Mesothelial-to-mesenchymal transition as a possible therapeutic target in peritoneal metastasis of ovarian cancer.
Mesothelial-to-mesenchymal transition as a possible therapeutic target in peritoneal metastasis of ovarian cancer.
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DOI：
10.1002/path.4889
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发表时间：
2017-06
期刊：
影响因子：
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通讯作者：
López-Cabrera M
中科院分区：
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作者：
Rynne-Vidal A;Au-Yeung CL;Jiménez-Heffernan JA;Pérez-Lozano ML;Cremades-Jimeno L;Bárcena C;Cristóbal-García I;Fernández-Chacón C;Yeung TL;Mok SC;Sandoval P;López-Cabrera M
腹膜播散是卵巢癌的主要转移途径，常伴有腹水积聚。腹膜腔内有间皮细胞(MC)，可通过间皮向间充质转化(MMT)转化为肿瘤相关成纤维细胞(CAF)。在这里，我们证明了从OvCa患者腹水(AFMC)中分离出来的MC也进行了MMT，并促进了小鼠皮下肿瘤的生长。对AFMC的RNA测序显示，包括转化生长因子-β信号转导在内的金属硫蛋白相关通路受到差异调控，并在卵巢癌患者的腹膜植入物中验证了基因签名。在小鼠模型中，预先诱导MMT导致腹膜肿瘤生长增加，而干扰转化生长因子-β受体则减少转移。MC来源的CAF表现出Smad依赖的转化生长因子-β信号的激活，这一信号在卵巢细胞中被破坏，尽管它们增加了转化生长因子-β的产生。因此，靶向Smad依赖的信号在小鼠的腹膜转移前壁龛中减少了肿瘤的定植，这表明依赖Smad的MMT可能在腹膜癌病中起关键作用。综上所述，这些结果表明，卵巢细胞和MC来源的CAF之间的双向交流，通过转化生长因子-β介导的MMT，似乎是形成合适的转移生态位的关键。我们建议MMT作为治疗干预的可能靶点，并作为改善OvCa诊断和/或预后的生物标记物的潜在来源。©2017作者。《病理学杂志》由John Wiley&Sons Ltd代表大不列颠和爱尔兰病理学会出版。
Peritoneal dissemination is the primary metastatic route of ovarian cancer (OvCa), and is often accompanied by the accumulation of ascitic fluid. The peritoneal cavity is lined by mesothelial cells (MCs), which can be converted into carcinoma‐associated fibroblasts (CAFs) through mesothelial‐to‐mesenchymal transition (MMT). Here, we demonstrate that MCs isolated from ascitic fluid (AFMCs) of OvCa patients with peritoneal implants also undergo MMT and promote subcutaneous tumour growth in mice. RNA sequencing of AFMCs revealed that MMT‐related pathways – including transforming growth factor (TGF)‐β signalling – are differentially regulated, and a gene signature was verified in peritoneal implants from OvCa patients. In a mouse model, pre‐induction of MMT resulted in increased peritoneal tumour growth, whereas interfering with the TGF‐β receptor reduced metastasis. MC‐derived CAFs showed activation of Smad‐dependent TGF‐β signalling, which was disrupted in OvCa cells, despite their elevated TGF‐β production. Accordingly, targeting Smad‐dependent signalling in the peritoneal pre‐metastatic niche in mice reduced tumour colonization, suggesting that Smad‐dependent MMT could be crucial in peritoneal carcinomatosis. Together, these results indicate that bidirectional communication between OvCa cells and MC‐derived CAFs, via TGF‐β‐mediated MMT, seems to be crucial to form a suitable metastatic niche. We suggest MMT as a possible target for therapeutic intervention and a potential source of biomarkers for improving OvCa diagnosis and/or prognosis. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.