Exp Mol Med.
2016 Sep;48(9):e261. 10.1038/emm.2016.87.
CTHRC1 promotes angiogenesis by recruiting Tie2-expressing monocytes to pancreatic tumors
- Affiliations
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- 1Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea. kims@kribb.re.kr
- 2Department of Biological Sciences, Dong-A University, Busan, South Korea. sskoh@dau.ac.kr
- 3Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
- 4Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
- 5Department of Immunology, School of Medicine, Konkuk University, Seoul, South Korea.
- 6Department of Biomedical Sciences and Physiology, Asan Medical Center, University of Ulsan School of Medicine, Ulsan, South Korea.
- 7Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
- 8Department of Surgery, Asan Medical Center, University of Ulsan School of Medicine, Ulsan, South Korea. drksc@amc.seoul.kr
- KMID: 2361548
- DOI: http://doi.org/10.1038/emm.2016.87
Abstract
- CTHRC1 (collagen triple-helix repeat-containing 1), a protein secreted during the tissue-repair process, is highly expressed in several malignant tumors, including pancreatic cancer. We recently showed that CTHRC1 has an important role in the progression and metastasis of pancreatic cancer. Although CTHRC1 secretion affects tumor cells, how it promotes tumorigenesis in the context of the microenvironment is largely unknown. Here we identified a novel role of CTHRC1 as a potent endothelial activator that promotes angiogenesis by recruiting bone marrow-derived cells to the tumor microenvironment during tumorigenesis. Recombinant CTHRC1 (rCTHRC1) enhanced endothelial cell (EC) proliferation, migration and capillary-like tube formation, which was consistent with the observed increases in neovascularization in vivo. Moreover, rCTHRC1 upregulated angiopoietin-2 (Ang-2), a Tie2 receptor ligand, through ERK-dependent activation of AP-1 in ECs, resulting in recruitment of Tie2-expressing monocytes (TEMs) to CTHRC1-overexpressing tumor tissues. Treatment with a CTHRC1-neutralizing antibody-abrogated Ang-2 expression in the ECs in vitro. Moreover, administration of a CTHRC1-neutralizing antibody to a xenograft mouse model reduced the tumor burden and infiltration of TEMs in the tumor tissues, indicating that blocking the CTHRC1/Ang-2/TEM axis during angiogenesis inhibits tumorigenesis. Collectively, our findings support the hypothesis that CTHRC1 induction of the Ang-2/Tie2 axis mediates the recruitment of TEMs, which are important for tumorigenesis and can be targeted to achieve effective antitumor responses in pancreatic cancers.
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