title: Mesothelial-to-mesenchymal transition as a possible therapeutic target in peritoneal metastasis of ovarian cancer.
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.
authors.affiliation: Centro de Biología Molecular-Severo Ochoa (CBMSO), Departamento de Biología Celular e Inmunología, Madrid, Spain.|Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Rynne-Vidal
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Chi Lam
authors.initials: CL
authors.lastname: Au-Yeung
authors.affiliation: Departamento de Anatomía Patológica, Hospital Universitario La Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Jiménez-Heffernan
authors.affiliation: Centro de Biología Molecular-Severo Ochoa (CBMSO), Departamento de Biología Celular e Inmunología, Madrid, Spain.
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Pérez-Lozano
authors.affiliation: Centro de Biología Molecular-Severo Ochoa (CBMSO), Departamento de Biología Celular e Inmunología, Madrid, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Cremades-Jimeno
authors.affiliation: Departamento de Anatomía Patológica, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Bárcena
authors.affiliation: Servicio de Oncología Ginecológica, Hospital de la Zarzuela Sanitas, Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Cristóbal-García
authors.affiliation: Servicio de Oncología Ginecológica, Hospital de la Zarzuela Sanitas, Madrid, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Fernández-Chacón
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Tsz Lun
authors.initials: TL
authors.lastname: Yeung
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Mok
authors.affiliation: Centro de Biología Molecular-Severo Ochoa (CBMSO), Departamento de Biología Celular e Inmunología, Madrid, Spain.
authors.forename: Pilar
authors.identifier: 0000-0002-5893-7037
authors.initials: P
authors.lastname: Sandoval
authors.affiliation: Centro de Biología Molecular-Severo Ochoa (CBMSO), Departamento de Biología Celular e Inmunología, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: López-Cabrera
mesh_terms: D000818:Animals; D001201:Ascites / Q000473:pathology; D001202:Ascitic Fluid / Q000473:pathology; D002277:Carcinoma / Q000473:pathology / Q000556:secondary*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000150:complications / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000473:pathology / Q000556:secondary*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta
keywords: ascites; carcinoma-associated fibroblasts; mesothelial-to-mesenchymal transition; ovarian cancer; peritoneal metastasis