title: 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 AT-hook 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.
authors.affiliation: Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zong
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.forename: Devipriya
authors.initials: D
authors.lastname: Sankarasharma
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Epstein
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Chada
authors.forename: Owen N
authors.initials: ON
authors.lastname: Witte
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009376:Neoplasms, Hormone-Dependent / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication; D011467:Prostate / Q000254:growth & development / Q000378:metabolism; D019048:Prostatic Intraepithelial Neoplasia / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment; D014566:Urogenital System / Q000196:embryology / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D025743:HMGA2 Protein; D011944:Receptors, Androgen