Human CAFs promote lymphangiogenesis in ovarian cancer via the Hh-VEGF-C signaling axis

Rui Wei, Mengqin Lv, Fei Li, Teng Cheng, Zhengzhong Zhang, Guiying Jiang, Ying Zhou, Ruiqiu Gao, Xiao Wei, Jicheng Lou, Xizi Wu, Danfeng Luo, Xiangyi Ma, Jin Jiang, Ding Ma, Ling Xi

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)67315-67328
Number of pages14
JournalOncotarget
Volume8
Issue number40
DOIs
StatePublished - Jun 27 2017

Keywords

  • Cancer associated fibroblasts
  • Hedgehog signaling
  • Lymphangiogenesis
  • Ovarian cancer
  • VEGF-C

ASJC Scopus subject areas

  • Oncology

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