A loop of cancer-stroma-cancer interaction promotes peritoneal metastasis of ovarian cancer via TNF[alpha]-TGF[alpha]-EGFR
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AbstractPeritoneum is the most common site for ovarian cancer metastasis. Here we investigate how cancer epigenetics regulates reciprocal tumor-stromal interactions in peritoneal metastasis of ovarian cancer. Firstly, we find that omental stromal fibroblasts enhance colony formation of metastatic ovarian cancer cells, and de novo expression of transforming growth factor-alpha (TGF-[alpha]) is induced in stromal fibroblasts co-cultured with ovarian cancer cells. We also observed an over-expression of tumor necrosis factor-alpha (TNF-[alpha]) in ovarian cancer cells, which is regulated by promoter DNA hypomethylation as well as chromatin remodeling. Interestingly, this ovarian cancer-derived TNF-[alpha] induces TGF-[alpha] transcription in stromal fibroblasts through nuclear factor-[kappa]B (NF-[kappa]B). We further show that TGF-[alpha] secreted by stromal fibroblasts in turn promotes peritoneal metastasis of ovarian cancer through epidermal growth factor receptor (EGFR) signaling. Finally, we identify a TNF[alpha]-TGF[alpha]-EGFR interacting loop between tumor and stromal compartments of human omental metastases. Our results therefore demonstrate cancer epigenetics induces a loop of cancer-stroma-cancer interaction in omental microenvironment that promotes peritoneal metastasis of ovarian cancer cells via TNF[alpha]-TGF[alpha]-EGFR.
All Author(s) ListLau TS, Chan LKY, Wong ECH, Hui CWC, Sneddon K, Cheung TH, Yim SF, Lee JHS, Yeung CSY, Chung TKH, Kwong J
Journal nameOncogene
Year2017
Month6
Volume Number36
Issue Number25
PublisherNature Publishing Group
Place of PublicationUnited Kingdom
Pages3576 - 3587
ISSN0950-9232
eISSN1476-5594
LanguagesEnglish-United States

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