Prostate cancer stem cells, telomerase biology, epigenetic modifiers, and molecular systemic therapy for the androgen-independent lethal phenotype.

Numerous, relatively well-characterized androgen-independent osteotropic prostate cancer cell lines are now available to interrogate clinically relevant fundamental questions of prostate cancer metastasis and lethal progression systematically. Mounting basic and translational science efforts reveal that, very likely, the currently incurable form of androgen independent osseous prostate cancer originates from a more undifferentiated or "stem cell" like component, coexisting within a heterogeneous tumor mass containing more differentiated epithelial cancer subtypes. Current therapeutic preclinical investigations point toward the use of epigenetic modifiers, such as histone deacetylase inhibitors, to abrogate the continued survival of prostate cancer cells and likely can be used relatively chronically, with little morbidity. Telomere maintenance is critical in the immortalization of prostate cancer cells, and all known androgen independent cell line variants invariably express telomerase, and, thus, an argument can be made that these aggressive cells are likened to immature, progenitor variants. The arena of telomere biology has evolved enough to provide precise, nontoxic small molecule inhibitors of telomerase that limit viability of androgen-independent cell lines, yielding apoptosis. Both epigenetic modifiers and telomerase-directed small molecule inhibitors have enhanced efficacy when given in combination with conventional and novel cytotoxic drugs. Better knowledge of the "stem cell" nature of prostate cancer will help direct the molecularly targeted therapies of the near future.