Abstract
2041
Prostate cancer is the most common malignancy in men and the second leading cause of male cancer-related deaths in the Western world. Therapies for advanced prostate cancer usually involve androgen ablation by surgical or medical castration. Although progress has been made in this domain, the molecular basis of androgen-independent or hormone refractory prostate cancer (HRPC) growth has not been solved to date Recently, it has been proposed that HRPC could derive from selection and expansion of the androgen-independent prostatic stem/progenitor cell populations. To unveil the nature of prostate cancer stem cells, we have created a murine prostate cancer model by specifically deleting the Pten tumor suppressor gene in the prostate using the Cre-Loxp system. Our analysis on this model system shown that 1) the pathological changes of Pten null mouse prostate cancer mimics the disease progression seen in the clinical course, i.e., lesions started from prostate intraepithelial neoplasia (PIN), followed by local invasive adenocarcinoma, and subsequent metastasis, 2) the molecular profile of Pten null mouse prostate cancer demonstrated gene expression changes observed in human disease, and 3) Pten null prostate cancers regressed upon androgen deprivation and relapsed after prolonged androgen ablation. Using this reliable model system, we demonstrated that Pten null prostate cancer is initiated from mutated stem/progenitor cells that closely associated with the prostatic basal cell compartment. The number of stem/progenitor cells, as identified in situ by a combination of epithelial markers, increased progressively with tumor progression in Pten null prostate glands. Pten null stem/progenitor cells proliferate and differentiate after long-term castration to replenish the atrophic gland which and contributes to androgen-independent prostate cancer growth. Our studies indicated that PTEN negatively regulates prostatic stem cell self-renewal and proliferation without blocking their differentiation and PTEN loss mobilizes androgen independent stem/progenitor cells to enter cell cycle. Our findings provide strong evidence that genetically altered prostatic stem/progenitor cells are responsible for tumor initiation, progression, and androgen-independent tumor growth in this murine model.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]