Role of Tumor Stem Cells Recurrent Prostate Cancer

肿瘤干细胞在复发性前列腺癌中的作用

• 批准号: 8243675
• 负责人: Gary Smith
• 金额: $ 46.71万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243675
• 关键词: Address; Adrenal Glands; Adverse effects; Aftercare; Androgens; Bacteriophages; Blood Vessels; Caring; Castration; Caveolae; Cell Surface Receptors; Cell surface; Commit; Data; Development; Disease; Endocytosis; Endothelial Cells; Epitopes; Fingerprint; Genes; Genetic Transcription; Homeostasis; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Movement; Pathway interactions; Peptides; Prostate; Reagent; Recurrence; Regulation; Role; Signal Transduction; Stem cells; Technology; Tissues; Transactivation; Treatment Failure; Tumor Stem Cells; adult stem cell; cancer stem cell; clinically significant; deprivation; killings; liquid chromatography mass spectrometry; non-genomic; novel strategies; prevent; stem cell niche; transcytosis

The progression of a cancer from the initiating cancer stem cell (CSC) to clinical significance, and ultimately to recurrence after treatment failure, is the culmination of a continuously evolving reciprocal interaction between the CSC and the "stem cell niche". The hypothesis of this proposal is that androgen deprivation perturbs the critical role of the prostate endothelial cell in regulation of the androgenic milieu of the prostate tissue microenvironment, and in regulation of the stem cell "niche", facilitating/accelerating the emergence of castration-recurrent prostate cancer To validate the hypothesis, the following Specific Aims are proposed. Aim 1 will characterize the role of endothelial cell caveolae in transcytosis of circulating androgens across the endothelial cell barrier, in endocytosis of circulating androgens resulting in AR-transactivation of genes associated with endothelial cell homeostasis and signaling, and in "non-genomic signaling" mediated through cell surface receptors for circulating androgens. Aim 2 will determine if androgen-deprivation induced killing of prostate endothelial cells results in transient, or irreversible, perturbation of the endothelial cells of the prostate microvasculature resulting in dysregulation of the tissue androgenic milieu (characterized using LC/MS/MS) and in creation/unmasking of unique, targetable "epitopes" or "vascular addresses" (characterized using phage peptide-display technology). Aim 3 will identify the effect of androgen deprivation on genes and gene pathways that are differentially expressed in prostate CSCs compared to adult stem cells (ASCs), identify the cell surface "epitope" fingerprint of prostate ASCs/CSCs, and determine if perturbation of the stem cell "niche" results in epigenetically-modulated dysregulation of the HNF-4(square) transcription network in prostate CSCs. The data and reagents generated in Aims 1-3 will support the studies of Aim 4 focused on development of novel approaches for utilizing androgen-deprivation to enable prostate-specific therapies by validating that: androgen deprivation exposes the ASC/CSC to targeted therapy; transcytosis of circulating androgens can be inhibited without perturbation of endothelial cell homeostasis; and endothelial cell initiated signaling to ASCs/CSCs can be reprogrammed to induce the stem cell to exit the "niche" and commit to differentiation.

癌症从起始癌症干细胞（CSC）发展到临床意义，并最终到治疗失败后复发，是CSC和“干细胞生态位”之间不断发展的相互作用的顶峰。该提议的假设是，雄激素剥夺扰乱了前列腺内皮细胞在调节前列腺组织微环境的雄激素环境和调节干细胞“生态位”中的关键作用，促进/加速了去势复发的出现前列腺癌 为了验证这一假设，提出了以下具体目标。 目标 1 将描述内皮细胞小窝在循环雄激素穿过内皮细胞屏障的转胞吞作用、循环雄激素的内吞作用中导致与内皮细胞稳态和信号传导相关的基因的 AR 反式激活以及在“非基因组信号传导”介导中的作用。通过循环雄激素的细胞表面受体。目标 2 将确定雄激素剥夺诱导的前列腺内皮细胞杀伤是否会导致前列腺微血管内皮细胞的短暂或不可逆的扰动，从而导致组织雄激素环境失调（使用 LC/MS/MS 表征）并产生创造/揭示独特的、可靶向的“表位”或“血管地址”（使用噬菌体肽展示技术表征）。目标 3 将确定雄激素剥夺对前列腺 CSC 与成体干细胞 (ASC) 中差异表达的基因和基因通路的影响，确定前列腺 ASC/CSC 的细胞表面“表位”指纹，并确定前列腺 CSC 的扰动是否干细胞“生态位”导致前列腺 CSC 中 HNF-4(square) 转录网络的表观遗传调节失调。目标 1-3 中生成的数据和试剂将支持目标 4 的研究，重点是开发利用雄激素剥夺来实现前列腺特异性治疗的新方法，方法是验证：雄激素剥夺使 ASC/CSC 暴露于靶向治疗；可以抑制循环雄激素的转胞吞作用而不扰乱内皮细胞稳态；内皮细胞发起的向 ASC/CSC 发出的信号可以被重新编程，以诱导干细胞退出“生态位”并进行分化。