title: Carcinoma-associated fibroblasts derive from mesothelial cells via mesothelial-to-mesenchymal transition in peritoneal metastasis.
abstract: Peritoneal dissemination is a frequent metastatic route for cancers of the ovary and gastrointestinal tract. Tumour cells metastasize by attaching to and invading through the mesothelial cell (MC) monolayer that lines the peritoneal cavity. Metastases are influenced by carcinoma-associated fibroblasts (CAFs), a cell population that derives from different sources. Hence, we investigated whether MCs, through mesothelial-mesenchymal transition (MMT), were a source of CAFs during peritoneal carcinomatosis and whether MMT affected the adhesion and invasion of tumour cells. Biopsies from patients with peritoneal dissemination revealed the presence of myofibroblasts expressing mesothelial markers in the proximity of carcinoma implants. Prominent new vessel formation was observed in the peritoneal areas harbouring tumour cells when compared with tumour-free regions. The use of a mouse model of peritoneal dissemination confirmed the myofibroblast conversion of MCs and the increase in angiogenesis at places of tumour implants. Treatment of omentum MCs with conditioned media from carcinoma cell cultures resulted in phenotype changes reminiscent of MMT. Adhesion experiments demonstrated that MMT enhanced the binding of cancer cells to MCs in a β1-integrin-dependent manner. Scanning electron microscopy imaging showed that the enhanced adhesion was mostly due to increased cell-cell interaction and not to a mere matrix exposure. Invasion assays suggested a reciprocal stimulation of the invasive capacity of tumour cells and MCs. Our results demonstrate that CAFs can derive from mesothelial cells during peritoneal metastasis. We suggest that MMT renders the peritoneum more receptive for tumour cell attachment/invasion and contributes to secondary tumour growth by promoting its vascularization.
authors.affiliation: Centro de Biología Molecular-Severo Ochoa, CSIC-UAM, Cantoblanco, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sandoval
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Jiménez-Heffernan
authors.forename: Ángela
authors.initials: Á
authors.lastname: Rynne-Vidal
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Pérez-Lozano
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Gilsanz
authors.forename: Vicente
authors.initials: V
authors.lastname: Ruiz-Carpio
authors.forename: Raquel
authors.initials: R
authors.lastname: Reyes
authors.forename: Julio
authors.initials: J
authors.lastname: García-Bordas
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Stamatakis
authors.forename: Javier
authors.initials: J
authors.lastname: Dotor
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Majano
authors.forename: Manuel
authors.initials: M
authors.lastname: Fresno
authors.forename: Carlos
authors.initials: C
authors.lastname: Cabañas
authors.forename: Manuel
authors.initials: M
authors.lastname: López-Cabrera
mesh_terms: D000818:Animals; D001706:Biopsy; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000473:pathology* / Q000502:physiology; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008855:Microscopy, Electron, Scanning; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D010051:Ovarian Neoplasms / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000098:blood supply / Q000473:pathology / Q000556:secondary* / Q000648:ultrastructure
chemical_list: D017077:Culture Media, Conditioned
keywords: carcinoma-associated fibroblasts; mesothelial cells; mesothelial-to-mesenchymal transition; peritoneal metastasis