Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophages
Background Colony-stimulating factor 1 receptor (CSF1R), a classic tyrosine kinase receptor, has been identified as a proto-oncogene in multiple cancers. The CSF1/CSF1R axis is essential for the survival and differentiation of M2-phenotype tumor-associated macrophages (M2 TAMs). However, we found he...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2022-12-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/12/e005610.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850163420044722176 |
|---|---|
| author | Rui Ma Ping Yuan Xiaolin Wang Yingjie Li Meijin Huang Huichuan Yu Yanxin Luo Mingxuan Zhu Liangliang Bai Xiaoxia Liu Shaoyong Peng Yumo Xie Hong Bai Jinxin Lin Linping Wu |
| author_facet | Rui Ma Ping Yuan Xiaolin Wang Yingjie Li Meijin Huang Huichuan Yu Yanxin Luo Mingxuan Zhu Liangliang Bai Xiaoxia Liu Shaoyong Peng Yumo Xie Hong Bai Jinxin Lin Linping Wu |
| author_sort | Rui Ma |
| collection | DOAJ |
| description | Background Colony-stimulating factor 1 receptor (CSF1R), a classic tyrosine kinase receptor, has been identified as a proto-oncogene in multiple cancers. The CSF1/CSF1R axis is essential for the survival and differentiation of M2-phenotype tumor-associated macrophages (M2 TAMs). However, we found here that the CSF1R expression was abnormally down-regulated in colorectal cancer (CRC), and its biological functions and underlying mechanisms have become elusive in CRC progression.Methods The expression of class III receptor tyrosine kinases in CRC and normal intestinal mucosa was accessed using The Cancer Genome Atlas and Gene Expression Omnibus datasets and was further validated by our tested cohort. CSF1R was reconstructed in CRC cells to identify its biological functions in vitro and in vivo. We compared CSF1R expression and methylation differences between CRC cells and macrophages. Furthermore, a co-culture system was used to mimic a competitive mechanism between CSF1R-overexpressed CRC cells and M2-like macrophages. We utilized a CSF1R inhibitor PLX3397 to ablate M2 TAMs and evaluated its efficacy on CRC treatment in animal models.Results We found here that the CSF1R is silenced in CRC, and the reintroduced expression of the receptor in CRC cells can be cleaved by caspases and constrain tumor growth in vitro and in vivo, functioning as a tumor suppressor gene. We further identified CSF1R as a novel dependence receptor, which has the potential to act as either a tumor suppressor gene or an oncogene, depending on its activated state. In CRC tumors, CSF1R expression is enriched in TAMs, and its expression is associated with poor prognosis in patients ith CRC. In a co-culture system, CRC cells expressing CSF1R compete with M2-like macrophages for CSF1R ligands, resulting in a decrease in CSF1R activation and cell proliferation in macrophages. Blocking CSF1R by PLX3397 could deplete M2 TAMs and augments CD8+ T cell infiltration, effectively inhibiting tumor growth and metastasis and improving responses to chemotherapy and immunotherapy.Conclusion Our findings revealed that CSF1R is a novel identified dependence receptor silenced in CRC. The silence abalienates its ligands to stimulate CSF1R expressed on M2 TAMs, which is an appealing therapeutic target for M2 TAM depletion and CRC treatment. |
| format | Article |
| id | doaj-art-4f55d7bbb7c54ab7b085143a3b1b7b8b |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-12-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-4f55d7bbb7c54ab7b085143a3b1b7b8b2025-08-20T02:22:16ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-12-01101210.1136/jitc-2022-005610Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophagesRui Ma0Ping Yuan1Xiaolin Wang2Yingjie Li3Meijin Huang4Huichuan Yu5Yanxin Luo6Mingxuan Zhu7Liangliang Bai8Xiaoxia Liu9Shaoyong Peng10Yumo Xie11Hong Bai12Jinxin Lin13Linping Wu14Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, ChinaCardio-Pulmonary Circulation, Tongji University Affiliated Shanghai Pulmonary Hospital, Shanghai, ChinaGuangdong Institute of Gastroenterology, The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing, ChinaGuangdong Institute of Gastroenterology, The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, ChinaGuangdong Institute of Gastroenterology, The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, ChinaDepartment of Colorectal Surgery, The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, ChinaGuangdong Institute of Gastroenterology, The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, ChinaSchool of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, ChinaGuangdong Institute of Gastroenterology, The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, ChinaGuangdong Institute of Gastroenterology, The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, ChinaGuangdong Institute of Gastroenterology, The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, ChinaGuangdong Institute of Gastroenterology, The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, ChinaGuangdong Institute of Gastroenterology, The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, ChinaCenter for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, ChinaBackground Colony-stimulating factor 1 receptor (CSF1R), a classic tyrosine kinase receptor, has been identified as a proto-oncogene in multiple cancers. The CSF1/CSF1R axis is essential for the survival and differentiation of M2-phenotype tumor-associated macrophages (M2 TAMs). However, we found here that the CSF1R expression was abnormally down-regulated in colorectal cancer (CRC), and its biological functions and underlying mechanisms have become elusive in CRC progression.Methods The expression of class III receptor tyrosine kinases in CRC and normal intestinal mucosa was accessed using The Cancer Genome Atlas and Gene Expression Omnibus datasets and was further validated by our tested cohort. CSF1R was reconstructed in CRC cells to identify its biological functions in vitro and in vivo. We compared CSF1R expression and methylation differences between CRC cells and macrophages. Furthermore, a co-culture system was used to mimic a competitive mechanism between CSF1R-overexpressed CRC cells and M2-like macrophages. We utilized a CSF1R inhibitor PLX3397 to ablate M2 TAMs and evaluated its efficacy on CRC treatment in animal models.Results We found here that the CSF1R is silenced in CRC, and the reintroduced expression of the receptor in CRC cells can be cleaved by caspases and constrain tumor growth in vitro and in vivo, functioning as a tumor suppressor gene. We further identified CSF1R as a novel dependence receptor, which has the potential to act as either a tumor suppressor gene or an oncogene, depending on its activated state. In CRC tumors, CSF1R expression is enriched in TAMs, and its expression is associated with poor prognosis in patients ith CRC. In a co-culture system, CRC cells expressing CSF1R compete with M2-like macrophages for CSF1R ligands, resulting in a decrease in CSF1R activation and cell proliferation in macrophages. Blocking CSF1R by PLX3397 could deplete M2 TAMs and augments CD8+ T cell infiltration, effectively inhibiting tumor growth and metastasis and improving responses to chemotherapy and immunotherapy.Conclusion Our findings revealed that CSF1R is a novel identified dependence receptor silenced in CRC. The silence abalienates its ligands to stimulate CSF1R expressed on M2 TAMs, which is an appealing therapeutic target for M2 TAM depletion and CRC treatment.https://jitc.bmj.com/content/10/12/e005610.full |
| spellingShingle | Rui Ma Ping Yuan Xiaolin Wang Yingjie Li Meijin Huang Huichuan Yu Yanxin Luo Mingxuan Zhu Liangliang Bai Xiaoxia Liu Shaoyong Peng Yumo Xie Hong Bai Jinxin Lin Linping Wu Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophages Journal for ImmunoTherapy of Cancer |
| title | Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophages |
| title_full | Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophages |
| title_fullStr | Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophages |
| title_full_unstemmed | Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophages |
| title_short | Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophages |
| title_sort | silence of a dependence receptor csf1r in colorectal cancer cells activates tumor associated macrophages |
| url | https://jitc.bmj.com/content/10/12/e005610.full |
| work_keys_str_mv | AT ruima silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages AT pingyuan silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages AT xiaolinwang silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages AT yingjieli silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages AT meijinhuang silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages AT huichuanyu silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages AT yanxinluo silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages AT mingxuanzhu silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages AT liangliangbai silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages AT xiaoxialiu silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages AT shaoyongpeng silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages AT yumoxie silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages AT hongbai silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages AT jinxinlin silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages AT linpingwu silenceofadependencereceptorcsf1rincolorectalcancercellsactivatestumorassociatedmacrophages |