title: 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.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
authors.forename: Song Yi
authors.initials: SY
authors.lastname: Ko
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barengo
authors.forename: Andras
authors.initials: A
authors.lastname: Ladanyi
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: Frank
authors.initials: F
authors.lastname: Marini
authors.forename: Ernst
authors.initials: E
authors.lastname: Lengyel
authors.forename: Honami
authors.initials: H
authors.lastname: Naora
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000556:secondary; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics; D017077:Culture Media, Conditioned / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D053208:Kaplan-Meier Estimate; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019899:Paracrine Communication / Q000187:drug effects; D010534:Peritoneal Neoplasms / Q000556:secondary; D010537:Peritoneum / Q000166:cytology; D011379:Prognosis; D053781:Transforming Growth Factor beta2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology / Q000637:transplantation; D059016:Tumor Microenvironment / Q000187:drug effects / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D017077:Culture Media, Conditioned; D018398:Homeodomain Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D009363:Neoplasm Proteins; C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C097899:homeobox protein HOXA9