In the United States a person is diagnosed with cancer every 23 seconds. In men, prostate cancer (PRCA) is the most frequently diagnosed of these cancers. Despite the huge incidences of cancer there are few models of human cancer that progress from a benign human tissue into malignant and metastatic tissues utilizing compounds normally found in body. The long term objective of this project is to develop better methods for the prevention and treatment of prostate cancer. Typically, PRCA arises in epithelial tissue and initially responds to androgen ablation therapy. The established paradigm to explain the role of androgen-signaling in the PRCA-progression posits that PRCA is mediated by sex hormone signal transduction in prostatic epithelial cells. This finding has led to the theory that aberrant androgen receptor (AR)-signaling in prostatic epithelial cells is an important early event in the development of prostate cancer. However, recent studies suggest that events in non-epithelial tissues may also contribute to the oncogenic process. To the end of understanding the true mechanisms of androgen-signaling and induction of PRCA-progression, we have developed two novel tissue recombination models that recapitulate key genetic and epigenetic events and processes found in human PRCA. Our data show that in contrast to the established paradigm of epithelial AR-mediated PRCA-progression, AR-signaling in stromal cells is the critical androgen regulated event in the earliest stages of PRCA-progression. Therefore, the central hypothesis of this proposal is that human PRCA is initiated by inappropriate AR activity in stroma. Utilizing these tissue recombinant models we will determine the mechanism of androgen action in PRCA-progression and determine the downstream mechanism by which AR mediates malignant transformation of the epithelium. These experiments will provide key insight into the prevention of human PRCA and lead to a better understanding of the mechanisms of androgen action in human prostate carcinogenesis. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA123199-02
Application #
7501922
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2007-09-28
Project End
2012-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$292,600
Indirect Cost
Name
University of Rochester
Department
Urology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Moses, Michael A; Henry, Ellen C; Ricke, William A et al. (2015) The heat shock protein 90 inhibitor, (-)-epigallocatechin gallate, has anticancer activity in a novel human prostate cancer progression model. Cancer Prev Res (Phila) 8:249-57
Bauman, Tyler M; Nicholson, Tristan M; Abler, Lisa L et al. (2014) Characterization of fibrillar collagens and extracellular matrix of glandular benign prostatic hyperplasia nodules. PLoS One 9:e109102
Bauman, Tyler M; Sehgal, Priyanka D; Johnson, Karen A et al. (2014) Finasteride treatment alters tissue specific androgen receptor expression in prostate tissues. Prostate 74:923-32
Ewald, Jonathan A; Downs, Tracy M; Cetnar, Jeremy P et al. (2013) Expression microarray meta-analysis identifies genes associated with Ras/MAPK and related pathways in progression of muscle-invasive bladder transition cell carcinoma. PLoS One 8:e55414
Nicholson, Tristan M; Uchtmann, Kristen S; Valdez, Conrad D et al. (2013) Renal capsule xenografting and subcutaneous pellet implantation for the evaluation of prostate carcinogenesis and benign prostatic hyperplasia. J Vis Exp :
Verdoorn, Brandon P; Feng, Changyong; Ricke, William A et al. (2012) An observational study of plasma vascular endothelial growth factors (VEGF) A and D expression in non-localized prostate cancer. J Mens Health 9:182-189
Nicholson, Tristan M; Ricke, Emily A; Marker, Paul C et al. (2012) Testosterone and 17?-estradiol induce glandular prostatic growth, bladder outlet obstruction, and voiding dysfunction in male mice. Endocrinology 153:5556-65
Ricke, Emily A; Williams, Karin; Lee, Yi-Fen et al. (2012) Androgen hormone action in prostatic carcinogenesis: stromal androgen receptors mediate prostate cancer progression, malignant transformation and metastasis. Carcinogenesis 33:1391-8
Cunha, Gerald R; Ricke, William A (2011) A historical perspective on the role of stroma in the pathogenesis of benign prostatic hyperplasia. Differentiation 82:168-72
Kohli, Manish; Williams, Karin; Yao, Jorge L et al. (2011) Thrombin expression in prostate: a novel finding. Cancer Invest 29:62-7

Showing the most recent 10 out of 13 publications