Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 122, Issue 10, Pages 3603-3617Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI62229
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Funding
- Cancer and Prevention Research Institute of Texas [RP120390]
- US NIH [CA101826, CA141078]
- MD Anderson Cancer Center Institutional Research Grant
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Epithelial ovarian cancers (EOCs) often exhibit morphologic features of embryonic Mullerian duct-derived tissue lineages and colonize peritoneal surfaces that overlie connective and adipose tissues. However, the mechanisms that enable EOC cells to readily adapt to the peritoneal environment are poorly understood. In this study, we show that expression of HOXA9, a Mullerian-patterning gene, is strongly associated with poor outcomes in patients with EOC and in mouse xenograft models of EOC. Whereas HOXA9 promoted EOC growth in vivo, HOXA9 did not stimulate autonomous tumor cell growth in vitro. On the other hand, expression of HOXA9 in EOC cells induced normal peritoneal fibroblasts to express markers of cancer-associated fibroblasts (CAFs) and to stimulate growth of EOC and endothelial cells. Similarly, expression of HOXA9 in EOC cells induced normal adipose- and bone marrow-derived mesenchymal stem cells (MSCs) to acquire features of CAFs. These effects of HOXA9 were due in substantial part to its transcriptional activation of the gene encoding TGF-beta 2 that acted in a paracrine manner on peritoneal fibroblasts and MSCs to induce CXCL12, IL-6, and VEGF-A expression. These results indicate that HOXA9 expression in EOC cells promotes a microenvironrnent that is permissive for tumor growth.
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