BERKELEY, CA (UroToday.com) - Androgen deprivation therapy (ADT) initially produces dramatic reductions in androgen-responsive prostatic tumors. However, eventual failure of ADT inevitably leads to recurrence of incurable androgen-refractory or castration-resistant tumors. How these refractory tumors arise is poorly understood and strategies for their treatment are limited. Thus, it is desirable to develop alternative approaches seeking to make ADT more effective such that castration-resistant populations are inhibited or eliminated during the initial treatment period. Our study suggests that the ADT-induced proliferative arrest, a phenomenon called cellular senescence, creates conditions that facilitate outgrowths of androgen-refractory variants, likely by inhibiting cell death pathways in the tumor cells. Further, senescent, but not proliferating androgen-responsive tumor cells, also release IL-8, a cytokine shown to promote androgen-refractory prostatic tumors. In fact, the microenvironment produced by senescent androgen-responsive cells appears to be very similar to that produced by fully androgen-refractory cells in terms of promoting ADT-resistant proliferation. Collectively our results suggest that ADT-induced senescence (ADIS) is a suboptimal tumor suppressor response in prostate cancer and should be combined with treatments that switch ADT response towards pervasive cell death. Our study further indicates that p53-activating drugs such as Nutlin-3, administered prior to or concurrently with ADT, may prove to be highly effective in this regard. Other treatments, particularly those that induce DNA damage or produce reactive oxygen species (ROS), may also produce a similar effect in conjunction with ADT and need to be investigated in this context.
Establishing androgen-refractory variants from androgen-responsive prostate cancer cells has made it possible to recapitulate the clinical disease progression of prostate cancer in cell culture models. While this process has simplified experimental therapeutic studies and the investigation of disease-associated molecular etiology, the methods that generate these androgen-refractory cells are time consuming and expensive. These currently involve either prolonged (8 months to a year) culture in androgen-depleted culture medium, increasing the possibility of contamination or unrelated long-term culture-associated changes, or isolation and propagation of cells from xenograft castration-resistant tumors formed in athymic mice. In our study, we used novel methodology to show that androgen-refractory LNCaP cells comprise a subpopulation that is resistant to ADT-induced senescence (ADIS). The methodology described in our study is simple and enables us to isolate these androgen-refractory variants in a significantly shorter time frame than existing methods.
A major advantage of our method is that it directly derives clonal variants from the parental androgen-responsive cell line and thus avoids artifacts that may arise from long-term cell culture or multiple propagations in animal models. Accordingly, our method represents a resource for other prostate cancer investigators, enabling them to generate ‘matched’ androgen-refractory cells from the specific cultures being used in their laboratories. Furthermore, the subpopulations isolated by application of our method likely possess critical early adaptive changes that promote androgen-refractory outgrowths. These molecular changes can be readily identified through direct comparative analyses of the variants with respect to their parental counterpart cell populations. The pathways mediating such acute changes represent excellent drug targets for effective elimination of early androgen-insensitive prostate cancer cells, thus potentially inhibiting hormone-refractory outgrowths.
Finally, it must be acknowledged that senescence is a major tumor suppressor pathway and that in other treatment contexts beside ADT, it may serve as an effective inhibitor of prostate cancer. We anticipate that the molecular mechanisms and markers identified via our study will enable others in the prostate cancer research field to assess whether senescence is likely to be tumor-suppressive or tumor-promoting within their particular treatment context. This is an important distinction and, in conjunction with using matched androgen-refractory variants, can directly impact the translational utility of cell culture-based experimental therapeutics findings. Thus, we hope and anticipate that our study will not only potentially inform effective treatment strategies to prevent androgen-refractory prostate cancer but will also advance research by other investigators towards clinically desirable directions.
Written by:
Priyamvada Rai, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Assistant Professor
Department of Medicine
Leonard M. Miller School of Medicine
University of Miami
Miami, FL USA
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