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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-β2 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 microen-vironment that is permissive for tumor growth., Introduction Approximately 70% of patients with epithelial ovarian cancer (EOC) present with disease that involves the peritoneal cavity (1). Unlike many other types of cancers, EOC rarely spreads via hematogenous [...]

Although epithelial ovarian cancers (EOCs) have been thought to arise from the simple epithelium lining the ovarian surface or inclusion cysts, the major subtypes of EOCs show morphologic features that resemble those of the m#252;llerian duct-derived epithelia of the reproductive tract. We found that HOX genes, which normally regulate m#252;llerian duct differentiation, are not expressed in normal ovarian surface epithelium (OSE), but are expressed in different EOC subtypes according to the pattern of m#252;llerian-like differentiation of these cancers. Ectopic expression of Hoxa9 in tumorigenic mouse OSE cells gave rise to papillary tumors resembling serous EOCs. In contrast, Hoxa10 and Hoxa11 induced morphogenesis of endometrioid-like and mucinous-like EOCs, respectively. Hoxa7 showed no lineage specificity, but promoted the abilities of Hoxa9, Hoxa10 and Hoxa11 to induce differentiation along their respective pathways. Therefore, inappropriate activation of a molecular program that controls patterning of the reproductive tract could explain the morphologic heterogeneity of EOCs and their assumption of m#252;llerian-like features., Author(s): Wenjun Cheng [1, 3]; Jinsong Liu [2]; Hiroyuki Yoshida [1]; Daniel Rosen [2]; Honami Naora (corresponding author) [1] A major challenge to improving diagnosis and treatment of EOC is [...]