Role of Tumor Stem Cells Recurrent Prostate Cancer

项目总结（见说明）： 癌症从起始癌症干细胞（CSC）到临床意义的进展，并最终 治疗失败后复发，是一个不断发展的相互作用的顶点 CSC和“干细胞生态位”之间的关系。这项提议的假设是， 干扰前列腺内皮细胞在调节前列腺的雄激素环境中的关键作用 组织微环境和调节干细胞“生态位”，促进/加速去势复发性前列腺癌的出现。为了验证这一假设，提出了以下具体目的。 目的1将表征内皮细胞小窝在循环雄激素跨内皮细胞屏障的转胞吞作用中的作用，在循环雄激素的内吞作用中导致与内皮细胞稳态和信号相关的基因的AR反式激活，以及在通过循环雄激素的细胞表面受体介导的“非基因组信号传导”中的作用。目的2将确定雄激素剥夺诱导的前列腺内皮细胞杀伤是否导致前列腺微血管内皮细胞的短暂或不可逆扰动，从而导致组织雄激素环境的失调（使用LC/MS/MS表征）和独特的靶向“表位”或“血管地址”的产生/暴露（使用噬菌体肽展示技术表征）。目的3将鉴定雄激素剥夺对前列腺CSC中与成体干细胞（ASC）相比差异表达的基因和基因通路的影响，鉴定前列腺ASC/CSC的细胞表面“表位”指纹，并确定干细胞“生态位”的扰动是否导致前列腺CSC中HNF-4 n转录网络的表观遗传调节失调。目标1-3中产生的数据和试剂将支持目标4的研究，该研究的重点是开发利用雄激素剥夺实现前列腺特异性治疗的新方法，通过验证：雄激素剥夺使ASC/CSC暴露于靶向治疗;循环雄激素的转胞吞作用可以被抑制而不干扰内皮细胞稳态;并且内皮细胞启动的向ASC/CSC的信号传导可以被重编程以诱导干细胞退出“小生境”并致力于分化。

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.