We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion.
- Authors
Kenny, Hilary A.; Chun-Yi Chiang; White, Erin A.; Schryver, Elizabeth M.; Habis, Mohammed; Romero, Iris L.; Ladanyi, Andras; Penicka, Carla V.; George, Joshy; Matlin, Karl; Montag, Anthony; Wroblewski, Kristen; Yamada, S. Diane; Mazar, Andrew P.; Bowtell, David; Lengyel, Ernst
- 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 ibronectin. Additionally, blocking α or β 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.
- Subjects
OVARIAN cancer; FIBRONECTINS; MESOTHELIUM; OMENTUM tumors; METASTASIS; LABORATORY mice; CANCER risk factors
- Publication
Journal of Clinical Investigation, 2014, Vol 124, Issue 10, p4614
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI74778