CTHRC1 promotes angiogenesis by recruiting Tie2-expressing monocytes to pancreatic tumors

• Published in: Experimental & molecular medicine 2016-09, Vol.48 (9), p.e261-e261
• Main Authors: Lee, Jaemin, Song, Jinhoi, Kwon, Eun-Soo, Jo, Seongyea, Kang, Min Kyung, Kim, Yeon Jeong, Hwang, Yeonsil, Bae, Hosung, Kang, Tae Heung, Chang, Suhwan, Cho, Hee Jun, Kim, Song Cheol, Kim, Seokho, Koh, Sang Seok
• Format: Article
• Language: English
• Subjects: 13/1; 13/31; 14/1; 14/34; 14/63; 38/77; 631/67/2328; 631/67/327; 64/60; 82/80; 96/31; Biomedical and Life Sciences; Biomedicine; Medical Biochemistry; Molecular Medicine; Original; original-article; Stem Cells
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/emm.2016.87

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. Pancreatic cancer: Building a blood supply A protein involved in tissue repair can support malignant tumors by promoting the formation of new blood vessels that sustain the tumors. Sang Seok Koh of Dong-A University and colleagues at several research centers in South Korea, investigated the role of the protein “CTHRC1” in pancreatic cancer. Studying human pancreatic cancer cells and cells that build blood vessels, they discovered the protein can recruit cells derived from bone marrow to create the blood vessels for a tumor. The researchers also demonstrated that antibodies against CTHRC1 could limit tumor formation in a mouse model of pancreatic cancer. This indicates that CTHRC1 may be an effective target for new anti-cancer therapies. Earlier studies have also linked the protein to breast and gastric cancers, suggesting wider relevance