Targeting prostate cancer stem cells to delay prostate cancer progression

靶向前列腺癌干细胞以延缓前列腺癌进展

• 批准号: 8286889
• 负责人: JIN-RONG ZHOU
• 金额: $ 22.71万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8286889
• 关键词: Ablation; Americas; Androgen Receptor; Androgens; B-Cell Lymphomas; Back; Black Tea; Cancer Etiology; Cells; Cessation of life; Complement Factor B; Down-Regulation; Drug resistance; Epigallocatechin Gallate; Gene Expression; Genes; Goals; Hormonal; Hormones; LNCaP; Malignant neoplasm of prostate; Metastatic to; Molecular; Nature; Neoplasm Metastasis; Pathway interactions; Patients; Phenotype; Play; Preventive; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Public Health; Recurrence; Refractory; Regimen; Research; Research Priority; Resistance; Role; Sampling; Second Primary Neoplasms; Staging; Stem cells; Testing; Theaflavins; Therapeutic; Therapeutic Uses; Time; Up-Regulation; androgen independent prostate cancer; anticancer research; base; cancer cell; cancer stem cell; clinically relevant; conventional therapy; deprivation; effective therapy; hormone refractory prostate cancer; in vivo; in vivo Model; men; novel; overexpression; receptor expression; response; self-renewal; stemness; therapeutic development; therapy development; transcription factor; tumor; tumor initiation; tumor progression; tumorigenesis

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.

描述（由申请人提供）：由于绝大多数前列腺癌细胞具有雄激素依赖性，雄激素剥夺仍然是雄激素依赖性前列腺癌的主要治疗方法，并且大多数患者最初对治疗有反应。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、雄激素非依赖性和激素难治性的肿瘤。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首要任务。癌症干细胞（CSC）假说认为，CSC具有自我更新和分化的能力，负责肿瘤的发生、进展、耐药、复发和转移。然而，目前尚不清楚前列腺 CSC 对激素消融治疗有何反应，以及前列腺 CSC 是否可以成为抑制前列腺进展的有效靶点。我们的初步研究表明，前列腺CSC过度表达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），红茶显着延缓雄激素消融诱导的前列腺肿瘤进展，与Bmi-1表达下调相关，并且红茶中的生物活性成分抑制前列腺的自我更新 CSCs/祖细胞并下调 Bmi-1 基因表达。这些有希望的初步研究提供了实验证据来支持新的假设，即前列腺CSC对激素消融治疗有抵抗力，激素剥夺可能部分通过Bmi-1的上调加速前列腺CSC的自我更新，红茶生物活性成分可能部分延缓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 通过 Bmi-1 的下调。具体目标 1 是表征源自原位前列腺肿瘤的前列腺 CSC 在雄激素剥夺诱导进展的不同阶段的细胞和分子变化。首先确定前列腺CSC在激素剥夺诱导进展的不同阶段的自我更新能力以及相关的Bmi-1表达（目标1A）；然后将确定 Bmi-1 在前列腺 CSC 对雄激素剥夺反应中的功能作用（目标 1B）。具体目标 2 是确定雄激素消融是否通过临床相关体内模型中 Bmi-1 的上调来加速前列​​腺 CSC 自我更新和肿瘤发生。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肿瘤进展的影响。研究结果将提供重要的实验证据，不仅支持前列腺癌干细胞在前列腺癌进展和复发中的重要作用，而且为确定针对雄激素非依赖性/激素难治性前列腺癌进展的有效预防和治疗方案提供范式转变。