Due to the androgen-dependent nature of the vast majority of prostate cancer cells, androgen deprivation remains the primary therapeutics for androgen-dependent prostate cancer, and most patients respond initially to the treatment. However, with time, the majority of patients eventually develop more aggressive, androgen- independent and hormone-refractory tumors. Thus the search for mechanism-based therapeutic strategies that can delay hormone ablation-induced prostate cancer progression remains the top priority in prostate cancer research. Cancer stem cell (CSC) hypothesis suggests that CSCs have the ability to self-renew and differentiate and are responsible for tumor initiation, progression, drug resistance, recurrence and metastasis. However, it is unclear how prostate CSCs may respond to hormone ablation treatment and if prostate CSCs can be an effective target for inhibiting prostate progression. Our preliminary studies showed that prostate CSCs had overexpression of the stem cell self-renewal marker, the transcription factor B lymphoma Mo-MLV insertion region 1 (Bmi-1), that black tea significantly delayed androgen ablation-induced progression of prostate tumors associated with downregulation of Bmi-1 expression, and that bioactive components in black tea inhibited self-renewal of prostate CSCs/progenitor cells and downregulated the gene expression of Bmi-1. These promising preliminary studies provide experimental evidence to support the novel hypotheses that prostate CSCs are resistant to hormone ablation treatment, that hormone deprivation may accelerate self- renewal of prostate CSC in part via upregulation of Bmi-1, and that black tea bioactive components may delay CSC-originated and hormone deprivation-induced progression of androgen-independent prostate cancer in part by downregulation of Bmi-1.
Specific aim 1 is to characterize cellular and molecular alterations in prostate CSCs derived from orthotopic prostate tumors at different stages of androgen deprivation-induced progression. The self-renewal capability of prostate CSCs at different stages of hormone deprivation-induced progression and associated Bmi-1 expression will be first determined (Aim 1A);then the functional role of Bmi-1 in prostate CSC response to androgen deprivation will be determined (Aim 1B).
Specific aim 2 is to determine if androgen ablation accelerates prostate CSC self-renewal and tumorigenesis by upregulation of Bmi-1 in clinically relevant in vivo models.
Specific aim 3 is to determine the effect of black tea components on prostate CSC- originated and androgen deprivation-induced prostate tumor progression. The research findings will provide crucial experimental evidence to support not only the essential role of prostate CSCs in the progression and recurrence of prostate cancer, but also a paradigm shift for identifying effective preventive and therapeutic regimens against progression of androgen-independent/hormone-refractory prostate cancer.
The goals of this application are to determine the potential causal roles of prostate cancer stem cells in resistance to androgen ablation therapy and in progression to androgen-independent/hormone-refractory prostate cancer, and to evaluate the therapeutic activity of black tea bioactive components by targeting prostate CSCs. The research findings will provide crucial experimental evidence to support not only the essential role of prostate CSCs in the progression and recurrence of prostate cancer, but also a potential paradigm shift for identifying effective therapeutic regimens against prostate cancer. Therefore it is expected that the proposed studies have significant impacts on public health, especially therapy and management of prostate cancer.