Lau T-S, Chan L K-Y, Wong E C-H, Hui C W-C, Sneddon K, Cheung T-H, Yim S-F, Lee J H-S, Yeung C S-Y, Chung T K-H, Kwong J
Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
Department of Clinical Oncology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
Oncogene. 2017 Jun 22;36(25):3576-3587. doi: 10.1038/onc.2016.509. Epub 2017 Feb 6.
Peritoneum 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-α) is induced in stromal fibroblasts co-cultured with ovarian cancer cells. We also observed an over-expression of tumor necrosis factor-alpha (TNF-α) in ovarian cancer cells, which is regulated by promoter DNA hypomethylation as well as chromatin remodeling. Interestingly, this ovarian cancer-derived TNF-α induces TGF-α transcription in stromal fibroblasts through nuclear factor-κB (NF-κB). We further show that TGF-α secreted by stromal fibroblasts in turn promotes peritoneal metastasis of ovarian cancer through epidermal growth factor receptor (EGFR) signaling. Finally, we identify a TNFα-TGFα-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 TNFα-TGFα-EGFR.
腹膜是卵巢癌转移最常见的部位。在此，我们研究癌症表观遗传学如何调节卵巢癌腹膜转移中肿瘤与基质之间的相互作用。首先，我们发现网膜基质成纤维细胞增强转移性卵巢癌细胞的集落形成，并且在与卵巢癌细胞共培养的基质成纤维细胞中诱导了转化生长因子-α（TGF-α）的从头表达。我们还观察到卵巢癌细胞中肿瘤坏死因子-α（TNF-α）的过表达，其受启动子DNA低甲基化以及染色质重塑的调控。有趣的是，这种源自卵巢癌的TNF-α通过核因子-κB（NF-κB）诱导基质成纤维细胞中TGF-α的转录。我们进一步表明，基质成纤维细胞分泌的TGF-α反过来通过表皮生长因子受体（EGFR）信号促进卵巢癌的腹膜转移。最后，我们在人网膜转移灶的肿瘤和基质区室之间鉴定出一个TNFα-TGFα-EGFR相互作用环。因此，我们的结果表明癌症表观遗传学在网膜微环境中诱导了一个癌症-基质-癌症相互作用环，其通过TNFα-TGFα-EGFR促进卵巢癌细胞的腹膜转移。
