Androgen hormone action in prostatic carcinogenesis: stromal androgen receptors mediate prostate cancer progression, malignant transformation and metastasis.

It has been postulated that prostatic carcinogenesis is androgen dependent and that androgens mediate their effects primarily through epithelial cells; however, definitive proof of androgen hormone action in prostate cancer (PRCA) progression is lacking. Here we demonstrate through genetic loss of function experiments that PRCA progression is androgen dependent and that androgen dependency occurs via prostatic stromal androgen receptors (AR) but not epithelial AR. Utilizing tissue recombination models of prostatic carcinogenesis, loss of AR function was evaluated by surgical castration or genetic deletion. Loss of AR function prevented prostatic carcinogenesis, malignant transformation and metastasis. Tissue-specific evaluation of androgen hormone action demonstrated that epithelial AR was not necessary for PRCA progression, whereas stromal AR was essential for PRCA progression, malignant transformation and metastasis. Stromal AR was not necessary for prostatic maintenance, suggesting that the lack of cancer progression due to stromal AR deletion was not related to altered prostatic homeostasis. Gene expression analysis identified numerous androgen-regulated stromal factors. Four candidate stromal AR-regulated genes were secreted growth factors: fibroblast growth factors-2, -7, -10 and hepatocyte growth factor which were significantly affected by androgens and anti-androgens in stromal cells grown in vitro. These data support the concept that androgens are necessary for PRCA progression and that the androgen-regulated stromal microenvironment is essential to carcinogenesis, malignant transformation and metastasis and may serve as a potential target in the prevention of PRCA.

[1]  S. Memarzadeh,et al.  Basal epithelial stem cells are efficient targets for prostate cancer initiation , 2010, Proceedings of the National Academy of Sciences.

[2]  H. Scher,et al.  Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer , 2009, Science.

[3]  S. Yeh,et al.  Targeting the stromal androgen receptor in primary prostate tumors at earlier stages , 2008, Proceedings of the National Academy of Sciences.

[4]  Jorge Yao,et al.  Androgen receptor is a tumor suppressor and proliferator in prostate cancer , 2008, Proceedings of the National Academy of Sciences.

[5]  Yuzhuo Wang,et al.  Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  M. Teitell,et al.  Enhanced paracrine FGF10 expression promotes formation of multifocal prostate adenocarcinoma and an increase in epithelial androgen receptor. , 2007, Cancer cell.

[7]  Leif E. Peterson,et al.  Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. , 2007, Cancer cell.

[8]  S. Yeh,et al.  Increased prostate cell proliferation and loss of cell differentiation in mice lacking prostate epithelial androgen receptor , 2007, Proceedings of the National Academy of Sciences.

[9]  Yuzhuo Wang,et al.  Steroid hormones stimulate human prostate cancer progression and metastasis , 2006, International journal of cancer.

[10]  T. Ratliff.  TGF-Beta Signaling in Fibroblasts Modulates the Oncogenic Potential of Adjacent Epithelia , 2004 .

[11]  M. Washington,et al.  TGF-ß Signaling in Fibroblasts Modulates the Oncogenic Potential of Adjacent Epithelia , 2004, Science.

[12]  P. Nelson,et al.  Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. , 2003, Cancer cell.

[13]  T. Graeber,et al.  Myc-driven murine prostate cancer shares molecular features with human prostate tumors. , 2003, Cancer cell.

[14]  S. Hayward,et al.  Malignant transformation in a nontumorigenic human prostatic epithelial cell line. , 2001, Cancer research.

[15]  W. Linehan,et al.  The consequences of chromosomal aneuploidy on gene expression profiles in a cell line model for prostate carcinogenesis. , 2001, Cancer research.

[16]  I. Leav,et al.  Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  R. Dahiya,et al.  A human prostatic epithelial model of hormonal carcinogenesis. , 2001, Cancer research.

[18]  R. Dahiya,et al.  Paracrine regulation of apoptosis by steroid hormones in the male and female reproductive system , 2001, Cell Death and Differentiation.

[19]  R. Cardiff,et al.  Sex hormone-induced carcinogenesis in Rb-deficient prostate tissue. , 2000, Cancer research.

[20]  E. Olapade-Olaopa,et al.  Malignant transformation of human prostatic epithelium is associated with the loss of androgen receptor immunoreactivity in the surrounding stroma. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[21]  J. Isaacs,et al.  Development of an androgen receptor-null model for identifying the initiation site for androgen stimulation of proliferation and suppression of programmed (apoptotic) death of PC-82 human prostate cancer cells. , 1998, Cancer research.

[22]  M. Kattan,et al.  Androgen-independent prostate cancer progression in the TRAMP model. , 1997, Cancer research.

[23]  M. Webber,et al.  Androgen responsive adult human prostatic epithelial cell lines immortalized by human papillomavirus 18. , 1997, Carcinogenesis.

[24]  J. Goméz,et al.  Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men. , 1994, The Journal of clinical endocrinology and metabolism.

[25]  G. Cunha,et al.  Assessment of prostatic protein secretion in tissue recombinants made of urogenital sinus mesenchyme and urothelium from normal or androgen-insensitive mice. , 1993, Endocrinology.

[26]  S. Ho,et al.  Selective increase in type II estrogen-binding sites in the dysplastic dorsolateral prostates of noble rats. , 1993, Cancer research.

[27]  I. Leav,et al.  Biochemical alterations in sex hormone-induced hyperplasia and dysplasia of the dorsolateral prostates of Noble rats. , 1988, Journal of the National Cancer Institute.

[28]  G. Cunha,et al.  The possible influence of temporal factors in androgenic responsiveness of urogenital tissue recombinants from wild-type and androgen-insensitive (Tfm) mice. , 1978, The Journal of experimental zoology.

[29]  R. Noble.  The development of prostatic adenocarcinoma in Nb rats following prolonged sex hormone administration. , 1977, Cancer research.

[30]  R. Cardiff,et al.  Simultaneous haploinsufficiency of Pten and Trp53 tumor suppressor genes accelerates tumorigenesis in a mouse model of prostate cancer. , 2009, Differentiation; research in biological diversity.

[31]  G. Cunha,et al.  The importance of stroma in morphogenesis and functional activity of urogenital epithelium , 2007, In Vitro.

[32]  R. Vessella,et al.  Molecular determinants of resistance to antiandrogen therapy , 2004, Nature Medicine.

[33]  R. Sutherland,et al.  Altered expression of androgen receptor in the malignant epithelium and adjacent stroma is associated with early relapse in prostate cancer. , 2001, Cancer research.

[34]  R. Bosch,et al.  Pathogenesis of benign prostatic hyperplasia. , 1991, European urology.