CTHRC1 promotes angiogenesis by recruiting Tie2-expressing monocytes to pancreatic tumors.
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.
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
Jaemin
J
Lee
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
Jinhoi
J
Song
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
Eun-Soo
ES
Kwon
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
Seongyea
S
Jo
Department of Biological Sciences, Dong-A University, Busan, South Korea.
Min Kyung
MK
Kang
Department of Biological Sciences, Dong-A University, Busan, South Korea.
Yeon Jeong
YJ
Kim
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Yeonsil
Y
Hwang
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Hosung
H
Bae
Department of Immunology, School of Medicine, Konkuk University, Seoul, South Korea.
Tae Heung
TH
Kang
Department of Biomedical Sciences and Physiology, Asan Medical Center, University of Ulsan School of Medicine, Ulsan, South Korea.
Suhwan
S
Chang
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
Hee Jun
HJ
Cho
Department of Surgery, Asan Medical Center, University of Ulsan School of Medicine, Ulsan, South Korea.
Song Cheol
SC
Kim
Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
Seokho
S
Kim
Department of Biological Sciences, Dong-A University, Busan, South Korea.
Sang Seok
SS
Koh
Trends Immunol. 2007 Dec;28(12):519-24
17981504
Circ Res. 2005 Feb 4;96(2):261-8
15618538
PLoS One. 2013 Jul 29;8(7):e70324
23922981
Cancer Res. 2007 Sep 15;67(18):8429-32
17875679
Pathol Oncol Res. 2013 Oct;19(4):731-7
23658133
Int J Oncol. 2014 Aug;45(2):541-8
24841500
J Clin Invest. 2010 Mar;120(3):694-705
20179352
Am J Cancer Res. 2015 Mar 15;5(4):1447-59
26101709
BMC Cancer. 2007 Mar 27;7:55
17389037
Br J Dermatol. 2011 Jan;164(1):135-40
20849518
Cell. 2006 Jan 13;124(1):175-89
16413490
J Mammary Gland Biol Neoplasia. 2010 Jun;15(2):169-90
20467795
Oncotarget. 2014 Jan 30;5(2):519-29
24504172
Cell. 2011 Mar 4;144(5):646-74
21376230
Oncogene. 2013 Aug 1;32(31):3638-47
22907431
Neoplasia. 2014 Mar;16(3):265-78, 278.e1-13
24726140
Carcinogenesis. 2013 Mar;34(3):694-702
23222813
Cancer Cell. 2005 Sep;8(3):211-26
16169466
Tumour Biol. 2015 May;36(5):3221-9
25510669
Hum Pathol. 2014 May;45(5):1031-8
24746208
Clin Cancer Res. 2006 Jun 15;12(12):3716-22
16778098
Nat Rev Mol Cell Biol. 2009 Mar;10(3):165-77
19234476
Circ Res. 2007 Mar 30;100(6):826-33
17322174
Trends Cardiovasc Med. 2007 Aug;17(6):202-5
17662915
Nat Rev Cancer. 2008 Aug;8(8):618-31
18633355
Nature. 2005 Dec 15;438(7070):932-6
16355210
J Clin Pathol. 2011 Nov;64(11):977-82
21742751
Cancer Sci. 2012 Jul;103(7):1327-33
22590977
Mol Med Rep. 2015 Mar;11(3):1784-92
25405379
Cancer Res. 2010 Jul 1;70(13):5270-80
20530679
Tumour Biol. 2014 Nov;35(11):11677-83
25139095
Biochim Biophys Acta. 2006 Aug;1766(1):159-66
16857321
J Biol Chem. 2013 Jul 12;288(28):20217-27
23703614
J Virol. 2007 Apr;81(8):3980-91
17287278
Annu Rev Pathol. 2008;3:157-88
18039136
Cancer Cell. 2011 Apr 12;19(4):512-26
21481792
Blood. 2007 Jun 15;109(12):5276-85
17327411
Nature. 2005 Dec 15;438(7070):967-74
16355214