Targeting prostate cancer stem cells to delay prostate cancer progression

描述(申请人提供)：由于绝大多数前列腺癌细胞具有雄激素依赖性，雄激素去除法仍然是雄激素依赖型前列腺癌的主要治疗方法，大多数患者最初对该疗法有反应。然而，随着时间的推移，大多数患者最终会发展成更具侵袭性的、雄激素非依赖性和激素难治性肿瘤。因此，寻找能够延缓激素消融诱导的前列腺癌进展的基于机制的治疗策略仍然是前列腺癌研究的重中之重。肿瘤干细胞假说认为，肿瘤干细胞具有自我更新和分化的能力，与肿瘤的发生、发展、耐药、复发和转移有关。然而，目前尚不清楚前列腺癌干细胞对激素消融治疗有何反应，以及前列腺癌干细胞是否可以作为抑制前列腺癌进展的有效靶点。我们的初步研究表明，前列腺CSCs存在干细胞自我更新标志物转录因子B淋巴瘤Mo-MLV插入区1(BMI-1)的过度表达，红茶显著延缓雄激素消融诱导的前列腺癌的进展，与Bmi-1表达下调有关，红茶中的活性成分抑制前列腺CSCs/祖细胞的自我更新，并下调BMI-1的基因表达。这些有希望的初步研究提供了实验证据，支持新的假设，即前列腺CSCs对激素去除治疗具有抵抗力，激素剥夺可能部分通过上调Bmi-1来加速前列腺CSC的自我更新，以及红茶生物活性成分可能部分通过下调Bmi-1来延缓CSC起源和激素剥夺诱导的雄激素非依赖性前列腺癌的进展。具体目的1是描述在雄激素剥夺诱导进展的不同阶段，来自原位前列腺癌的前列腺CSCs的细胞和分子变化。首先将确定在激素剥夺诱导进展的不同阶段的前列腺CSC的自我更新能力和相关的Bmi-1表达(目标1A)；然后将确定Bmi-1在前列腺CSC对雄激素剥夺的反应中的功能作用(目标1B)。具体目的2是确定在临床相关的活体模型中，雄激素治疗是否通过上调BMI-1来加速前列腺CSC的自我更新和肿瘤的发生。具体目标3是确定红茶成分对前列腺CSC起源和雄激素剥夺诱导的前列腺癌进展的影响。研究结果将提供重要的实验证据，不仅支持前列腺癌CSCs在前列腺癌进展和复发中的重要作用，而且还将转变为寻找有效的预防和治疗方案，防止雄激素非依赖性/激素难治性前列腺癌的进展。 公共卫生相关性：这项应用的目标是确定前列腺癌干细胞在雄激素消融治疗抵抗和进展为雄激素非依赖性/激素难治性前列腺癌中的潜在原因，并通过靶向前列腺癌干细胞来评估红茶生物活性成分的治疗活性。研究结果将提供重要的实验证据，不仅支持前列腺癌CSCs在前列腺癌进展和复发中的关键作用，而且还将为寻找有效的前列腺癌治疗方案提供潜在的范式转变。因此，预计拟议的研究将对公众健康，特别是前列腺癌的治疗和管理产生重大影响。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.