HOXA9 promotes ovarian cancer growth by stimulating cancer-associated fibroblasts
Song Yi Ko, Nicolas Barengo, Andras Ladanyi, Ju-Seog Lee, Frank Marini, Ernst Lengyel, Honami Naora
Song Yi Ko, Nicolas Barengo, Andras Ladanyi, Ju-Seog Lee, Frank Marini, Ernst Lengyel, Honami Naora
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Research Article Oncology

HOXA9 promotes ovarian cancer growth by stimulating cancer-associated fibroblasts

Abstract

Epithelial ovarian cancers (EOCs) often exhibit morphologic features of embryonic Müllerian 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 Müllerian-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 microenvironment that is permissive for tumor growth.

Authors

Song Yi Ko, Nicolas Barengo, Andras Ladanyi, Ju-Seog Lee, Frank Marini, Ernst Lengyel, Honami Naora

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Figure 3

HOXA9 expression in EOC is associated with increased CAF abundance.

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HOXA9 expression in EOC is associated with increased CAF abundance. (A) ...
(A) Differences in transcript levels of ACTA2 (encoding αSMA) and FAP, between HOXA9-Low and HOXA9-High tumors in the AOCS data set, as estimated by Mann Whitney U test. In box-and-whisker plots, horizontal bars indicate the medians, boxes indicate 25th to 75th percentiles, and whiskers indicate minimum and maximum values. (B–D) αSMA expression was evaluated in tumors of mice sacrificed at 20 days after inoculation with SKOV3ip and ES-2 lines. (B) The average number of αSMA+ cells per 1,000 tumor cells was calculated by scoring 5 random fields of stained tissue sections of each mouse (n = 5 mice per group). *P < 0.0001. Immunofluorescence staining of GFP-expressing tumor cells (green) and αSMA (red) in tumors of mice inoculated with (C) +HOXA9 control and HOXA9-knockdown SKOV3ip lines (scale bar: 100 μm) and (D) +HOXA9 control (nontargeting) SKOV3ip and ES-2 lines (scale bar: 50 μm). Nuclei were visualized by staining with DAPI (blue).