Human CAFs promote lymphangiogenesis in ovarian cancer via the Hh-VEGF-C signaling axis
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Rui Wei1, Mengqin Lv1,*, Fei Li1, Teng Cheng1, Zhengzhong Zhang1, Guiying Jiang1, Ying Zhou1, Ruiqiu Gao1, Xiao Wei1, Jicheng Lou1, Xizi Wu1, Danfeng Luo1, Xiangyi Ma1, Jin Jiang2, Ding Ma1 and Ling Xi1
1Cancer Biology Research Center, Key Laboratory of The Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
2Department of Molecular Biology, UT Southwestern Medical Center at Dallas, TX, Dallas, USA
Ling Xi, email: [email protected]
Keywords: ovarian cancer, hedgehog signaling, cancer associated fibroblasts, VEGF-C, lymphangiogenesis
Received: October 07, 2016 Accepted: May 01, 2017 Published: June 27, 2017
Cancer-associated fibroblasts (CAFs) play a pivotal role in the development and progression of many human cancers. Recent studies have shown that Hedgehog (Hh) signalling modulates the stromal microenvironment and prepares a suitable niche for tumour metastasis. However, the detailed molecular mechanisms underlying CAF-mediated lymphangiogenesis have not been fully elucidated. Therefore, our goal is to illustrate whether Hh ligands can activate Hh signalling in CAFs in a paracrine fashion and elucidate the effect of CAFs on lymphangiogenesis. We determined here that Sonic Hedgehog (SHH) secreted by ovarian cancer (OC) cells activated Hh signalling in CAFs and promoted the proliferation of CAFs. Moreover, we co-injected SHH-overexpressing OC cells and CAFs in a xenograft model and found that the CAFs accelerated tumourigenesis and lymphangiogenesis in OC. Mechanistically, we found that SHH secreted by the OC cells induced VEGF-C expression in CAFs. Inhibition of Hh signalling in CAFs decreased VEGF-C expression and diminished the positive role of CAFs in supporting tumourigenesis and lymphangiogenesis in a murine xenograft model. Our results demonstrate that CAFs constitute a supportive niche for cancer lymphangiogenesis via the Hh/VEGF-C signalling axis and provide evidence for the clinical application of Hh inhibitors in the treatment of OC.
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