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: 7963188
• 负责人: Gary Smith
• 金额: $ 37.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7963188
• 关键词: Acute; Address; Adrenal Glands; Adult; Adverse effects; Aftercare; Aging; Androgen Receptor; Androgens; Apoptotic; Architecture; Bacteriophages; Basal Cell; Benign; Biological Models; Blood Vessels; Caring; Castration; Caveolae; Cell Surface Receptors; Cell physiology; Cell surface; Cells; Cessation of life; Chronic; Commit; Complex; Data; Development; Disease; Endocytosis; Endothelial Cells; Epitopes; Fingerprint; Gene Expression; Genes; Genetic Transcription; Genotype; Goals; Growth; Homeostasis; Human; Individual; Inflammation; Intervention; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolism; Modeling; Molecular; Movement; Natural Selections; Paracrine Communication; Pathway interactions; Peptides; Prostate; Reagent; Recurrence; Regulation; Role; Signal Transduction; Source; Stem cells; Steroids; Techniques; Technology; Tissues; Transactivation; Treatment Failure; Tumor Stem Cells; Undifferentiated; Xenograft procedure; adult stem cell; base; cancer stem cell; clinically significant; dehydroepiandrosterone receptor; deprivation; in vivo Model; killings; non-genomic; novel strategies; prevent; research study; response; sex hormone-binding globulin receptor; stem cell niche; transcytosis; tumor progression; uptake

PROJECT SUMMARY (See instmctions): 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 ofthe 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-4n 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.

项目摘要（请参阅Instmctions）： 癌症从引发癌症干细胞（CSC）的临床意义的发展，最终 治疗失败后复发是连续发展的相互作用的高潮 在CSC和“干细胞生态位”之间。该提议的假设是雄激素剥夺 前列腺内皮细胞在前列腺雄激素环境中的关键作用 组织微环境以及在调节干细胞“利基”的调节中，促进/加速了castration-castration-recurrent前列腺癌以验证假设，提出了以下特定目的。 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将确定雄激素 - 释放诱导的前列腺内皮细胞是否导致前列腺微举行的内皮细胞的短暂或不可逆地扰动，从而导致组织雄激素环境失调（使用LC/MS/MS/MS/MS/MS/MS的特征），以及verminiel/MS的特征，并具有独特的epites of Assector of Espect，'噬菌体肽 - 播放技术）。 AIM 3将确定雄激素剥夺对与成年干细胞（ASC）相比在前列腺CSC中差异表达的基因和基因途径的影响，确定了前列腺ASC/CSC的细胞表面“表位”指纹，并确定干细胞“ NICHE” niche“ niche”的扰动是否会导致型号的protsscription-Scomped-Scomped-Scomped-4NNNF-4NNF。 AIM 1-3中产生的数据和试剂将支持AIM 4的研究，重点是开发新的方法，用于利用雄激素剥夺，通过验证该方法来实现前列腺特异性疗法：雄激素剥夺使ASC/CSC暴露于目标治疗；可以抑制循环雄激素的转胞膜，而不会扰动内皮细胞稳态；并且可以重新编程向ASC/CSC发起信号的内皮细胞，以诱导干细胞退出“利基”并进行分化。