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

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

doi:10.1038/emm.2016.87

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

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

Jaemin Lee, Jinhoi Song, Eun-Soo Kwon, Seongyea Jo, Min Kyung Kang, Yeon Jeong Kim, Yeonsil Hwang, Hosung Bae, Tae Heung Kang, Suhwan Chang, …

Experimental & molecular medicine, Vol.48(9), pp.e261-e261

09/01/2016

DOI: 10.1038/emm.2016.87

PMCID: PMC5050301

PMID: 27686285

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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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Title: Subtitle: CTHRC1 promotes angiogenesis by recruiting Tie2-expressing monocytes to pancreatic tumors
Creators: Jaemin Lee - Korea Research Institute of Bioscience and Biotechnology
Jinhoi Song - Korea Research Institute of Bioscience and Biotechnology
Eun-Soo Kwon - Korea Research Institute of Bioscience and Biotechnology
Seongyea Jo - Korea Research Institute of Bioscience and Biotechnology
Min Kyung Kang - Dong-A University
Yeon Jeong Kim - Department of Biological Sciences, Dong-A University
Yeonsil Hwang - Korea Advanced Institute of Science and Technology
Hosung Bae - Korea Advanced Institute of Science and Technology
Tae Heung Kang - Konkuk University
Suhwan Chang - Asan Medical Center
Hee Jun Cho - Korea Research Institute of Bioscience and Biotechnology
Song Cheol Kim - Asan Medical Center
Seokho Kim - Korea Research Institute of Bioscience and Biotechnology
Sang Seok Koh - Dong-A University
Resource Type: Journal article
Publication Details: Experimental & molecular medicine, Vol.48(9), pp.e261-e261
DOI: 10.1038/emm.2016.87
PMID: 27686285
PMCID: PMC5050301
NLM abbreviation: Exp Mol Med
ISSN: 1226-3613
eISSN: 2092-6413
Publisher: Nature Publishing Group
Alternative title: CTHRC1 recruits Tie-2-expressing monocytes to pancreatic tumors
Language: English
Date published: 09/01/2016
Academic Unit: Internal Medicine
Record Identifier: 9985217131402771

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