TY - JOUR
T1 - Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling
AU - Zong, Yang
AU - Huang, Jiaoti
AU - Sankarasharma, Devipriya
AU - Morikawa, Teppei
AU - Fukayama, Masashi
AU - Epstein, Jonathan I.
AU - Chada, Kiran K.
AU - Witte, Owen N.
N1 - Funding Information:
partly supported by funds from a Prostate Cancer Foundation challenge award and National Cancer Institute Grant 1U01CA164188. O.N.W. is an Investigator and Y.Z. is an Associate of the Howard Hughes Medical Institute. J.H. is also supported by US Department of Defense Prostate Cancer Research
Funding Information:
This work was partly supported by funds from a Prostate Cancer Foundation challenge award and National Cancer Institute Grant 1U01CA164188. O.N.W. is an Investigator and Y.Z. is an Associate of the Howard Hughes Medical Institute. J.H. is also supported by US Department of Defense Prostate Cancer Research Program Grant PC1001008, University of California, Los Angeles Specialized Program of Research Excellence in prostate cancer [Principal Investigator (PI), R. Reiter], a creativity award from the Prostate Cancer Foundation (PI, M. Rettig), and National Institutes of Health Grant 1R01CA158627 (PI, L. Marks).
Funding Information:
Program Grant PC1001008, University of California, Los Angeles Specialized Program of Research Excellence in prostate cancer [Principal Investigator (PI), R. Reiter], a creativity award from the Prostate Cancer Foundation (PI, M. Rettig), and National Institutes of Health Grant 1R01CA158627 (PI, L. Marks).
PY - 2012/12/11
Y1 - 2012/12/11
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.1217982109
DO - 10.1073/pnas.1217982109
M3 - Article
C2 - 23184966
AN - SCOPUS:84874440778
SN - 0027-8424
VL - 109
SP - E3395-E3404
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 50
ER -