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Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion
Hilary A. Kenny, … , David Bowtell, Ernst Lengyel
Hilary A. Kenny, … , David Bowtell, Ernst Lengyel
Published October 1, 2014; First published September 9, 2014
Citation Information: J Clin Invest. 2014;124(10):4614-4628. https://doi.org/10.1172/JCI74778.
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Category: Research Article

Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion

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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

Hilary A. Kenny, Chun-Yi Chiang, Erin A. White, Elizabeth M. Schryver, Mohammed Habis, Iris L. Romero, Andras Ladanyi, Carla V. Penicka, Joshy George, Karl Matlin, Anthony Montag, Kristen Wroblewski, S. Diane Yamada, Andrew P. Mazar, David Bowtell, Ernst Lengyel

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Figure 1

Fibronectin is overexpressed in the stroma of omental metastases.

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Fibronectin is overexpressed in the stroma of omental metastases.
(A) Im...
(A) Immunohistochemistry for fibronectin (FN) levels in the tumor and stromal compartments of omental metastases (n = 108) was analyzed in tumor sample cores using Aperio ImageScope and Spectrum software (see Supplemental Figure 9). Black dots, outliers; boxes, interquartile range (IQR); lines within boxes, median. ***P < 0.001, Wilcoxon rank test (median ± 1.5 IQR). 3 different tumor tissue cores from separate patients are shown. (B) Immunohistochemistry for fibronectin in tissue from a patient coincidentally detected with early, microscopic OvCa metastasis to the omentum (stage IIIA; representative sections of affected areas are shown). Arrowhead, mesothelial cells; arrows, OvCa cells. (C) Immunohistochemistry for fibronectin expression in omental tissues (n = 11) sampled from patients treated for benign disease and omental metastases (n = 43) removed from patients with serous papillary OvCa (mean ± SEM). *P < 0.05. (D) Immunoblot analysis of ECM extracted from omental tissues (n = 3) sampled from patients treated for benign disease and omental metastases removed from patients with serous papillary OvCa. rh-FN, recombinant human fibronectin. (E) Left: Adhesion (30 minutes) of OvCa lines SKOV3ip1 and HeyA8 to the isolated ECM in D. Right: Pretreatment of SKOV3ip1 cells for 30 minutes with integrin function blocking antibodies or peptides, followed by the adhesion assay to isolated ECM (mean ± SEM; n = 5; 3 independent experiments). mIgG, murine IgG control. *P < 0.05, Student’s t test. Scale bars: 100 μm.
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