AUA 2011 - Androgen independent, tumor-reinitiating cells are selected by androgen deprivation in models of androgen dependent prostate cancer - Session Highlights

WASHINGTON, DC USA (UroToday.com) - This research importantly shows that androgen deprivation therapy (ADT) selects for stem/progenitor (S/P) and neuroendocrine (NE) cells that can reinitiate tumor growth in an androgen-independent fashion.

The investigators previously demonstrated that radical prostatectomy samples and prostate cancer xenograft models and cell lines contain S/P and NE cells. Although the normal prostate depends on androgens for growth and secretory functions, its acinar epithelium cells reinitiate growth when androgens are given thus indicating the presence of S/P and NE cells surviving ADT. They investigated whether ADT selects for S/P- and NE-like cells in androgen-dependent prostate cancer models in vivo and in vitro.

Two models were studied; the BM18 human xenograft model, which shows a nearly complete regression and no spontaneous relapse after ADT, and the androgen dependent cell line LNCaP. ADT was achieved in vivo by castration of tumor bearing mice and in vitro by bicalutamide treatment. Hormone replacement (HR) after ADT was accomplished in vivo by administration of testosterone-pellets to tumor bearing mice and in vitro by androgen-replenished medium. Gene expression was measured by real-time PCR and immunostaining. Cell cycle analysis and Ki67 immunostaining assessed apoptosis and proliferation.

BM18 tumors regressed on average 96.5% in volume within 14 days of ADT. Residual cells were positive for the luminal cytokeratin 18, but compared to intact tumors show a loss of luminal markers such as AR, Nkx3.1 and PSA. They also found that the expression of S/P markers and NE markers is strongly increased. In LNCaP cells ADT selects for CK18 positive cells with decreased Nkx3.1 and PSA expression and with increased NSE expression. After ADT residual BM18 tumor cells were quiescent, while residual LNCaP cells maintained a subset of proliferative cells. In both models, HR reactivates proliferation and Nkx3.1 and PSA expression while reducing NSE expression. These data suggest that ADT selects for S/P- and NE-like prostate cancer cells in vitro and in vivo, which are able to reinitiate a tumor. This in turn suggests that ADT may select for the outgrowth of a more malignant cellular phenotype leading to castration resistance.

 

 

Presented by Markus Germann, et al. at the American Urological Association (AUA) Annual Meeting - May 14 - 19, 2011 - Walter E. Washington Convention Center, Washington, DC USA


Reported for UroToday by Christopher P. Evans, MD, FACS, Professor and Chairman, Department of Urology, University of California, Davis, School of Medicine.


 

The opinions expressed in this article are those of the UroToday.com Contributing Editor and do not necessarily reflect the viewpoints of the American Urological Association.


 

 



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