factor causing cancer-related death. To elucidate the underlying molecular mechanisms of CRC metastasis is the difficult and research focus on the investigation of the CRC mechanism. On the other hand, the tumor microenvironment (TME) has been confirmed as having an essential role in the tumorigenesis and metastasis of malignancies, including CRCs. Among the different factors in the TME, exosomes as extracellular vesicles, function as bridges in the communication between cancer cells and different components of the TME to promote the progression and metastasis of CRC. MicroRNAs packaged in exosomes can be derived from different sources and transported into the TME to perform oncogenic or tumor-suppressor roles accordingly. This article focuses on CRC exosomes and illustrates their role in regulating the metastasis of CRC, especially through the packaging of miRNAs, to evoke exosomes as novel biomarkers for their impact on the metastasis of CRC progression.
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Affiliation(s)
- Zheng Wu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Ze-Xuan Fang
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yan-Yu Hou
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Bing-Xuan Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu Deng
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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23
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Andrade-Meza A, Arias-Romero LE, Armas-López L, Ávila-Moreno F, Chirino YI, Delgado-Buenrostro NL, García-Castillo V, Gutiérrez-Cirlos EB, Juárez-Avelar I, Leon-Cabrera S, Mendoza-Rodríguez MG, Olguín JE, Perez-Lopez A, Pérez-Plasencia C, Reyes JL, Sánchez-Pérez Y, Terrazas LI, Vaca-Paniagua F, Villamar-Cruz O, Rodríguez-Sosa M. Mexican Colorectal Cancer Research Consortium (MEX-CCRC): Etiology, Diagnosis/Prognosis, and Innovative Therapies. Int J Mol Sci 2023; 24:ijms24032115. [PMID: 36768437 PMCID: PMC9917340 DOI: 10.3390/ijms24032115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/22/2022] [Accepted: 12/22/2022] [Indexed: 01/25/2023] Open
Abstract
In 2013, recognizing that Colorectal Cancer (CRC) is the second leading cause of death by cancer worldwide and that it was a neglected disease increasing rapidly in Mexico, the community of researchers at the Biomedicine Research Unit of the Facultad de Estudios Superiores Iztacala from the Universidad Nacional Autónoma de México (UNAM) established an intramural consortium that involves a multidisciplinary group of researchers, technicians, and postgraduate students to contribute to the understanding of this pathology in Mexico. This article is about the work developed by the Mexican Colorectal Cancer Research Consortium (MEX-CCRC): how the Consortium was created, its members, and its short- and long-term goals. Moreover, it is a narrative of the accomplishments of this project. Finally, we reflect on possible strategies against CRC in Mexico and contrast all the data presented with another international strategy to prevent and treat CRC. We believe that the Consortium's characteristics must be maintained to initiate a national strategy, and the reported data could be useful to establish future collaborations with other countries in Latin America and the world.
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Affiliation(s)
- Antonio Andrade-Meza
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México 04510, Mexico
| | - Luis E. Arias-Romero
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Leonel Armas-López
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Federico Ávila-Moreno
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Yolanda I. Chirino
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Norma L. Delgado-Buenrostro
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Verónica García-Castillo
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Emma B. Gutiérrez-Cirlos
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Imelda Juárez-Avelar
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Programa de Doctorado en Ciencias Biológicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de México 04510, Mexico
| | - Sonia Leon-Cabrera
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Carrera de Médico Cirujano, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Mónica G. Mendoza-Rodríguez
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Jonadab E. Olguín
- Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Araceli Perez-Lopez
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Carlos Pérez-Plasencia
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México 14080, Mexico
| | - José L. Reyes
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Yesennia Sánchez-Pérez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México 14080, Mexico
| | - Luis I. Terrazas
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Felipe Vaca-Paniagua
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México 14080, Mexico
| | - Olga Villamar-Cruz
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
| | - Miriam Rodríguez-Sosa
- Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores-Iztacala (FES-I), Universidad Nacional Autónoma de México (UNAM), Tlalnepantla 54090, Mexico
- Correspondence: ; Tel.: +52-55-5623-1333
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Identification of Aging and Young Subtypes for Predicting Colorectal Cancer Prognosis and Immunotherapy Responses. Int J Mol Sci 2023; 24:ijms24021516. [PMID: 36675039 PMCID: PMC9862647 DOI: 10.3390/ijms24021516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/14/2023] Open
Abstract
Colorectal cancer (CRC) is critically related to aging and severely threatens human lives. To better explore the effects of aging on CRC progression and therapy outcome, a reliable aging subtypes identification of CRC is urgently desired. Here, 28 aging-related genes associated with the CRC prognosis were selected by univariate Cox analyses. Based on these 28 genes, CRC patients were divided into the aging subtype and young subtype by non-negative matrix factorization clustering. Aging subtype and young subtype of CRC were identified with distinct molecular features and clinical prognosis. The aging subtype was characterized by upregulation of senescence-associated secretory phenotype, higher frequencies of TP53 and immune checkpoint molecules, and high sensitivity to protein kinase and angiogenesis inhibitors. Furthermore, 14 genes were selected by LASSO penalized Cox regression analyses for aging-related risk signature construction. The constructed aging risk signature exhibited good prediction and the nomogram showed robust discrimination power over the traditional CRC staging system. In conclusion, this study successfully established aging subtype and young subtype of CRC, which is helpful to identify patients with aging characteristics to evaluate prognosis and treatment outcomes. Introducing aging-based subtypes into clinical concern and patient prognostication provides new opportunities for personalized CRC treatment.
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SRICHOMCHEY PATNAPA, SUKPRASERT SOPHIDA, KHULASITTIJINDA NATHAPONG, VORAVUD NARIN, SAHAKITRUNGRUANG CHUCHEEP, LUMJIAKTASE PUTTHAPOOM. Vitamin D 3 Supplementation Promotes Regulatory T-Cells to Maintain Immune Homeostasis After Surgery for Early Stages of Colorectal Cancer. In Vivo 2023; 37:286-293. [PMID: 36593062 PMCID: PMC9843780 DOI: 10.21873/invivo.13078] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 12/06/2022] [Accepted: 12/07/2022] [Indexed: 01/03/2023]
Abstract
BACKGROUND/AIM Vitamin D3 (VD3) affects the regulation of the immune system, including the differentiation and function of regulatory T-cells (Tregs). Tregs play an important role in maintaining immune homeostasis in patients with colorectal cancer (CRC). The effects of VD3 on Treg-associated immune function were investigated in Thai patients in the early stages of CRC. MATERIALS AND METHODS Twenty-eight patients were randomized to one of two groups: Untreated or treatment with VD3 for 3 months. Whole blood samples were collected at baseline, and at 1 and 3 months. Peripheral blood mononuclear cells were isolated and the populations of forkhead box P3-positive Treg cells was analyzed by flow cytometry. The levels of Treg-associated cytokines, interleukin 10 (IL-10) and transforming growth factor beta 1 (TGF-β1), were measured by enzyme-linked immunosorbent assays. RESULTS Serum VD3 levels of the VD3-treated group were significantly increased at 1 (p=0.017) and 3 months (p<0.001) compared to the untreated control group. The mean percentage of Tregs was maintained between 1 and 3 months in the VD3-treated group. At 3 months, the untreated group had significantly lower Treg levels than the VD3-treated group (p=0.043). Serum IL-10 levels of the VD3-treated group were statistically increased at 1 month compared to the control group (p=0.032). No significant difference in serum TGF-β1 levels was observed between the two groups. However, the TGF-β1 level in the VD3-treated group at 1 month was lower than that of the control. CONCLUSION Our findings suggest that VD3 supplementation can maintain immune responses in the early stages of CRC, helping to control Treg function. Therefore, VD3 should be supplemented to maintain immune homeostasis, especially in patients with vitamin D deficiency.
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Affiliation(s)
- PATNAPA SRICHOMCHEY
- Graduate Program in Integrative Medicine, Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand,Center of Nutrition and Dietetics, Theptarin Hospital, Bangkok, Thailand
| | - SOPHIDA SUKPRASERT
- Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand
| | | | - NARIN VORAVUD
- Section of Medical Oncology Unit, Department of Medicine, Chulalongkorn University Hospital, Bangkok, Thailand
| | - CHUCHEEP SAHAKITRUNGRUANG
- Colorectal Surgery Division, Department of Surgery, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - PUTTHAPOOM LUMJIAKTASE
- Clinical Immunology Laboratory, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Salaya, Thailand
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Jin R, Luo Z, Jun-Li, Tao Q, Wang P, Cai X, Jiang L, Zeng C, Chen Y. USP20 is a predictor of poor prognosis in colorectal cancer and associated with lymph node metastasis, immune infiltration and chemotherapy resistance. Front Oncol 2023; 13:1023292. [PMID: 36874086 PMCID: PMC9978104 DOI: 10.3389/fonc.2023.1023292] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 01/17/2023] [Indexed: 02/18/2023] Open
Abstract
Background Colorectal cancer (CRC) is a highly prevalent malignancy with a poor prognosis. USP20 can support progression of variety of tumors. USP20 was shown to promote breast tumor metastasis, and proliferation of oral squamous carcinoma cells. However, the role of USP20 in CRC remains unclear. Methods We used bioinformatics to analyze the expression and prognosis of USP20 in pan-cancer and explore the relationship between USP20 expression and immune infiltration, immune checkpoints, and chemotherapy resistance in CRC. The differential expression and prognostic role of USP20 in CRC was validated by qRT-PCR and immunohistochemistry. Cox univariate and multivariate analyses were performed to assess risk factors for poor prognosis of CRC, and new prognostic prediction models were constructed and evaluated by decision curve analysis (ROC) and receiver operating characteristic (DCA). USP20 was overexpressed in CRC cell lines to explore the effect of USP20 on the functionalities of CRC cells. Enrichment analyses were used to explore the possible mechanism of USP20 in CRC. Results The expression of USP20 was lower in CRC tissues than adjacent normal tissues. Compared with low USP20 expression patients, CRC patients with high USP20 expression level had shorter OS. Correlation analysis showed that USP20 expression was associated with lymph node metastasis. Cox regression analysis revealed USP20 as an independent risk factor for poor prognosis in CRC patients. ROC and DCA analyses showed that the performance of the newly constructed prediction model was better than the traditional TNM model. Immune infiltration analysis shown that USP20 expression is closely associated with T cell infiltration in CRC. A co-expression analysis showed that USP20 expression was positively correlated with several immune checkpoint genes including ADORA2A, CD160, CD27 and TNFRSF25 genes and positively associated with multiple multi-drug resistance genes such as MRP1, MRP3, and MRP5 genes. USP20 expression positively correlated with the sensitivity of cells to multiple anticancer drugs. Overexpression of USP20 enhanced the migration and invasive ability of CRC cells. Enrichment pathway analyses showed the USP20 may play a role via the Notch pathway, Hedgehog pathway and beta-catenin pathway. Conclusion USP20 is downregulated in CRC and associated with prognosis in CRC. USP20 enhances CRC cells metastasis and is associated with immune infiltration, immune checkpoints, and chemotherapy resistance.
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Affiliation(s)
- RuiRi Jin
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - ZhiPeng Luo
- Department of Abdominal Tumor Surgery, Jiangxi Cancer Hospital, Nanchang, China
| | - Jun-Li
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qing Tao
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Peng Wang
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - XueSheng Cai
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - LongZhou Jiang
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - ChunYan Zeng
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Interdisciplinary Science, Nanchang University, Nanchang, China
| | - YouXiang Chen
- Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Sampaio-Ribeiro G, Ruivo A, Silva A, Santos AL, Oliveira RC, Laranjeira P, Gama J, Cipriano MA, Tralhão JG, Paiva A. Extensive Phenotypic Characterization of T Cells Infiltrating Liver Metastasis from Colorectal Cancer: A Potential Role in Precision Medicine. Cancers (Basel) 2022; 14:cancers14246069. [PMID: 36551555 PMCID: PMC9775680 DOI: 10.3390/cancers14246069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/05/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, with liver metastasis being its main cause of death. This study harvested fresh biological material from non-tumor and tumor tissue from 47 patients with CRC liver metastasis after surgery, followed by mechanical cellular extraction and stain-lyse-wash direct immunofluorescence technique. Here, 60 different T-cell populations were characterized by flow cytometry. Tumor samples were also subdivided according to their growth pattern into desmoplastic and non-desmoplastic. When we compared tumor versus non-tumor samples, we observed a significantly lower percentage of T-lymphocyte infiltration in the tumor in which the CD4+ T-cell density increased compared to the CD8+ T cells. T regulatory cells also increased within the tumor, even with an activated phenotype (HLA-DR+). A higher percentage of IL-17-producing cells was present in tumor samples and correlated with the metastasis size. In contrast, we also observed a significant increase in CD8+ follicular-like T cells (CD185+), suggesting a cytotoxic response to cancer cells. Additionally, most infiltrated T cells exhibit an intermediate activation phenotype (CD25+). In conclusion, our results revealed potential new targets and prognostic biomarkers that could take part in an algorithm for personalized medicine approaches improving CRC patients' outcomes.
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Affiliation(s)
- Gabriela Sampaio-Ribeiro
- Flow Cytometry Unit, Clinical Pathology Department, Centro Hospitalar e Universitário de Coimbra EPE, 3000-075 Coimbra, Portugal
- Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Ana Ruivo
- Surgery Department, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Ana Silva
- Flow Cytometry Unit, Clinical Pathology Department, Centro Hospitalar e Universitário de Coimbra EPE, 3000-075 Coimbra, Portugal
| | - Ana Lúcia Santos
- Flow Cytometry Unit, Clinical Pathology Department, Centro Hospitalar e Universitário de Coimbra EPE, 3000-075 Coimbra, Portugal
| | - Rui Caetano Oliveira
- Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Germano de Sousa—Centro de Diagnóstico Histopatológico CEDAP, 3000-377 Coimbra, Portugal
- Centre of Investigation on Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical and Academic Center of Coimbra (CACC), 3000-075 Coimbra, Portugal
| | - Paula Laranjeira
- Flow Cytometry Unit, Clinical Pathology Department, Centro Hospitalar e Universitário de Coimbra EPE, 3000-075 Coimbra, Portugal
- Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Neuroscience and Cell Biology (CNC), Faculty of Medicine, Polo 1, 1st Floor, University of Coimbra, 3004-504 Coimbra, Portugal
| | - João Gama
- Pathology Department, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal
| | - Maria Augusta Cipriano
- Pathology Department, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal
| | - José Guilherme Tralhão
- Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Surgery Department, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Centre of Investigation on Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Clinical and Academic Center of Coimbra (CACC), 3000-075 Coimbra, Portugal
| | - Artur Paiva
- Flow Cytometry Unit, Clinical Pathology Department, Centro Hospitalar e Universitário de Coimbra EPE, 3000-075 Coimbra, Portugal
- Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal
- Ciências Biomeédicas Laboratoriais, ESTESC-Coimbra Health School, Instituto Politeécnico de Coimbra, 3046-854 Coimbra, Portugal
- Correspondence:
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Shan J, Han D, Shen C, Lei Q, Zhang Y. Mechanism and strategies of immunotherapy resistance in colorectal cancer. Front Immunol 2022; 13:1016646. [PMID: 36238278 PMCID: PMC9550896 DOI: 10.3389/fimmu.2022.1016646] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 09/05/2022] [Indexed: 11/15/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world. Although there are standard treatment options for CRC, most patients respond poorly to these treatments. Immunotherapies have gradually emerged due to the increasing awareness and understanding of tumor immunity, exhibiting good therapeutic efficacy in various cancers. Immunotherapies include cytokines, immune checkpoint inhibitors (ICIs), and adoptive cell therapies. In particular, ICIs, which are antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), or its ligand PD-L1, have been successfully applied clinically for solid tumors, relieving the inhibitory effect of the tumor microenvironment on T cells. However, only a minority of patients with cancer achieve a durable clinical response during immunotherapy. Several factors restrict the efficacy of immunotherapy, leading to the development of drug resistance. In this review, we aimed to discuss the current status of immunotherapy for CRC and elaborate on the mechanisms that mediate resistance to immunotherapy and other potential therapeutic strategies.
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Affiliation(s)
- Jiqi Shan
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dong Han
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chunyi Shen
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qingyang Lei
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yi Zhang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, China
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Xing C, Du Y, Duan T, Nim K, Chu J, Wang HY, Wang RF. Interaction between microbiota and immunity and its implication in colorectal cancer. Front Immunol 2022; 13:963819. [PMID: 35967333 PMCID: PMC9373904 DOI: 10.3389/fimmu.2022.963819] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the world. Besides genetic causes, colonic inflammation is one of the major risk factors for CRC development, which is synergistically regulated by multiple components, including innate and adaptive immune cells, cytokine signaling, and microbiota. The complex interaction between CRC and the gut microbiome has emerged as an important area of current CRC research. Metagenomic profiling has identified a number of prominent CRC-associated bacteria that are enriched in CRC patients, linking the microbiota composition to colitis and cancer development. Some microbiota species have been reported to promote colitis and CRC development in preclinical models, while a few others are identified as immune modulators to induce potent protective immunity against colitis and CRC. Mechanistically, microbiota regulates the activation of different immune cell populations, inflammation, and CRC via crosstalk between innate and adaptive immune signaling pathways, including nuclear factor kappa B (NF-κB), type I interferon, and inflammasome. In this review, we provide an overview of the potential interactions between gut microbiota and host immunity and how their crosstalk could synergistically regulate inflammation and CRC, thus highlighting the potential roles and mechanisms of gut microbiota in the development of microbiota-based therapies to prevent or alleviate colitis and CRC.
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Affiliation(s)
- Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Kelly Nim
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Junjun Chu
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y. Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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30
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Martínez-Montoro JI, Martínez-Sánchez MA, Balaguer-Román A, Gil-Martínez J, Mesa-López MJ, Egea-Valenzuela J, Ruiz-Alcaraz AJ, Queipo-Ortuño MI, Ferrer M, Fernández-García JC, Ramos-Molina B. Dietary modulation of gut microbiota in patients with colorectal cancer undergoing surgery: A review. Int J Surg 2022; 104:106751. [PMID: 35803517 DOI: 10.1016/j.ijsu.2022.106751] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 06/19/2022] [Accepted: 06/20/2022] [Indexed: 11/16/2022]
Abstract
Colorectal cancer (CRC) is the third most frequent malignancy and the second cause of cancer death worldwide. Several factors have been postulated to be involved in CRC pathophysiology, including physical inactivity, unhealthy dietary habits, obesity, and the gut microbiota. Emerging data suggest that the microbiome may play a key role in CRC prognosis and derived complications in patients undergoing colorectal surgery. On the other hand, dietary intervention has been demonstrated to be able to induce significant changes in the gut microbiota and related metabolites in different conditions; therefore, the manipulation of gut microbiota through dietary intervention may constitute a useful approach to improve perioperative dysbiosis and post-surgical outcomes in patients with CRC. In this article, we review the role of the gut microbiota in CRC surgery complications and the potential therapeutic modulation of gut microbiome through nutritional intervention in patients with CRC undergoing surgery.
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Affiliation(s)
- José Ignacio Martínez-Montoro
- Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Instituto de Investigacion Biomedica de Malaga (IBIMA), Faculty of Medicine, University of Malaga, Malaga, Spain
| | | | - Andrés Balaguer-Román
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain; Department of General and Digestive System Surgery, Virgen de la Arrixaca University Hospital, Murcia, Spain
| | - José Gil-Martínez
- Department of General and Digestive System Surgery, Virgen de la Arrixaca University Hospital, Murcia, Spain
| | - María José Mesa-López
- Department of Digestive Diseases- Unit of Gastrointestinal Endoscopy, Virgen de la Arrixaca University Hospital, Murcia, Spain
| | - Juan Egea-Valenzuela
- Department of Digestive Diseases- Unit of Gastrointestinal Endoscopy, Virgen de la Arrixaca University Hospital, Murcia, Spain
| | - Antonio José Ruiz-Alcaraz
- Department of Biochemistry, Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, Murcia, Spain
| | - María Isabel Queipo-Ortuño
- Department of Medical Oncology, Virgen de la Victoria and Regional University Hospitals-IBIMA, UMA-CIMES, Malaga, Spain
| | - Mercedes Ferrer
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain; Department of Endocrinology and Nutrition, Virgen de la Arrixaca University Hospital, Murcia, Spain
| | - José Carlos Fernández-García
- Department of Endocrinology and Nutrition, Regional University Hospital of Malaga, Instituto de Investigacion Biomedica de Malaga (IBIMA), Faculty of Medicine, University of Malaga, Malaga, Spain.
| | - Bruno Ramos-Molina
- Obesity and Metabolism Laboratory, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain.
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31
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Wang P, Zhao W, Cao H. Development of a Platelet-Related Prognostic Model for Colorectal Cancer. Front Genet 2022; 13:904168. [PMID: 35719389 PMCID: PMC9198283 DOI: 10.3389/fgene.2022.904168] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 04/26/2022] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) represents one of the most common malignancies with high morbidity worldwide. Growing evidence has suggested that platelets are a fundamental component of the tumor microenvironment and play crucial roles in driving tumor biological behavior. The construction of a platelet-related prognostic model that can reliably predict CRC prognosis is of great clinical significance. The 1427 CRC-specific platelet-related genes were collected and mainly enriched in the ribosome and immune-related pathways. Based on platelet-related genes, three subtypes of TCGA CRC samples were identified by consensus clustering and characterized by differences in angiogenesis, epithelial–mesenchymal transition, immune infiltration, and prognosis. A total of 100 prognostic platelet-related genes were identified by univariate Cox regression. LASSO Cox regression further shrank those genes and constructed a 10-gene prognostic model. The patients with higher risk scores had significantly worse disease-specific survival than those with lower scores in both TCGA and validation cohorts. The risk score demonstrated good predictive performance for prognosis by receiver operating characteristic (ROC) curves. Furthermore, multivariate Cox regression analysis showed that the risk score was independent of TNM stage, sex, and age, and a graphic nomogram based on the risk score and clinical factors was developed to predict survival probability of CRC patients. Patients from the high-risk group were characterized by higher infiltration of immunosuppressive cells such as MDSC and Treg and higher expression of checkpoints CTLA4, CD86, and PDCD1LG2. Taken together, we identified three platelet-related subtypes and specifically constructed a promising 10-gene prognostic model in CRC. Our results highlighted the potential survival effects of platelet-related genes and provided evidence about their roles in regulating tumor immunity.
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Affiliation(s)
- Pengcheng Wang
- Department of Colorectal and Anal Surgery, Shanxi Province Cancer Hospital, Taiyuan, China
| | - Wei Zhao
- Department of Anesthesiology, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hailei Cao
- Department of Colorectal and Anal Surgery, Shanxi Province Cancer Hospital, Taiyuan, China
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32
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Obata-Ninomiya K, de Jesus Carrion S, Hu A, Ziegler SF. Emerging role for thymic stromal lymphopoietin-responsive regulatory T cells in colorectal cancer progression in humans and mice. Sci Transl Med 2022; 14:eabl6960. [PMID: 35584230 DOI: 10.1126/scitranslmed.abl6960] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recruitment of regulatory T cells (Tregs) to tumors is a hallmark of cancer progression. Tumor-derived factors, such as the cytokine thymic stromal lymphopoietin (TSLP), can influence Treg function in tumors. In our study, we identified a subset of Tregs expressing the receptor for TSLP (TSLPR+ Tregs) that were increased in colorectal tumors in humans and mice and largely absent in adjacent normal colon. This Treg subset was also found in the peripheral blood of patients with colon cancer but not in the peripheral blood of healthy control subjects. Mechanistically, we found that this Treg subset coexpressed the interleukin-33 (IL-33) receptor [suppressor of tumorigenicity 2 (ST2)] and had high programmed cell death 1 (PD-1) and cytotoxic lymphocyte-associated antigen 4 (CTLA-4) expression, regulated in part by the transcription factor Mef2c. Treg-specific deletion of TSLPR, but not ST2, was associated with a reduction in tumor number and size with concomitant increase in TH1 cells in tumors in chemically induced mouse models of colorectal cancer. Therapeutic blockade of TSLP using TSLP-specific monoclonal antibodies effectively inhibited the progression of colorectal tumors in this mouse model. Collectively, these data suggest that TSLP controls the progression of colorectal cancer through regulation of tumor-specific Treg function and represents a potential therapeutic target that requires further investigation.
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Affiliation(s)
| | | | - Alex Hu
- Center for Systems Immunology, Benaroya Research Institute, Seattle, WA 98101, USA
| | - Steven F Ziegler
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA 98101, USA
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Stachtea X, Loughrey MB, Salvucci M, Lindner AU, Cho S, McDonough E, Sood A, Graf J, Santamaria-Pang A, Corwin A, Laurent-Puig P, Dasgupta S, Shia J, Owens JR, Abate S, Van Schaeybroeck S, Lawler M, Prehn JHM, Ginty F, Longley DB. Stratification of chemotherapy-treated stage III colorectal cancer patients using multiplexed imaging and single-cell analysis of T-cell populations. Mod Pathol 2022; 35:564-576. [PMID: 34732839 PMCID: PMC8964416 DOI: 10.1038/s41379-021-00953-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 10/06/2021] [Accepted: 10/11/2021] [Indexed: 11/08/2022]
Abstract
Colorectal cancer (CRC) has one of the highest cancer incidences and mortality rates. In stage III, postoperative chemotherapy benefits <20% of patients, while more than 50% will develop distant metastases. Biomarkers for identification of patients at increased risk of disease recurrence following adjuvant chemotherapy are currently lacking. In this study, we assessed immune signatures in the tumor and tumor microenvironment (TME) using an in situ multiplexed immunofluorescence imaging and single-cell analysis technology (Cell DIVETM) and evaluated their correlations with patient outcomes. Tissue microarrays (TMAs) with up to three 1 mm diameter cores per patient were prepared from 117 stage III CRC patients treated with adjuvant fluoropyrimidine/oxaliplatin (FOLFOX) chemotherapy. Single sections underwent multiplexed immunofluorescence staining for immune cell markers (CD45, CD3, CD4, CD8, FOXP3, PD1) and tumor/cell segmentation markers (DAPI, pan-cytokeratin, AE1, NaKATPase, and S6). We used annotations and a probabilistic classification algorithm to build statistical models of immune cell types. Images were also qualitatively assessed independently by a Pathologist as 'high', 'moderate' or 'low', for stromal and total immune cell content. Excellent agreement was found between manual assessment and total automated scores (p < 0.0001). Moreover, compared to single markers, a multi-marker classification of regulatory T cells (Tregs: CD3+/CD4+FOXP3+/PD1-) was significantly associated with disease-free survival (DFS) and overall survival (OS) (p = 0.049 and 0.032) of FOLFOX-treated patients. Our results also showed that PD1- Tregs rather than PD1+ Tregs were associated with improved survival. These findings were supported by results from an independent FOLFOX-treated cohort of 191 stage III CRC patients, where higher PD1- Tregs were associated with an increase overall survival (p = 0.015) for CD3+/CD4+/FOXP3+/PD1-. Overall, compared to single markers, multi-marker classification provided more accurate quantitation of immune cell types with stronger correlations with outcomes.
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Affiliation(s)
- Xanthi Stachtea
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK
| | - Maurice B Loughrey
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK
- Department of Cellular Pathology, Royal Victoria Hospital, Belfast Health and Social Care trust, Belfast, UK
| | - Manuela Salvucci
- Department of Physiology and Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, 123 St. Stephen's Green, Dublin 2, Ireland
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | - Andreas U Lindner
- Department of Physiology and Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, 123 St. Stephen's Green, Dublin 2, Ireland
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | - Sanghee Cho
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | | | - Anup Sood
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | - John Graf
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | | | - Alex Corwin
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | | | | | - Jinru Shia
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jonathan R Owens
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | - Samantha Abate
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | - Sandra Van Schaeybroeck
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK
| | - Mark Lawler
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, 123 St. Stephen's Green, Dublin 2, Ireland
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | - Fiona Ginty
- GE Research Center, 1 Research Circle, Niskayuna, NY, 12309, USA
| | - Daniel B Longley
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Northern Ireland, UK.
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Bandaru SS, Boyilla R, Merchant N, Nagaraju GP, El-Rayes B. Targeting T regulatory cells: their role in colorectal carcinoma progression and current clinical trials. Pharmacol Res 2022; 178:106197. [DOI: 10.1016/j.phrs.2022.106197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 10/18/2022]
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Traxinger BR, Richert-Spuhler LE, Lund JM. Mucosal tissue regulatory T cells are integral in balancing immunity and tolerance at portals of antigen entry. Mucosal Immunol 2022; 15:398-407. [PMID: 34845322 PMCID: PMC8628059 DOI: 10.1038/s41385-021-00471-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 10/19/2021] [Accepted: 11/03/2021] [Indexed: 02/04/2023]
Abstract
Foxp3+ regulatory T cells (Tregs) are a subset of CD4+ T cells that exert suppressive control over other immune cells. Tregs are critical for preventing systemic autoimmunity and maintaining peripheral tolerance, and yet they also assist in orchestration of immunity to pathogenic insult, wherein they limit collateral immunopathology and assist in facilitating a fine balance between immune tolerance and effector activity. Tregs have been extensively studied in lymphoid tissues, and a growing body of work has characterized phenotypically distinct Tregs localized in various nonlymphoid tissue compartments. These tissue Tregs can perform location-specific, alternative functions, highlighting their dynamic, context-dependent roles. Tregs have also been identified in mucosal tissues where specialized physiological functions are paramount, including helping the host to respond appropriately to pathogenic versus innocuous antigens that are abundant at mucosal portals of antigen entry. As in other tissue Treg compartments, mucosal Tregs in the respiratory, gastrointestinal, and genitourinary tracts are distinct from circulating counterparts and can carry out mucosa-specific functions as well as classic suppressive functions that are the hallmark of Tregs. In this review, we summarize current knowledge regarding mucosal Tregs in both health and disease.
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Affiliation(s)
- Brianna R Traxinger
- Department of Global Health, University of Washington, Seattle, WA, USA
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Laura E Richert-Spuhler
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Jennifer M Lund
- Department of Global Health, University of Washington, Seattle, WA, USA.
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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Li W, Lou Y, Wang G, Zhang K, Xu L, Liu P, Xu LX. A Novel Multi-Mode Thermal Therapy for Colorectal Cancer Liver Metastasis: A Pilot Study. Biomedicines 2022; 10:biomedicines10020280. [PMID: 35203498 PMCID: PMC8869583 DOI: 10.3390/biomedicines10020280] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 01/17/2023] Open
Abstract
A novel multi-mode thermal therapy was developed for local tumor ablation and the systemic stimulation of anti-tumor immunity, consisting of a rapid liquid nitrogen freezing, and followed by the radiofrequency heating of target tumor tissue. This pilot study aimed to compare the therapeutic effects of the new therapy with conventional radiofrequency ablation (RFA) on patients with colorectal cancer liver metastasis (CRCLM). From August 2016 to September 2019, thirty-one patients with CRCLM received either multi-mode thermal therapy (n = 17) or RFA (n = 14). Triphasic contrast-enhanced magnetic resonance imaging (MRI), routine blood tests, and peripheral blood immune responses were evaluated before the treatment and in 1, 3, 6, and 12 months after. Local tumor response and progression-free survival (PFS) were assessed using the Kaplan-Meier method, and pre- and post-treatment immune cell counts were analyzed using Mann-Whitney U and Wilcoxon tests. A significantly longer PFS was observed in the multi-mode thermal therapy group in comparison to that of the conventional RFA group (median, 11.4 versus 3.4 months, p = 0.022). It was found that multi-mode therapy induced the functional maturation of dendritic cells, promoted CD4+ T cell-mediated antitumor responses, and decreased regulatory T cells, contributing to better therapeutic efficacy in CRCLM patients.
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Affiliation(s)
- Wentao Li
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center, Shanghai 200030, China; (W.L.); (L.X.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200030, China
| | - Yue Lou
- Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (Y.L.); (G.W.); (K.Z.)
| | - Guangzhi Wang
- Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (Y.L.); (G.W.); (K.Z.)
| | - Kangwei Zhang
- Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (Y.L.); (G.W.); (K.Z.)
| | - Lichao Xu
- Department of Interventional Radiology, Fudan University Shanghai Cancer Center, Shanghai 200030, China; (W.L.); (L.X.)
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200030, China
| | - Ping Liu
- Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (Y.L.); (G.W.); (K.Z.)
- Correspondence: (P.L.); (L.X.X.)
| | - Lisa X. Xu
- Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China; (Y.L.); (G.W.); (K.Z.)
- Correspondence: (P.L.); (L.X.X.)
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37
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Zhao W, Dai S, Yue L, Xu F, Gu J, Dai X, Qian X. Emerging mechanisms progress of colorectal cancer liver metastasis. Front Endocrinol (Lausanne) 2022; 13:1081585. [PMID: 36568117 PMCID: PMC9772455 DOI: 10.3389/fendo.2022.1081585] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastasis. The hepatic portal venous system, responsible for collecting most intestinal blood, makes the liver the most common site of CRC metastasis. The formation of liver metastases from colorectal cancer is a long and complex process. It involves the maintenance of primary tumors, vasculature invasion, distant colonization, and metastasis formation. In this review, we serve on how the CRC cells acquire stemness, invade the vascular, and colonize the liver. In addition, we highlight how the resident cells of the liver and immune cells interact with CRC cells. We also discuss the current immunotherapy approaches and challenges we face, and finally, we look forward to finding new therapeutic targets based on novel sequencing technologies.
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The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis. Cancers (Basel) 2021; 13:cancers13246206. [PMID: 34944826 PMCID: PMC8699466 DOI: 10.3390/cancers13246206] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Colorectal cancer (CRC) is the third most common cancer worldwide. Metastasis to secondary organs, such as the liver and lungs, is a key driver of CRC-related mortality. The tumor microenvironment, which consists of the primary cancer cells, as well as associated support and immune cells, significantly affects the behavior of CRC cells at the primary tumor site, as well as in metastatic lesions. In this paper, we review the role of the individual components of the tumor microenvironment on tumor progression, immune evasion, and metastasis, and we discuss the implications of these components on antitumor therapies. Abstract Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastases, most frequently to the liver and lung. In the primary tumor, as well as at each metastatic site, the cellular components of the tumor microenvironment (TME) contribute to tumor engraftment and metastasis. These include immune cells (macrophages, neutrophils, T lymphocytes, and dendritic cells) and stromal cells (cancer-associated fibroblasts and endothelial cells). In this review, we highlight how the TME influences tumor progression and invasion at the primary site and its function in fostering metastatic niches in the liver and lungs. We also discuss emerging clinical strategies to target the CRC TME.
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Zhao C, Chen J, Liu Y, Ju S, Wang G, Wang X. Large tumor suppressor 2 is a prognostic biomarker and correlated with immune infiltrates in colorectal cancer. Bioengineered 2021; 12:11648-11661. [PMID: 34699318 PMCID: PMC8810027 DOI: 10.1080/21655979.2021.1996513] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Colorectal cancer (CRC) is a common malignancy that has both low 5-year survival and high prevalence. Immunotherapy has achieved impressive progress for treatment of CRC, but still faces huge challenges. Although large tumor suppressor 2 (LATS2) is well accepted to be related to cancer progression, the prognostic potential and immune response role of LATS2 expression in CRC remain unclear. To investigate the value of LATS2 for prognosis and immune infiltration, a retrospective study of 213 CRC patients was carried out. We determined the expression of LATS2 in tumor tissues by immunohistochemistry. The results indicated that LATS2 expression was down-regulated in CRC tissues and clearly related to tumor differentiation (P = 0.002) and TNM stage (P = 0.002). Low LATS2 expression and TNM stage were subsequently identified as significant independent predictors of prognosis in CRC by univariate and multivariate analyses. In Kaplan–Meier survival analyses, CRC patients with elevated LATS2 expression and early TNM stage had better overall survival. We further found that LATS2 was involved in the regulation of immune-related pathways and that its expression was positively related to tumor-infiltrating immune cells by GSEA, TIMER, and ssGSEA analyses. In summary, our data imply that LATS2 may act as a cancer suppressor gene and be correlated with clinical prognosis and immune infiltration in CRC. Thus, LATS2 may be applied as a novel biomarker for predicting clinical outcomes and immune infiltration levels in CRC.
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Affiliation(s)
- Chengwen Zhao
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jianping Chen
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Yonghui Liu
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Shaoqing Ju
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.,School of Public Health, Nantong University, Nantong, Jiangsu, China
| | - Guihua Wang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Xudong Wang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.,School of Public Health, Nantong University, Nantong, Jiangsu, China
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DiToro D, Basu R. Emerging Complexity in CD4 +T Lineage Programming and Its Implications in Colorectal Cancer. Front Immunol 2021; 12:694833. [PMID: 34489941 PMCID: PMC8417887 DOI: 10.3389/fimmu.2021.694833] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 08/04/2021] [Indexed: 12/17/2022] Open
Abstract
The intestinal immune system has the difficult task of protecting a large environmentally exposed single layer of epithelium from pathogens without allowing inappropriate inflammatory responses. Unmitigated inflammation drives multiple pathologies, including the development of colorectal cancer. CD4+T cells mediate both the suppression and promotion of intestinal inflammation. They comprise an array of phenotypically and functionally distinct subsets tailored to a specific inflammatory context. This diversity of form and function is relevant to a broad array of pathologic and physiologic processes. The heterogeneity underlying both effector and regulatory T helper cell responses to colorectal cancer, and its impact on disease progression, is reviewed herein. Importantly, T cell responses are dynamic; they exhibit both quantitative and qualitative changes as the inflammatory context shifts. Recent evidence outlines the role of CD4+T cells in colorectal cancer responses and suggests possible mechanisms driving qualitative alterations in anti-cancer immune responses. The heterogeneity of T cells in colorectal cancer, as well as the manner and mechanism by which they change, offer an abundance of opportunities for more specific, and likely effective, interventional strategies.
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Affiliation(s)
- Daniel DiToro
- Brigham and Women's Hospital, Boston, MA, United States.,Harvard Medical School, Boston, MA, United States.,Ragon Institute of MGH MIT and Harvard, Cambridge, MA, United States
| | - Rajatava Basu
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham (UAB), Birmingham, AL, United States
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STAT6 Is Critical for the Induction of Regulatory T Cells In Vivo Controlling the Initial Steps of Colitis-Associated Cancer. Int J Mol Sci 2021; 22:ijms22084049. [PMID: 33919941 PMCID: PMC8070924 DOI: 10.3390/ijms22084049] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/09/2021] [Accepted: 04/09/2021] [Indexed: 01/05/2023] Open
Abstract
Inflammation is the main driver of the tumor initiation and progression in colitis-associated colorectal cancer (CAC). Recent findings have indicated that the signal transducer and activator of transcription 6 (STAT6) plays a fundamental role in the early stages of CAC, and STAT6 knockout (STAT6−/−) mice are highly resistant to CAC development. Regulatory T (Treg) cells play a major role in coordinating immunomodulation in cancer; however, the role of STAT6 in the induction and function of Treg cells is poorly understood. To clarify the contribution of STAT6 to CAC, STAT6−/− and wild type (WT) mice were subjected to an AOM/DSS regimen, and the frequency of peripheral and local Treg cells was determined during the progression of CAC. When STAT6 was lacking, a remarkable reduction in tumor growth was observed, which was associated with decreased inflammation and an increased number of CD4+CD25+Foxp3+ cells in the colon, circulation, and spleen, including an over-expression of TGF-beta, IL-10, and Foxp3, compared to WT mice, during the early stages of CAC development. Conversely, WT mice showed an inverse frequency of Treg cells compared with STAT6−/− mice, which was followed by intestinal tumor formation. Increased mucosal inflammation, histological damage, and tumorigenesis were restored to levels observed in WT mice when an early inhibition/depletion of Treg cells was performed in STAT6−/− mice. Thus, with STAT6 deficiency, an increased number of Treg cells induce resistance against tumorigenesis, arresting tumor-promoting inflammation. We reported a direct role of STAT6 in the induction and function of Treg cells during CAC development and suggest that STAT6 is a potential target for the modulation of immune response in colitis and CAC.
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Liu J, Huang X, Liu H, Wei C, Ru H, Qin H, Lai H, Meng Y, Wu G, Xie W, Mo X, Johnson CH, Zhang Y, Tang W. Immune landscape and prognostic immune-related genes in KRAS-mutant colorectal cancer patients. J Transl Med 2021; 19:27. [PMID: 33413474 PMCID: PMC7789428 DOI: 10.1186/s12967-020-02638-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 11/27/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND KRAS gene is the most common type of mutation reported in colorectal cancer (CRC). KRAS mutation-mediated regulation of immunophenotype and immune pathways in CRC remains to be elucidated. METHODS 535 CRC patients were used to compare the expression of immune-related genes (IRGs) and the abundance of tumor-infiltrating immune cells (TIICs) in the tumor microenvironment between KRAS-mutant and KRAS wild-type CRC patients. An independent dataset included 566 cases of CRC and an in-house RNA sequencing dataset were served as validation sets. An in-house dataset consisting of 335 CRC patients were used to analyze systemic immune and inflammatory state in the presence of KRAS mutation. An immue risk (Imm-R) model consist of IRG and TIICs for prognostic prediction in KRAS-mutant CRC patients was established and validated. RESULTS NF-κB and T-cell receptor signaling pathways were significantly inhibited in KRAS-mutant CRC patients. Regulatory T cells (Tregs) was increased while macrophage M1 and activated CD4 memory T cell was decreased in KRAS-mutant CRC. Prognosis correlated with enhanced Tregs, macrophage M1 and activated CD4 memory T cell and was validated. Serum levels of hypersensitive C-reactive protein (hs-CRP), CRP, and IgM were significantly decreased in KRAS-mutant compared to KRAS wild-type CRC patients. An immune risk model composed of VGF, RLN3, CT45A1 and TIICs signature classified CRC patients with distinct clinical outcomes. CONCLUSIONS KRAS mutation in CRC was associated with suppressed immune pathways and immune infiltration. The aberrant immune pathways and immune cells help to understand the tumor immune microenvironments in KRAS-mutant CRC patients.
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Affiliation(s)
- Jungang Liu
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
- Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, CT, 06520, USA
| | - Xiaoliang Huang
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Haizhou Liu
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Chunyin Wei
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Haiming Ru
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Haiquan Qin
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Hao Lai
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Yongsheng Meng
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Guo Wu
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Weishun Xie
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xianwei Mo
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Caroline H Johnson
- Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, CT, 06520, USA.
| | - Yawei Zhang
- Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, CT, 06520, USA.
| | - Weizhong Tang
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China.
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