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- Title
Mesothelial-to-mesenchymal transition as a possible therapeutic target in peritoneal metastasis of ovarian cancer.
- Authors
Rynne‐Vidal, Angela; Au‐Yeung, Chi Lam; Jiménez‐Heffernan, José A; Pérez‐Lozano, María Luisa; Cremades‐Jimeno, Lucía; Bárcena, Carmen; Cristóbal‐García, Ignacio; Fernández‐Chacón, Concepción; Yeung, Tsz Lun; Mok, Samuel C; Sandoval, Pilar; López‐Cabrera, Manuel
- Abstract
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.
- Publication
Journal of Pathology, 2017, Vol 242, Issue 2, p140
- ISSN
0022-3417
- Publication type
Article
- DOI
10.1002/path.4889