Space Invaders
After an ovarian tumor forms, clumps of cancer cells are shed from the surface and released into the peritoneal cavity. These clumps then float around until they come into contact with another surface: abdominal organs, the diaphragm, the omentum, and the peritoneum. To successfully invade these tissues, the ovarian cancer cells have to adapt to the cells that surround them (stromal cells). In a new study in the JCI, Ko et al. demonstrate that ovarian cancer cells brainwash the stromal cells by upregulating pathways that alter the environment to support tumor growth. The frames above show fluorescent ovarian cancer cells in the peritoneal cavities of untreated mice (left), mice that have had the brainwashing pathways disrupted (middle frames), and mice that have been given a protein that allows the ovarian cancer cells to invade (right).
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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
Copyright © 2020 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)