Abstract B67: The epigenetic regulator Hmga2 is sufficient to initiate prostate cancer via paracrine Wnt signaling

Abstract

Abstract Carcinomas result from the stepwise acquisition of multiple genetic alterations within the epithelial compartment. The surrounding stroma, including extracellular matrix, blood vasculature, inflammatory cells and fibroblasts, also plays important roles in cancer initiation and progression. Aberrant microenvironment resulting from aging and chronic inflammation as well as tumor stress can provide “field effects” to facilitate the development of multifocal malignant lesions with independent clonal origin. Given the rare frequency of genetic changes identified in cancer associated stroma, it is likely that epigenetic alterations, such as histone modifications and chromatin remodeling, could contribute to the tumor-promoting phenotype of cancer associated stromal cells. Here we utilize high-mobility group AT-hook 2 (Hmga2), a nonenzymatic epigenetic regulator, to modify prostate stromal cells, and demonstrate that perturbation of the microenvironment by stromal-specific overexpression of this chromatin remodeling protein is sufficient to induce multiple high-grade prostatic intraepithelial neoplasia lesions from adjacent naïve epithelial cells. The growth-promoting effects of Hmga2-expressing stromal cells are predominantly mediated by increased Wnt/β-catenin signaling and preferentially act on prostate stem cells-enriched basal epithelial cells. Enhancement of Hmga2-induced paracrine signaling by overexpression of androgen receptor (AR) in the stroma drives full carcinoma in the adjacent epithelial tissues, indicating that combined targeted therapies against augmented Wnt and stromal AR signaling may represent as an effective treatment strategy for prostate cancer. Our findings provide compelling evidence for the critical contribution of epigenetic changes in stromal cells to multifocal tumorigenesis, and for the first time reveal that Hmga2, a cell intrinsic oncoprotein, could exert its function via paracrine Wnt signaling. Citation Format: Yang Zong, Jiaoti Huang, Owen N. Witte. The epigenetic regulator Hmga2 is sufficient to initiate prostate cancer via paracrine Wnt signaling [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B67.