Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling

Abstract

Carcinomas most often result from the stepwise acquisition of genetic alterations within the epithelial compartment. The surrounding stroma can also play an important role in cancer initiation and progression. Given the rare frequencies of genetic events identified in cancer-associated stroma, it is likely that epigenetic changes in the tumor microenvironment could contribute to its tumor-promoting activity. We use Hmga2 (High-mobility group AThook 2) an epigenetic regulator, to modify prostate stromal cells, and demonstrate that perturbation of the microenvironment by stromal-specific overexpression of this chromatin remodeling protein alone is sufficient to induce dramatic hyperplasia and multifocal prostatic intraepithelial neoplasia lesions from adjacent naïve epithelial cells. Importantly, we find that this effect is predominantly mediated by increased Wnt/β-catenin signaling. Enhancement of Hmga2-induced paracrine signaling by overexpression of androgen receptor in the stroma drives frank murine prostate adenocarcinoma in the adjacent epithelial tissues. Our findings provide compelling evidence for the critical contribution of epigenetic changes in stromal cells to multifocal tumorigenesis.

SOX9 drives WNT pathway activation in prostate cancer

“…However, it has become clear that nuclear β-catenin staining is not a sensitive indicator of WNT/β-catenin pathway activation and that robust biomarkers and mechanisms of WNT signaling are needed to fully elucidate the role of this pathway in PCa (47)(48)(49)(50)(51)(52)(53)(54). We believe that our study establishes a novel link between SOX9 and WNT pathway activation in PCa and shows mechanistically that SOX9 positively regulates multiple genes required for WNT signaling.…”

Autotaxin–lysophosphatidic acid– LPA 3 signaling at the embryo‐epithelial boundary controls decidualization pathways

“…Thus, LPA–LPA 3 signaling is critical in the development of endometriosis. Furthermore, HB‐EGF, COX‐2, and Wnt4 as well as Bmp2 have been shown to be risk factors for sex hormone‐dependent diseases, such as prostatic hyperplasia, breast cancer, and ovarian cancer (Bentley et al , 1992; Ferrandina et al , 2002; Levin, 2003; Zong et al , 2012). Since LPA 3 is highly expressed in the prostate, mammary gland, and ovary (Bandoh et al , 1999), LPA 3 signaling might contribute to the progression of such diseases.…”

Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells

“…S4). Elevated Wnt signaling in the prostate microenvironment can transform adjacent naïve benign epithelium (26). Wnt ligands are elevated in prostate cancer stromal cells following treatment, leading to beta-catenin activation in the adjacent tumor cells (27).…”