Abstract 3390: CTHRC1 promotes angiogenesis by recruiting Tie2-expressing monocytes to pancreatic tumors

Abstract

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 plays 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 demonstrate a novel role of CTHRC1 as a potent endothelial activator, promoting angiogenesis by recruiting bone marrow-derived cells into the tumor microenvironment during tumorigenesis. Recombinant CTHRC1 (rCTHRC1) enhanced endothelial cell (EC) proliferation, migration and capillary-like tube formation, consistent with observed increases in neovascularization in vivo. Moreover, rCTHRC1 induced upregulation of 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 ECs in vitro. Moreover, CTHRC1-neutralizing antibody treatment in a xenograft mouse model reduced tumor burden and infiltration of TEMs in tumor tissues, indicating that blocking the CTHRC1/Ang-2/TEM axis during angiogenesis inhibits tumorigenesis. Collectively, our findings support the conclusion 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. Citation Format: Seongyea Jo, Jaemin Lee, jinhoi song. CTHRC1 promotes angiogenesis by recruiting Tie2-expressing monocytes to pancreatic tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3390.