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Growth Inhibitory and Stimulatory Signals in Prostate Cancer

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Annual rept. 1 Apr 2000-31 Mar 2001

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Growth factors play an important role in the development and growth of human prostate cancer CaP. In normal prostatic cells, Transforming Growth Factor-alpha TGF alpha stimulates while Transforming Growth Factor-TGF beta inhibits cell growth. To study the role that these growth factors play in CaP, we have created transgenic mouse models where the over expression of TGF alpha occurs MT-TGF alpha or the TGF beta signal is lost MT-DNIIR. Since the loss of the tumor suppressor genes p53 and RB are associated with CaP, we established LPB-Tag transgenic mice that disrupt these pathways. The transgenic mice which over express the stimulatory growth factor, TGF alpha, develop prostatic intraepithelial neoplasia PIN, a precursor lesion seen in human CaP. Also, mice that cannot respond to TGF beta inhibition develop PIN. LPB-Tag mice develop PIN and eventually invasive CaP. Cross breeding the MT-TGF alpha and MT-DNIIR mice results in offspring rapidly developing high grade PIN. If LPB-Tag mice are bred with MT-DNIIR mice, the offspring rapidly develop CaP. These results demonstrate that combining increased expression of MT-TGF alpha with the loss ofthe TGF beta signal increases the rate of PIN development. Further, the loss ofthe TGF beta signal and the loss of two tumor suppressors genes are sufficient to develop CaP. We are now testing the role that loss of the TGF beta plays in progression of CaP from an androgen-dependent to androgen-independent cancer. The answers to these questions will provide insight 6n the disease process and possible sites for intervention to treat CaP.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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