title: Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion.
abstract: Ovarian cancer (OvCa) metastasizes to organs in the abdominal cavity, such as the omentum, which are covered by a single layer of mesothelial cells. Mesothelial cells are generally thought to be "bystanders" to the metastatic process and simply displaced by OvCa cells to access the submesothelial extracellular matrix. Here, using organotypic 3D cultures, we found that primary human mesothelial cells secrete fibronectin in the presence of OvCa cells. Moreover, we evaluated the tumor stroma of 108 human omental metastases and determined that fibronectin was consistently overexpressed in these patients. Blocking fibronectin production in primary mesothelial cells in vitro or in murine models, either genetically (fibronectin 1 floxed mouse model) or via siRNA, decreased adhesion, invasion, proliferation, and metastasis of OvCa cells. Using a coculture model, we determined that OvCa cells secrete TGF-β1, which in turn activates a TGF-β receptor/RAC1/SMAD-dependent signaling pathway in the mesothelial cells that promotes a mesenchymal phenotype and transcriptional upregulation of fibronectin. Additionally, blocking α5 or β1 integrin function with antibodies reduced metastasis in an orthotopic preclinical model of OvCa metastasis. These findings indicate that cancer-associated mesothelial cells promote colonization during the initial steps of OvCa metastasis and suggest that mesothelial cells actively contribute to metastasis.
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Kenny
authors.forename: Chun-Yi
authors.initials: CY
authors.lastname: Chiang
authors.forename: Erin A
authors.initials: EA
authors.lastname: White
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Schryver
authors.forename: Mohammed
authors.initials: M
authors.lastname: Habis
authors.forename: Iris L
authors.initials: IL
authors.lastname: Romero
authors.forename: Andras
authors.initials: A
authors.lastname: Ladanyi
authors.forename: Carla V
authors.initials: CV
authors.lastname: Penicka
authors.forename: Joshy
authors.initials: J
authors.lastname: George
authors.forename: Karl
authors.initials: K
authors.lastname: Matlin
authors.forename: Anthony
authors.initials: A
authors.lastname: Montag
authors.forename: Kristen
authors.initials: K
authors.lastname: Wroblewski
authors.forename: S Diane
authors.initials: SD
authors.lastname: Yamada
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Mazar
authors.forename: David
authors.initials: D
authors.lastname: Bowtell
authors.forename: Ernst
authors.initials: E
authors.lastname: Lengyel
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000166:cytology*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016023:Integrins / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D005353:Fibronectins; D016023:Integrins; D034741:RNA, Small Interfering; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1