CTHRC1 promotes liver metastasis by reshaping infiltrated macrophages through physical interactions with TGF-β receptors in colorectal cancer

Metastasis is a major cause of cancer-related deaths. Tumor-intrinsic properties can determine whether tumor metastasis occurs or not. Here, by comparing the gene expression patterns in primary colorectal cancer (CRC) patients with or without metastasis, we found that Collagen Triple Helix Repeat Co...

Full description

Saved in:

Bibliographic Details
Published in:	Oncogene 2021-06, Vol.40 (23), p.3959-3973
Main Authors:	Zhang, Xue-Li, Hu, Li-Peng, Yang, Qin, Qin, Wei-Ting, Wang, Xu, Xu, Chun-Jie, Tian, Guang-Ang, Yang, Xiao-Mei, Yao, Lin-Li, Zhu, Lei, Nie, Hui-Zhen, Li, Qing, Xu, Qing, Zhang, Zhi-Gang, Zhang, Yan-Li, Li, Jun, Wang, Ya-Hui, Jiang, Shu-Heng
Format:	Article
Language:	eng
Subjects:	Animals Antibodies, Monoclonal - pharmacology Bisphosphonates Blocking antibodies Cancer Cell Line, Tumor Cell Proliferation - drug effects Clodronic acid Collagen Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Databases, Genetic Disease Models, Animal Extracellular Matrix Proteins - antagonists & inhibitors Extracellular Matrix Proteins - genetics Extracellular Matrix Proteins - metabolism Gene expression Humans Liver Liver Neoplasms - drug therapy Liver Neoplasms - genetics Liver Neoplasms - metabolism Liver Neoplasms - secondary Macrophages Macrophages - immunology Macrophages - metabolism Macrophages - pathology Male Metastases Metastasis Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Monoclonal antibodies Neoplasm Staging PD-1 protein Phenotypes Programmed Cell Death 1 Receptor - antagonists & inhibitors Receptors, Transforming Growth Factor beta - metabolism Survival Rate Treatment Outcome
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Metastasis is a major cause of cancer-related deaths. Tumor-intrinsic properties can determine whether tumor metastasis occurs or not. Here, by comparing the gene expression patterns in primary colorectal cancer (CRC) patients with or without metastasis, we found that Collagen Triple Helix Repeat Containing 1 (CTHRC1) in primary CRC served as a metastasis-associated gene. Animal experiments verified that CTHRC1 secreted by CRC cells promoted hepatic metastasis, which was closely correlated with macrophage infiltration. Depletion of macrophages by liposomal clodronate largely abolished the promoting effect of CTHRC1 on CRC liver metastasis. Furthermore, we demonstrated that CTHRC1 modulated macrophage polarization to M2 phenotypes through TGF-β signaling. A mechanistic study revealed that CTHRC1 bound directly to TGF-β receptor II and TGF-β receptor III, stabilized the TGF-β receptor complex, and activated TGF-β signaling. The combination treatment of CTHRC1 monoclonal antibody and anti-PD-1 blocking antibody effectively suppressed CRC hepatic metastasis. Taken together, our data demonstrated that CTHRC1 is an intrinsic marker of CRC metastasis and further revealed that CTHRC1 promoted CRC liver metastasis by reshaping infiltrated macrophages through TGF-β signaling, suggesting that CTHRC1 could be a potential biomarker for the early prediction of and a therapeutic target of CRC hepatic metastasis.
ISSN:	0950-9232 1476-5594