| Prostate cancer is the second most common cause of cancer-related death in men, necessitating improved disease eradication procedures that yield increased quality of life for patients. Cryosurgical ablation of the prostate has emerged as a commonly applied therapy. However, the presumption that freezing serves as a ubiquitous lethal stress in prostate cancer is challenged by anecdotal clinical experience (disease recurrence) and experimental evidence demonstrating time-temperature related cell death dependence. While often successful, complete cryoablation of cancerous tissues sometimes fails due to technical challenges and/or age-related tumor transformation from androgen-dependent to androgen-independent phenotype, which is refractory to most in situ therapies. Therefore, we questioned whether technical factors and prostate cancer progression to androgen-independence makes cryosurgery less effective, due to molecular changes in tumor populations to a more aggressive phenotype that have been exacerbated by androgen-ablation treatments commonly administered to reduce overall tumor size. A series of studies were designed to improve cryoablation for advanced stage prostate cancer. Investigation into cryosurgical technique indicated that utilization of lower end-temperatures, rapid cooling rates, longer freezing duration, and use of multiple freezing cycles lead to improved ablation, however, androgen-independent cells exhibited increased resistance to treatment compared to androgen-dependent cells. Investigation into underlying cellular mechanisms contributing to variations in freeze response indicated that loss of the cytosolic steroid hormone androgen receptor (AR) in androgen-independent cells resulted in: (1) Increased proliferation rates due to increased cell survival signaling that bypassed AR signaling via the Akt pathway. (2) Increased freeze resistance due to decreased apoptotic cascade activity. Furthermore, AR loss correlated with alpha6beta4 integrin overexpression that contributed to morphological changes and aggressive phenotype, resulting in: (1) Increased adhesion to extracellular matrices during freezing leading to increased post-freeze survival. (2) Decreased post-freeze apoptotic activity. Finally, investigation into vitamin D3 (low levels of which correlate with increased risk of developing prostate cancer) as a neo-adjunctive agent used prior to freezing exhibited equal therapeutic efficacy for androgen-dependent and -independent cells due to its ability to increase post-freeze mitochondrial-mediated apoptosis through reductions in Bcl-2 expression. This study supports the interpretation that younger patients may prove to be ideal candidates for neo-adjunctive prostate cryoablation as a primary therapy, before cancer progresses to androgen-independence. |
