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HOXA9 promotes ovarian cancer growth by stimulating cancer-associated fibroblasts
Song Yi Ko, … , Ernst Lengyel, Honami Naora
Song Yi Ko, … , Ernst Lengyel, Honami Naora
Published September 4, 2012
Citation Information: J Clin Invest. 2012;122(10):3603-3617. https://doi.org/10.1172/JCI62229.
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Research Article Oncology

HOXA9 promotes ovarian cancer growth by stimulating cancer-associated fibroblasts

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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 2

HOXA9 promotes tumor growth in mouse xenograft models of EOC.

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HOXA9 promotes tumor growth in mouse xenograft models of EOC.
(A–C) Comp...
(A–C) Comparison of survival rates of female nude mice inoculated i.p. with vector-control and with (A) +HOXA9, (B) +HOXA10, and (C) +HOXA11 MOSEC lines (n = 10 per group). (D) Western blot of HOXA9 in SKOV3ip and ES-2 lines stably expressing empty pGFP-V-RS vector, nontargeting shRNA, and shRNAs targeting different sites of HOXA9 (shA9-A, shA9-B). Full uncut gels are shown in the Supplemental Material. (E and F) Growth rates of s.c. tumors derived from +HOXA9 control (Empty vector, Nontargeting) and HOXA9-knockdown (shA9-A, shA9-B) (E) SKOV3ip and (F) ES-2 lines (n = 5 per group). *P < 0.0005. (G and H) Mice were inoculated i.p. with GFP-expressing (G) SKOV3ip and (H) ES-2 lines and sacrificed at 4 weeks and 20 days, respectively. Implants were viewed under a fluorescence stereoscope. Omental implants in +HOXA9 control groups are indicated by arrows. Original magnification, ×0.8.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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