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

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 5

HOXA9 expression in EOC cells promotes the ability of fibroblasts to stimulate endothelial cell growth.

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HOXA9 expression in EOC cells promotes the ability of fibroblasts to sti...
(A) The average number of microvessels per 104 tumor cells was calculated in tumors derived from +HOXA9 control (nontargeting) and HOXA9-knockdown (shA9-B) SKOV3ip lines by scoring 5 random fields of CD34-stained tissue sections of each mouse (n = 5 mice per group). *P < 0.005. (B) Relative mRNA levels of IL6 and VEGFA in cultured SKOV3ip cells and of IL6 and VEGFA (in human EOC cells) and Il6 and Vegfa (in mouse host cells) in omental tumors of mice that were inoculated with SKOV3ip lines (n = 5 mice per group). *P = 0.03; †P = 0.007. P values > 0.05 were considered not significant. Evaluation of specificity of human- and mouse- specific qRT-PCR primers is shown in Supplemental Figure 6B. (C) Growth rates of mouse endothelial cells incubated in nonconditioned medium and in SKOV3ip-conditioned media. **P < 0.005. (D) Normal omental fibroblasts were left unprimed or primed with SKOV3ip-conditioned media (shown in pink) for 5 days. Fresh nonconditioned medium was added to washed fibroblasts. Two days thereafter, medium conditioned by fibroblasts (shown in light blue) was collected. Growth rates of endothelial cells incubated in fibroblast-conditioned medium were measured. *P < 0.005. Average results of assays using 3 independent sets of each type of conditioned medium are shown in C and D.