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Zeng C, Niu F, Li H, Huang Z, Ke Y, Yu L, Chen M. Progress of IL-10 and liver metastasis. Cytokine 2025; 190:156932. [PMID: 40168924 DOI: 10.1016/j.cyto.2025.156932] [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: 05/03/2024] [Revised: 03/13/2025] [Accepted: 03/26/2025] [Indexed: 04/03/2025]
Abstract
Liver metastasis can occur in a wide range of cancers and have a significant impact on patient survival and prognosis. Once liver metastasis occurs, patients often lose the opportunity for surgery, and although a small percentage of patients can undergo hepatic resection to prolong survival, the benefit is not great. There were also many factors affecting liver metastasis, including reprogramming of the primary tumor metabolism, disturbances in the immune microenvironment and immune cells, alterations in the gut microbiota, and epigenetic changes. Interleukin-10 (IL-10) has a dual role as a cytokine that has been found in recent years to be pro-inflammatory as well as pro-liver metastasis. IL-10 exerts pro-metastatic effects mainly by regulating the polarization of tumor macrophages in the tumor microenvironment, especially by promoting the polarization of M2 macrophages. However, the role of IL-10 in tumorigenesis and progression remains controversial and the molecular mechanism involved in promoting liver metastasis is currently unclear. In view of the increasing role of IL-10 in promoting liver metastasis, this review summarizes the role of IL-10 in liver metastasis of colorectal cancer, breast cancer and other tumors in recent years, and provides ideas for subsequent clinical practice and basic research.
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Affiliation(s)
- Chuanfei Zeng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan, Hubei, 430000, PR China
| | - Fengyuan Niu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan, Hubei, 430000, PR China
| | - Huan Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan, Hubei, 430000, PR China
| | - Ziyin Huang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan, Hubei, 430000, PR China
| | - Yujia Ke
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan, Hubei, 430000, PR China
| | - Linxin Yu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan, Hubei, 430000, PR China
| | - Mingkai Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhang Zhidong Road, Wuhan, Hubei, 430000, PR China.
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Wan M, Yu H, Zhai H. Suppression of JAK2/STAT3 Pathway by Notoginsenoside R1 Reduces Epithelial-Mesenchymal Transition in Non-small Cell Lung Cancer. Mol Biotechnol 2025; 67:1526-1538. [PMID: 38565774 DOI: 10.1007/s12033-024-01136-3] [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: 11/24/2023] [Accepted: 02/21/2024] [Indexed: 04/04/2024]
Abstract
It has bene reported that a novel saponin-notoginsenoside R1 (NGR1) possesses strong anti-tumor activities. This study aimed to investigate the role and mechanism of NGR1 in non-small cell lung cancer (NSCLC). NSCLC cell viability, proliferation, migration, and invasiveness were assessed using the ex vivo assays. NSCLC xenograft mouse models were constructed to confirm the role of NGR1 in vivo. Epithelial-mesenchymal transition (EMT)-related proteins and key markers in the JAK2/STAT3 pathway were examined using immunoblotting and immunohistochemistry analyses. NGR1 treatment suppressed NSCLC cell growth ex vivo and in vivo. It also decreased the migratory and invasive capacities of NSCLC cells. Additionally, NGR1 increased E-cadherin expression and reduced N-cadherin, vimentin, and snail expression in TGF-β1-treated NSCLC cells and xenograft tumors. JAK2/STAT3 pathway was inhibited by NGR1. Moreover, a specific inhibitor of JAK2, AG490, or STAT3 silencing significantly enhanced the effects of NGR1 against the EMT process in NSCLC cells. NGR1 restrains EMT process in NSCLC by inactivating JAK2/STAT3 signaling, suggesting the potential of NGR1 in anti-NSCLC therapy.
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Affiliation(s)
- Min Wan
- Department of Medical Laboratory, Wuhan Hospital of Traditional Chinese Medicine, Wuhan, 430014, China
| | - Hong Yu
- Department of Medical Laboratory, Wuhan Hospital of Traditional Chinese Medicine, Wuhan, 430014, China
| | - Haoqing Zhai
- Department of Oncology Hematology, Qianjiang Central Hospital, No.22 Zhanghua Road, Qianjiang, 433100, Hubei, China.
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Zhu C, Liao JY, Liu YY, Chen ZY, Chang RZ, Chen XP, Zhang BX, Liang JN. Immune dynamics shaping pre-metastatic and metastatic niches in liver metastases: from molecular mechanisms to therapeutic strategies. Mol Cancer 2024; 23:254. [PMID: 39543660 PMCID: PMC11562679 DOI: 10.1186/s12943-024-02171-z] [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: 06/19/2024] [Accepted: 11/06/2024] [Indexed: 11/17/2024] Open
Abstract
Liver metastases are commonly detected in the advanced stages of various malignant tumors, representing a significant clinical challenge. Throughout the process of liver metastases formation, immune cells play a pivotal role, particularly in the pre-metastatic and metastatic niches within the liver. Immune cells establish extensive and intricate interactions with tumor cells and other components in the liver, collectively promoting and sustaining the growth of liver metastases. Despite the limited efficacy of existing therapeutic modalities against some advanced liver metastases, novel immune-based treatment approaches are continuously being explored and validated. Building on the systematic elucidation of the immunosuppressive characteristics of liver metastases, we explored the potential of novel immunotherapies applicable to patients with liver metastases from multiple dimensions.
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Affiliation(s)
- Chang Zhu
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Jing-Yu Liao
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Yi-Yang Liu
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Ze-Yu Chen
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Rui-Zhi Chang
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Xiao-Ping Chen
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Bi-Xiang Zhang
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.
| | - Jun-Nan Liang
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.
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Shiri AM, Zhang T, Bedke T, Zazara DE, Zhao L, Lücke J, Sabihi M, Fazio A, Zhang S, Tauriello DVF, Batlle E, Steglich B, Kempski J, Agalioti T, Nawrocki M, Xu Y, Riecken K, Liebold I, Brockmann L, Konczalla L, Bosurgi L, Mercanoglu B, Seeger P, Küsters N, Lykoudis PM, Heumann A, Arck PC, Fehse B, Busch P, Grotelüschen R, Mann O, Izbicki JR, Hackert T, Flavell RA, Gagliani N, Giannou AD, Huber S. IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction. J Hepatol 2024; 80:634-644. [PMID: 38160941 PMCID: PMC10964083 DOI: 10.1016/j.jhep.2023.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 12/12/2023] [Accepted: 12/18/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND & AIMS The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo. METHODS To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10. RESULTS We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. CONCLUSIONS Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases. IMPACT AND IMPLICATIONS Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.
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Affiliation(s)
- Ahmad Mustafa Shiri
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Tao Zhang
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Tanja Bedke
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Dimitra E Zazara
- Division for Experimental Feto-Maternal Medicine, Department of Obstetrics and Fetal Medicine, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany; University Children's Hospital, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany
| | - Lilan Zhao
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Jöran Lücke
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Morsal Sabihi
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Antonella Fazio
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Siwen Zhang
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Daniele V F Tauriello
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, The Netherlands
| | - Eduard Batlle
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Babett Steglich
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Jan Kempski
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Theodora Agalioti
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Mikołaj Nawrocki
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Yang Xu
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Kristoffer Riecken
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Imke Liebold
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Protozoa Immunology, Bernard-Nocht-Institute for Tropical Medicine, 20359 Hamburg, Germany
| | - Leonie Brockmann
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Leonie Konczalla
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Lidia Bosurgi
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Protozoa Immunology, Bernard-Nocht-Institute for Tropical Medicine, 20359 Hamburg, Germany
| | - Baris Mercanoglu
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Philipp Seeger
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Natalie Küsters
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Panagis M Lykoudis
- 3rd Department of Surgery, National & Kapodistrian University of Athens, Greece; Division of Surgery & Interventional Science, University College London (UCL), UK
| | - Asmus Heumann
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Petra C Arck
- University Children's Hospital, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany
| | - Boris Fehse
- Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Philipp Busch
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Rainer Grotelüschen
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Oliver Mann
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Jakob R Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Thilo Hackert
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Richard A Flavell
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Nicola Gagliani
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany
| | - Anastasios D Giannou
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
| | - Samuel Huber
- Section of Molecular Immunology and Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
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Ma M, Zheng Z, Li J, He Y, Kang W, Ye X. Association between the gut microbiota, inflammatory factors, and colorectal cancer: evidence from Mendelian randomization analysis. Front Microbiol 2024; 15:1309111. [PMID: 38562480 PMCID: PMC10982360 DOI: 10.3389/fmicb.2024.1309111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 03/06/2024] [Indexed: 04/04/2024] Open
Abstract
Background Colorectal cancer (CRC) is one of the most common malignant tumors primarily affecting individuals over the age of 50 years. Recent studies have suggested that the dysbiosis of the gut microbiota, a community of microorganisms in the human gut, is closely associated with the occurrence and development of CRC. Additionally, inflammatory factors (IFs) have also been reported to play a significant role in the development of CRC. However, the causal relationships between the gut microbiota, IFs, and CRC remain unclear. Methods In this study, we performed Mendelian randomization (MR) analysis using publicly available genome-wide association study (GWAS) data to explore the causal relationship between the gut microbiota, IFs, and CRC. The gut microbiota GWAS data were obtained from the MiBioGen study, while the IFs GWAS data were derived from the comprehensive analysis of three independent cohorts. Causal relationship analysis was conducted using appropriate instrumental variables (IVs) and statistical models. Results MR analysis of the gut microbiota and CRC revealed a negative correlation between the Lachnospiraceae species in the gut and CRC risk, while a positive correlation was observed between Porphyromonadaceae species, Lachnospiraceae UCG010 genus, Lachnospira genus, and Sellimonas genus in the gut, and CRC risk. Additionally, we observed a causal relationship between IL-10 and CRC risk. These findings suggest that the dysbiosis of the gut microbiota might be associated with an increased risk of CRC and that specific bacterial groups may play a crucial role in the occurrence and development of CRC. Conclusion Using MR analysis, this study revealed the causal relationships between the gut microbiota, IFs, and CRC. The negative correlation between the Lachnospiraceae species in the gut and CRC risk, as well as the causal relationship between IL-10 and CRC, provide important clues for the potential roles of gut microbiota regulation and inflammatory factor control in the prevention and treatment of CRC.
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Affiliation(s)
| | | | | | | | - Weiming Kang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xin Ye
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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Kuznetsova O, Fedyanin M, Zavalishina L, Moskvina L, Kuznetsova O, Lebedeva A, Tryakin A, Kireeva G, Borshchev G, Tjulandin S, Ignatova E. Prognostic and predictive role of immune microenvironment in colorectal cancer. World J Gastrointest Oncol 2024; 16:643-652. [PMID: 38577454 PMCID: PMC10989368 DOI: 10.4251/wjgo.v16.i3.643] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 12/20/2023] [Accepted: 01/22/2024] [Indexed: 03/12/2024] Open
Abstract
Colorectal cancer (CRC) represents a molecularly heterogeneous disease and one of the most frequent causes of cancer-related death worldwide. The traditional classification of CRC is based on pathomorphological and molecular characteristics of tumor cells (mucinous, ring-cell carcinomas, etc.), analysis of mechanisms of carcinogenesis involved (chromosomal instability, microsatellite instability, CpG island methylator phenotype) and mutational statuses of commonly altered genes (KRAS, NRAS, BRAF, APC, etc.), as well as expression signatures (CMS 1-4). It is also suggested that the tumor microenvironment is a key player in tumor progression and metastasis in CRC. According to the latest data, the immune microenvironment can also be predictive of the response to immune checkpoint inhibitors. In this review, we highlight how the immune environment influences CRC prognosis and sensitivity to systemic therapy.
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Affiliation(s)
- Olesya Kuznetsova
- Department of Chemotherapy, Federal State Budgetary Institution (N.N. Blokhin National Medical Research Center of Oncology) of the Ministry of Health of the Russian Federation, Moscow 115478, Russia
| | - Mikhail Fedyanin
- Department of Chemotherapy, Federal State Budgetary Institution (N.N. Blokhin National Medical Research Center of Oncology) of the Ministry of Health of the Russian Federation, Moscow 115478, Russia
| | - Larisa Zavalishina
- Department of Pathology, Russian Medical Academy of Continuous Professional Education, Moscow 123242, Russia
| | - Larisa Moskvina
- Department of Pathology, Russian Medical Academy of Continuous Professional Education, Moscow 123242, Russia
| | - Olga Kuznetsova
- Department of Pathology, Russian Medical Academy of Continuous Professional Education, Moscow 123242, Russia
| | | | - Alexey Tryakin
- Department of Chemotherapy, Federal State Budgetary Institution (N.N. Blokhin National Medical Research Center of Oncology) of the Ministry of Health of the Russian Federation, Moscow 115478, Russia
| | - Galina Kireeva
- Federal State Budgetary Institution “National Medical and Surgical Center named after N.I. Pirogov” of the Ministry of Health of the Russian Federation, Moscow 105203, Russia
| | - Gleb Borshchev
- Federal State Budgetary Institution “National Medical and Surgical Center named after N.I. Pirogov” of the Ministry of Health of the Russian Federation, Moscow 105203, Russia
| | - Sergei Tjulandin
- Department of Chemotherapy, Federal State Budgetary Institution (N.N. Blokhin National Medical Research Center of Oncology) of the Ministry of Health of the Russian Federation, Moscow 115478, Russia
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Yao S, Han Y, Yang M, Jin K, Lan H. It's high-time to re-evaluate the value of induced-chemotherapy for reinforcing immunotherapy in colorectal cancer. Front Immunol 2023; 14:1241208. [PMID: 37920463 PMCID: PMC10619163 DOI: 10.3389/fimmu.2023.1241208] [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: 06/16/2023] [Accepted: 10/09/2023] [Indexed: 11/04/2023] Open
Abstract
Immunotherapy has made significant advances in the treatment of colorectal cancer (CRC), revolutionizing the therapeutic landscape and highlighting the indispensable role of the tumor immune microenvironment. However, some CRCs have shown poor response to immunotherapy, prompting investigation into the underlying reasons. It has been discovered that certain chemotherapeutic agents possess immune-stimulatory properties, including the induction of immunogenic cell death (ICD), the generation and processing of non-mutated neoantigens (NM-neoAgs), and the B cell follicle-driven T cell response. Based on these findings, the concept of inducing chemotherapy has been introduced, and the combination of inducing chemotherapy and immunotherapy has become a standard treatment option for certain cancers. Clinical trials have confirmed the feasibility and safety of this approach in CRC, offering a promising method for improving the efficacy of immunotherapy. Nevertheless, there are still many challenges and difficulties ahead, and further research is required to optimize its use.
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Affiliation(s)
- Shiya Yao
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Yuejun Han
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Mengxiang Yang
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
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Das K, Basak M, Mahata T, Biswas S, Mukherjee S, Kumar P, Moniruzzaman M, Stewart A, Maity B. Cardiac RGS7 and RGS11 drive TGFβ1-dependent liver damage following chemotherapy exposure. FASEB J 2023; 37:e23064. [PMID: 37440271 DOI: 10.1096/fj.202300094r] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 06/03/2023] [Accepted: 06/15/2023] [Indexed: 07/14/2023]
Abstract
Off target damage to vital organ systems is an unfortunate side effect of cancer chemotherapy and remains a major limitation to the use of these essential drugs in the clinic. Despite decades of research, the mechanisms conferring susceptibility to chemotherapy driven cardiotoxicity and hepatotoxicity remain unclear. In the livers of patients with a history of chemotherapy, we observed a twofold increase in expression of G protein regulator RGS7 and a corresponding decrease in fellow R7 family member RGS11. Knockdown of RGS7 via introduction of RGS7 shRNA via tail vein injection decreased doxorubicin-induced hepatic collagen and lipid deposition, glycogen accumulation, and elevations in ALT, AST, and triglycerides by approximately 50%. Surprisingly, a similar result could be achieved via introduction of RGS7 shRNA directly to the myocardium without impacting RGS7 levels in the liver directly. Indeed, doxorubicin-treated cardiomyocytes secrete the endocrine factors transforming growth factor β1 (TGFβ1) and TGFβ superfamily binding protein follistatin-related protein 1 (FSTL1). Importantly, RGS7 overexpression in the heart was sufficient to recapitulate the impacts of doxorubicin on the liver and inhibition of TGFβ1 signaling with the receptor blocker GW788388 ameliorated the effect of cardiac RGS7 overexpression on hepatic fibrosis, steatosis, oxidative stress, and cell death as well as the resultant elevation in liver enzymes. Together these data demonstrate that RGS7 controls both the release of TGFβ1 from the heart and the profibrotic and pro-oxidant actions of TGFβ1 in the liver and emphasize the functional significance of endocrine cardiokine signaling in the pathogenesis of chemotherapy drive multiorgan damage.
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Affiliation(s)
- Kiran Das
- Centre of Biomedical Research (CBMR), Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Madhuri Basak
- Centre of Biomedical Research (CBMR), Lucknow, India
| | - Tarun Mahata
- Centre of Biomedical Research (CBMR), Lucknow, India
| | - Sayan Biswas
- Forensic Medicine, College of Medicine and Sagore Dutta Hospital, Kolkata, India
| | | | - Pranesh Kumar
- Institute of Pharmaceutical Sciences, University of Lucknow, Lucknow, India
| | | | - Adele Stewart
- Department of Biomedical Science, Florida Atlantic University, Jupiter, Florida, USA
| | - Biswanath Maity
- Centre of Biomedical Research (CBMR), Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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9
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Kaps L, Limeres MJ, Schneider P, Svensson M, Zeyn Y, Fraude S, Cacicedo ML, Galle PR, Gehring S, Bros M. Liver Cell Type-Specific Targeting by Nanoformulations for Therapeutic Applications. Int J Mol Sci 2023; 24:11869. [PMID: 37511628 PMCID: PMC10380755 DOI: 10.3390/ijms241411869] [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: 05/05/2023] [Revised: 06/21/2023] [Accepted: 07/21/2023] [Indexed: 07/30/2023] Open
Abstract
Hepatocytes exert pivotal roles in metabolism, protein synthesis and detoxification. Non-parenchymal liver cells (NPCs), largely comprising macrophages, dendritic cells, hepatic stellate cells and liver sinusoidal cells (LSECs), serve to induce immunological tolerance. Therefore, the liver is an important target for therapeutic approaches, in case of both (inflammatory) metabolic diseases and immunological disorders. This review aims to summarize current preclinical nanodrug-based approaches for the treatment of liver disorders. So far, nano-vaccines that aim to induce hepatitis virus-specific immune responses and nanoformulated adjuvants to overcome the default tolerogenic state of liver NPCs for the treatment of chronic hepatitis have been tested. Moreover, liver cancer may be treated using nanodrugs which specifically target and kill tumor cells. Alternatively, nanodrugs may target and reprogram or deplete immunosuppressive cells of the tumor microenvironment, such as tumor-associated macrophages. Here, combination therapies have been demonstrated to yield synergistic effects. In the case of autoimmune hepatitis and other inflammatory liver diseases, anti-inflammatory agents can be encapsulated into nanoparticles to dampen inflammatory processes specifically in the liver. Finally, the tolerance-promoting activity especially of LSECs has been exploited to induce antigen-specific tolerance for the treatment of allergic and autoimmune diseases.
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Affiliation(s)
- Leonard Kaps
- I. Department of Medicine, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - María José Limeres
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Paul Schneider
- I. Department of Medicine, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Malin Svensson
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Yanira Zeyn
- Department of Dermatology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Silvia Fraude
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Maximiliano L Cacicedo
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Peter R Galle
- I. Department of Medicine, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Stephan Gehring
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Matthias Bros
- Department of Dermatology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
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10
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Zhang Y, Zhao X, Gao C, Lin LY, Li Y. Treatment outcome analysis of bevacizumab combined with cyclophosphamide and oxaliplatin in advanced pseudomyxoma peritonei. World J Gastrointest Surg 2023; 15:1149-1158. [PMID: 37405093 PMCID: PMC10315110 DOI: 10.4240/wjgs.v15.i6.1149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 03/18/2023] [Accepted: 04/14/2023] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND Pseudomyxoma peritonei (PMP) is a rare peritoneal malignant tumor syndrome. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is its standard treatment. However, there are few studies and insufficient evidence regarding systemic chemotherapy of advanced PMP. Regimens for colorectal cancer are often used clinically, but there is no uniform standard for late-stage treatment.
AIM To determine if bevacizumab combined with cyclophosphamide and oxaliplatin (Bev+CTX+OXA) is effective for treatment of advanced PMP. The primary study endpoint was progression-free survival (PFS).
METHODS Retrospective analysis was conducted on the clinical data of patients with advanced PMP who received Bev+CTX+OXA regimen (bevacizumab 7.5 mg/kg ivgtt d1, oxaliplatin 130 mg/m2 ivgtt d1 and cyclophosphamide 500 mg/m2 ivgtt d1, q3w) in our center from December 2015 to December 2020. Objective response rate (ORR), disease control rate (DCR) and incidence of adverse events were evaluated. PFS was followed up. Kaplan-Meier method was used to draw survival curve, and log-rank test was used for comparison between groups. Multivariate Cox proportional hazards regression model was used to analyze the independent influencing factors of PFS.
RESULTS A total of 32 patients were enrolled. After 2 cycles, the ORR and DCR were 3.1% and 93.7%, respectively. The median follow-up time was 7.5 mo. During the follow-up period, 14 patients (43.8%) had disease progression, and the median PFS was 8.9 mo. Stratified analysis showed that the PFS of patients with a preoperative increase in CA125 (8.9 vs 2.1, P = 0.022) and a completeness of cytoreduction score of 2-3 (8.9 vs 5.0, P = 0.043) was significantly longer than that of the control group. Multivariate analysis showed that a preoperative increase in CA125 was an independent prognostic factor for PFS (HR = 0.245, 95%CI: 0.066-0.904, P = 0.035).
CONCLUSION Our retrospective assessment confirmed that the Bev+CTX+OXA regimen is effective in second- or posterior-line treatment of advanced PMP and that adverse reactions can be tolerated. A preoperative increase in CA125 is an independent prognostic factor of PFS.
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Affiliation(s)
- Ying Zhang
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Xin Zhao
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Chao Gao
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Lin-Yu Lin
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Yan Li
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
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11
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Ros J, Balconi F, Baraibar I, Saoudi Gonzalez N, Salva F, Tabernero J, Elez E. Advances in immune checkpoint inhibitor combination strategies for microsatellite stable colorectal cancer. Front Oncol 2023; 13:1112276. [PMID: 36816981 PMCID: PMC9932591 DOI: 10.3389/fonc.2023.1112276] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/18/2023] [Indexed: 02/05/2023] Open
Abstract
Immune checkpoint inhibitors have reshaped the prognostic of several tumor types, including metastatic colorectal tumors with microsatellite instability (MSI). However, 90-95% of metastatic colorectal tumors are microsatellite stable (MSS) in which immunotherapy has failed to demonstrate meaningful clinical results. MSS colorectal tumors are considered immune-cold tumors. Several factors have been proposed to account for this lack of response to immune checkpoint blockade including low levels of tumor infiltrating lymphocytes, low tumor mutational burden, a high rate of WNT/β-catenin pathway mutations, and liver metastases which have been associated with immunosuppression. However, studies with novel combinations based on immune checkpoint inhibitors are showing promising activity in MSS colorectal cancer. Here, we review the underlying biological facts that preclude immunotherapy activity, and detail the different immune checkpoint inhibitor combinations evaluated, along with novel immune-based therapies, to overcome innate mechanisms of resistance in MSS colorectal cancer.
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Affiliation(s)
- Javier Ros
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain,Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
| | - Francesca Balconi
- Medical Oncology, University Hospital and University of Cagliari, Cagliari, Italy
| | - Iosune Baraibar
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - Francesc Salva
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Josep Tabernero
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Elena Elez
- Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain,*Correspondence: Elena Elez,
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12
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Fe 3O 4 Nanoparticles in Combination with 5-FU Exert Antitumor Effects Superior to Those of the Active Drug in a Colon Cancer Cell Model. Pharmaceutics 2023; 15:pharmaceutics15010245. [PMID: 36678874 PMCID: PMC9865889 DOI: 10.3390/pharmaceutics15010245] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/05/2023] [Accepted: 01/07/2023] [Indexed: 01/13/2023] Open
Abstract
(1) Background: Colon cancer is one of the most common cancer types, and treatment options, unfortunately, do not continually improve the survival rate of patients. With the unprecedented development of nanotechnologies, nanomedicine has become a significant direction in cancer research. Indeed, chemotherapeutics with nanoparticles (NPs) in cancer treatment is an outstanding new treatment principle. (2) Methods: Fe3O4 NPs were synthesized and characterized. Caco-2 colon cancer cells were treated during two different periods (24 and 72 h) with Fe3O4 NPs (6 μg/mL), various concentrations of 5-FU (4−16 μg/mL), and Fe3O4 NPs in combination with 5-FU (4−16 μg/mL) (Fe3O4 NPs + 5-FU). (3) Results: The MTT assay showed that treating the cells with Fe3O4 NPs + 5-FU at 16 µg/mL for 24 or 72 h decreased cell viability and increased their LDH release (p < 0.05 and p < 0.01, respectively). Furthermore, at the same treatment concentrations, total antioxidant capacity (TAC) was decreased (p < 0.05 and p < 0.01, respectively), and total oxidant status (TOS) increased (p < 0.05 and p < 0.01, respectively). Moreover, after treatment with Fe3O4-NPs + 5-FU, the IL-10 gene was downregulated and PTEN gene expression was upregulated (p < 0.05 and p < 0.01, respectively) compared with those of the control. (4) Conclusions: Fe3O4 NPs exert a synergistic cytotoxic effect with 5-FU on Caco-2 cells at concentrations below the active drug threshold levels.
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13
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Ishitobi K, Kotani H, Iida Y, Taniura T, Notsu Y, Tajima Y, Harada M. A modulatory effect of L-arginine supplementation on anticancer effects of chemoimmunotherapy in colon cancer-bearing aged mice. Int Immunopharmacol 2022; 113:109423. [DOI: 10.1016/j.intimp.2022.109423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 10/21/2022] [Accepted: 10/31/2022] [Indexed: 11/10/2022]
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14
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Sahin IH, Ciombor KK, Diaz LA, Yu J, Kim R. Immunotherapy for Microsatellite Stable Colorectal Cancers: Challenges and Novel Therapeutic Avenues. Am Soc Clin Oncol Educ Book 2022; 42:1-12. [PMID: 35658496 DOI: 10.1200/edbk_349811] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
With the development of immune checkpoint inhibitors, immunotherapy researchers have facilitated substantial progress for patients with mismatch repair deficient/microsatellite instability-high colorectal cancer, which has led to practice changes at a head-spinning pace. However, this benefit has not been translated into microsatellite stable colorectal cancer, which carries the hallmarks of chromosomal instability. So far, clinical trials have not shown any substantial clinical benefits of immune checkpoint inhibitor therapy for patients with microsatellite stable colorectal cancer, which has been disappointing. Recently, combinations of immune checkpoint inhibitors with tyrosine kinase inhibitors and targeted therapies have been investigated for potential synergistic effects that may increase antitumor activity in the tumor microenvironment and achieve more substantial clinical and radiologic responses. In this article, we discuss the current state of the science for the use of immune checkpoint inhibitors in microsatellite stable colorectal cancers, and we review the molecular underpinnings of inherited physiologic barriers for the delivery of effective immunotherapy. We also elaborate on existing therapeutic opportunities to convert microsatellite stable colorectal cancer into an "immune hot" cancer, which may define the future treatment paradigm of colorectal cancer for which there is a great unmet need.
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Affiliation(s)
| | | | - Luis A Diaz
- Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Richard Kim
- H. Lee Moffitt Cancer Center and Research Institute, Tampa FL
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15
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Zhang F, Qiao S. Research Progress on the Relationship Between Inflammation and Colorectal Cancer. Ann Gastroenterol Surg 2022; 6:204-211. [PMID: 35261946 PMCID: PMC8889855 DOI: 10.1002/ags3.12517] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/15/2021] [Accepted: 09/29/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is one of the common malignant tumors. Relevant epidemiology and a large number of experimental studies have proved that chronic inflammation is highly correlated with the occurrence and development of colorectal cancer. And inflammatory bowel disease has been proven to be an independent risk factor for colorectal cancer. Various inflammatory cells participate in the establishment of the chronic inflammatory intestinal microenvironment required for the onset of colorectal cancer. The abnormal signal pathways mediated by various inflammatory factors and inflammatory mediators promote the occurrence of tumors, which are related to colorectal cancer and pathogenesis-related inflammation mechanisms. At the gene level, miRNAs can also affect the pathogenesis of colorectal cancer by regulating mesenchymal epithelial transformation. This article reviews the relationship between inflammation and colorectal cancer as well as the related inflammatory mechanisms.
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Affiliation(s)
- Feng Zhang
- Department of General SurgeryTongren Municipal People’s Hospital of Guizhou Medical University (GMU)GuizhouChina
| | - Song Qiao
- Department of General SurgeryTongren Municipal People’s Hospital of Guizhou Medical University (GMU)GuizhouChina
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16
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Chemotherapy: a double-edged sword in cancer treatment. Cancer Immunol Immunother 2021; 71:507-526. [PMID: 34355266 DOI: 10.1007/s00262-021-03013-3] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 07/07/2021] [Indexed: 12/24/2022]
Abstract
Chemotherapy is a well-known and effective treatment for different cancers; unfortunately, it has not been as efficient in the eradication of all cancer cells as been expected. The mechanism of this failure was not fully clarified, yet. Meanwhile, alterations in the physiologic conditions of the tumor microenvironment (TME) were suggested as one of the underlying possibilities. Chemotherapy drugs can activate multiple signaling pathways and augment the secretion of inflammatory mediators. Inflammation may show two opposite roles in the TME. On the one hand, inflammation, as an innate immune response, tries to suppress tumor growth but on the other hand, it might be not powerful enough to eradicate the cancer cells and even it can provide appropriate conditions for cancer promotion and relapse as well. Therefore, the administration of mild anti-inflammatory drugs during chemotherapy might result in more successful clinical results. Here, we will review and discuss this hypothesis. Most chemotherapy agents are triggers of inflammation in the tumor microenvironment through inducing the production of senescence-associated secretory phenotype (SASP) molecules. Some chemotherapy agents can induce systematic inflammation by provoking TLR4 signaling or triggering IL-1B secretion through the inflammasome pathway. NF-kB and MAPK are key signaling pathways of inflammation and could be activated by several chemotherapy drugs. Furthermore, inflammation can play a key role in cancer development, metastasis and exacerbation.
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17
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Treatment with lentiviral vectors encoding shRNA against interleukin 10 modulates the immunosuppressive activity of murine colon carcinoma-associated myeloid-derived suppressor cells. Oncol Lett 2021; 22:582. [PMID: 34122633 PMCID: PMC8190769 DOI: 10.3892/ol.2021.12843] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 03/23/2021] [Indexed: 12/22/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity and their accumulation is often associated with poor prognosis. The aim of the present study was to determine the mechanisms of action of lentiviral vectors encoding short hairpin (sh)RNA against interleukin-10 (IL-10), with particular emphasis on their influence on the activity of tumor-derived MDSCs. Lentiviral vectors encoding shRNA against IL-10 (shIL-10 LVs) were utilized to silence the expression of IL-10 either in MDSCs that were generated ex vivo from bone marrow cells cultured in the presence of supernatant from MC38 colon carcinoma cells, or in situ in the MC38 murine colon carcinoma environment. Although monocytic MDSCs (M-MDSCs) transduced with shIL-10 LVs exhibited increased suppressor activity, transduction of polymorphonuclear MDSCs (PMN-MDSCs) appeared to reduce their ability to inhibit T lymphocyte functions. Analysis of EGFP expression in MC38 tumors revealed that intratumorally inoculated shIL-10 LVs transduced tumor-infiltrating myeloid cells with the highest efficiency and, led to a decreased IL-10 level in the tumor microenvironment. However, the effect was accompanied by increased influx of PMN-MDSCs into tumors observed both on the 6th and on the 10th day after shIL-10 LV injections. Nevertheless, it was noted that suppressor activity of myeloid cells isolated from tumors was dependent on the efficiency of tumor-derived PMN-MDSC transduction with shIL-10 LVs. The increased percentage of transduced PMN-MDSCs on the 10th day was associated with diminished immunosuppressive activity of tumor-derived myeloid cells and an elevated ratio of cytotoxic T lymphocytes to M-MDSCs. The obtained data indicated that treatment with shIL-10 LVs may result in modulation of the immunosuppressive activity of MC38 colon carcinoma-derived MDSCs.
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18
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Hall MR, Dehbi HM, Banerjee S, Lord R, Clamp A, Ledermann JA, Nicum S, Lilleywhite R, Bowen R, Michael A, Feeney A, Glasspool R, Hackshaw A, Rustin G. A phase II randomised, placebo-controlled trial of low dose (metronomic) cyclophosphamide and nintedanib (BIBF1120) in advanced ovarian, fallopian tube or primary peritoneal cancer. Gynecol Oncol 2020; 159:692-698. [PMID: 33077258 DOI: 10.1016/j.ygyno.2020.09.048] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 09/27/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND We investigated the safety and efficacy of a combination of the oral tyrosine kinase inhibitor, nintedanib (BIBF 1120) with oral cyclophosphamide in patients with relapsed ovarian cancer. PATIENTS AND METHODS Patients with relapsed ovarian, fallopian tube or primary peritoneal cancer received oral cyclophosphamide (100 mg o.d.) and were randomised (1,1) to also have either oral nintedanib or placebo. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), response rate, toxicity, and quality of life. RESULTS 117 patients were randomised, 3 did not start trial treatment, median age 64 years. Forty-five (39%) had received ≥5 lines chemotherapy. 30% had received prior bevacizumab. The median OS was 6.8 (nintedanib) versus 6.4 (placebo) months (hazard ratio 1.08; 95% confidence interval 0.72-1.62; P = 0.72). The 6-month PFS rate was 29.6% versus 22.8% (P = 0.57). Grade 3/4 adverse events occurred in 64% (nintedanib) versus 54% (placebo) of patients (P = 0.28); the most frequent G3/4 toxicities were lymphopenia (18.6% nintedanib versus 16.4% placebo), diarrhoea (13.6% versus 0%), neutropenia (11.9% versus 0%), fatigue (10.2% versus 9.1%), and vomiting (10.2% versus 7.3%). Patients who had received prior bevacizumab treatment had 52 days less time on treatment (P < 0.01). 26 patients (23%) took oral cyclophosphamide for ≥6 months. There were no differences in quality of life between treatment arms. CONCLUSIONS This is the largest reported cohort of patients with relapsed ovarian cancer treated with oral cyclophosphamide. Nintedanib did not improve outcomes when added to oral cyclophosphamide. Although not significant, more patients than expected remained on treatment for ≥6 months. This may reflect a higher proportion of patients with more indolent disease or the higher dose of cyclophosphamide used. CLINICAL TRIAL REGISTRATION Clinicaltrials.govNCT01610869.
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Affiliation(s)
- M R Hall
- Mount Vernon Cancer Centre, Northwood, UK.
| | - H-M Dehbi
- Comprehensive Clinical Trials Unit at UCL, London, UK.
| | - S Banerjee
- Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK.
| | - R Lord
- Clatterbridge Cancer Centre, Liverpool, UK.
| | - A Clamp
- The Christie NHS Foundation Trust and University of Manchester, UK.
| | - J A Ledermann
- Cancer Research UK & UCL Cancer Trials Centre, London, UK.
| | - S Nicum
- Churchill Hospital, Oxford, UK.
| | - R Lilleywhite
- Cancer Research UK & UCL Cancer Trials Centre, London, UK.
| | - R Bowen
- Royal United Hospital, Bath, UK.
| | - A Michael
- Royal Surrey County Hospital, Guildford, UK.
| | - A Feeney
- Cancer Research UK & UCL Cancer Trials Centre, London, UK.
| | | | - A Hackshaw
- Cancer Research UK & UCL Cancer Trials Centre, London, UK.
| | - G Rustin
- Mount Vernon Cancer Centre, Northwood, UK.
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19
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Müller L, Berkeley R, Barr T, Ilett E, Errington-Mais F. Past, Present and Future of Oncolytic Reovirus. Cancers (Basel) 2020; 12:E3219. [PMID: 33142841 PMCID: PMC7693452 DOI: 10.3390/cancers12113219] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/28/2020] [Accepted: 10/30/2020] [Indexed: 12/12/2022] Open
Abstract
Oncolytic virotherapy (OVT) has received significant attention in recent years, especially since the approval of talimogene Laherparepvec (T-VEC) in 2015 by the Food and Drug administration (FDA). Mechanistic studies of oncolytic viruses (OVs) have revealed that most, if not all, OVs induce direct oncolysis and stimulate innate and adaptive anti-tumour immunity. With the advancement of tumour modelling, allowing characterisation of the effects of tumour microenvironment (TME) components and identification of the cellular mechanisms required for cell death (both direct oncolysis and anti-tumour immune responses), it is clear that a "one size fits all" approach is not applicable to all OVs, or indeed the same OV across different tumour types and disease locations. This article will provide an unbiased review of oncolytic reovirus (clinically formulated as pelareorep), including the molecular and cellular requirements for reovirus oncolysis and anti-tumour immunity, reports of pre-clinical efficacy and its overall clinical trajectory. Moreover, as it is now abundantly clear that the true potential of all OVs, including reovirus, will only be reached upon the development of synergistic combination strategies, reovirus combination therapeutics will be discussed, including the limitations and challenges that remain to harness the full potential of this promising therapeutic agent.
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