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

Jaemin Lee,Suhwan Chang,Yeonsil Hwang,Seongyea Jo,Seokho Kim,Song Cheol Kim,Tae Heung Kang,Yeon Jeong Kim,Min Kyung Kang,Hee Jun Cho,Eun-Soo Kwon,Sang Seok Koh,Hosung Bae,Jinhoi Song

doi: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.

Highlights

Pancreatic ductal adenocarcinoma is one of the most aggressive and lethal malignancies in the world, with a mean survival of ~ 5 months and a 5-year survival rate of ~ 14%.1 More than 80% of patients present with late-diagnosis, metastatic disease and often exhibit resistance to conventional chemotherapy and radiotherapy
CTHRC1 enhances tumor vascularity and angiogenesis in a non-autonomous manner We previously showed that CTHRC1 is an intrinsic factor that promotes tumorigenesis and metastasis in a pancreatic cancer xenograft model.[7]
The CD45+ and CD31+ cell populations were significantly increased in tumor tissues from MiaPaCA-2/CTHRC1 cellinjected mice compared with those from mice injected with MiaPaCa-2/Mock cells (Figure 1a), indicating that CTHRC1 has the potential to modulate vascularity

Summary

Introduction

Pancreatic ductal adenocarcinoma is one of the most aggressive and lethal malignancies in the world, with a mean survival of ~ 5 months and a 5-year survival rate of ~ 14%.1 More than 80% of patients present with late-diagnosis, metastatic disease and often exhibit resistance to conventional chemotherapy and radiotherapy. More than 80% of patients present with late-diagnosis, metastatic disease and often exhibit resistance to conventional chemotherapy and radiotherapy. Despite numerous ongoing clinical trials, pancreatic cancer has been shown to be highly refractory to combined treatment with gemcitabine and other therapeutics as well as newly developed agents. There is a critical need for novel therapeutic strategies or targets to reduce mortality and increase the overall survival rate of patients with pancreatic cancer. CTHRC1 (collagen triple helix repeat containing-1), a secreted protein that has hormone-like characteristics, is known to be involved in tissue remodeling processes affecting vascularity and bone formation. CTHCR1 is expressed in injured arteries and participates in remodeling the adventitia of injured vessels by promoting cell migration and inhibiting collagen synthesis in fibroblasts and smooth muscle cells.[2]

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