While significant progress has been made upon defining the molecular steps in androgen action in prostatic tissue, there are a series of major controversies which have not been resolved particularly with regard to the importance of cell/cell interaction in such androgen action. One of the most significant of these controversies involves whether androgen action in the normal vs neoplastic prostate involves an intracrine, autocrine, or paracrine pathway. Since prostatic glandular cells express the androgen receptor, originally it was assumed that androgen action involves a completely intracellular (i.e., intracrine) pathway. In this intracrine model, once testosterone is converted to DHT within glandular cells it binds to the androgen receptor and the binding of the dihydrotestosterone (DHT) androgen receptor complex to androgen response elements within the promoter region of specific androgen responsive genes leads to the production of specific mRNAs whose expression results in proteins retained within the glandular cell itself to generate specific signals either to maintain secretory function and suppress programmed death to proliferate. Recent studies have questioned whether androgens act directly within the prostatic glandular cells themselves. These studies suggest that the critical DHT-androgen receptor interactions actually occur in prostatic stromal cells inducing these stromal cells to synthesize and release soluble factors whose functions are to regulate the balance between proliferation and death of the prostatic glandular cells. Since during the development of both BPH and prostate cancer, this balance is abnormally disrupted, there is a critical need to resolve the role of stromal cells in androgen regulated normal and abnormal growth of the prostate. This is particularly critical since there is experimental data supporting the idea that during prostatic neoplastic progression, there is a shift from the normal paracrine to an autocrine or intracrine mechanism of androgen action. Resolving this issue is critical since depending on the answer, the choice of theoretical, as well as practical targets and/or methods to prevent the development of these prostatic disorders would be profoundly different. Based upon this realization, the present RFA specifically has called for applications to study cell/cell interaction and prostate growth. In the present application, a series of unique xenograft and molecular biologic methods will be used to clarify the role of stromal cell interactions in the androgen regulation of the in vivo growth of normal, BPH, and malignant human prostate tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052645-02
Application #
2713458
Study Section
Special Emphasis Panel (SRC (05))
Project Start
1997-07-07
Project End
2001-05-31
Budget Start
1998-07-27
Budget End
1999-05-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Antony, Lizamma; van der Schoor, Freek; Dalrymple, Susan L et al. (2014) Androgen receptor (AR) suppresses normal human prostate epithelial cell proliferation via AR/?-catenin/TCF-4 complex inhibition of c-MYC transcription. Prostate 74:1118-31
Vander Griend, Donald J; Litvinov, Ivan V; Isaacs, John T (2014) Conversion of androgen receptor signaling from a growth suppressor in normal prostate epithelial cells to an oncogene in prostate cancer cells involves a gain of function in c-Myc regulation. Int J Biol Sci 10:627-42
Isaacs, John T; D'Antonio, Jason M; Chen, Shuangling et al. (2012) Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer. Prostate 72:1491-505
Williams, Simon A; Jelinek, Christine A; Litvinov, Ivan et al. (2011) Enzymatically active prostate-specific antigen promotes growth of human prostate cancers. Prostate 71:1595-607
D'Antonio, Jason M; Vander Griend, Donald J; Antony, Lizamma et al. (2010) Loss of androgen receptor-dependent growth suppression by prostate cancer cells can occur independently from acquiring oncogenic addiction to androgen receptor signaling. PLoS One 5:e11475
Vander Griend, Donald J; D'Antonio, Jason; Gurel, Bora et al. (2010) Cell-autonomous intracellular androgen receptor signaling drives the growth of human prostate cancer initiating cells. Prostate 70:90-9
Sedelaar, J P Michiel; Isaacs, John T (2009) Tissue culture media supplemented with 10% fetal calf serum contains a castrate level of testosterone. Prostate 69:1724-9
Vander Griend, Donald J; Konishi, Yuko; De Marzo, Angelo M et al. (2009) Dual-label centromere and telomere FISH identifies human, rat, and mouse cell contribution to Multispecies recombinant urogenital sinus xenografts. Prostate 69:1557-64
Vander Griend, Donald J; Karthaus, Wouter L; Dalrymple, Susan et al. (2008) The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells. Cancer Res 68:9703-11
Collins, Connie; Carducci, Michael A; Eisenberger, Mario A et al. (2007) Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint. Cancer Biol Ther 6:1360-7

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