Tumor stem cells in androgen independent prostate cancer

雄激素非依赖性前列腺癌中的肿瘤干细胞

• 批准号: 6652758
• 负责人: GARY Joseph SMITH
• 金额: $ 20.83万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-26 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6652758
• 关键词: African American; androgen receptor; androgens; athymic mouse; biomarker; caucasian American; cell line; hormone related neoplasm /cancer; human tissue; laboratory rat; male; neoplasm /cancer genetics; neoplasm /cancer transplantation; neoplastic cell; neoplastic growth; neoplastic transformation; prostate neoplasms; racial /ethnic difference; stem cells

Prostate cancer cells that survive androgen deprivation are a potential source for androgen-independent CaP. Recurrent CaP shares many phenotypic characteristics with the purported prostate epithelial stem cells suggesting a possible linear evolution from undifferentiated prostate stem-like cell, though a tumor stem cell with arrested differentiation and resistance to androgen deprivation-induced apoptosis, to recurrent androgen-independent CaP. Therefore, the hypothesis to be tested in this proposal is that a stem-like cell in the prostate undergoes genetic changes and gives rise to a malignant tumor stem cell that proliferates in response to androgen, resists apoptosis upon androgen deprivation, and is the source of androgen-dependent CaP. The experimental plan to test this hypothesis is divided into two strategies: Specific Aims 1 and 2 will focus on the prostate stem cell as a target for neoplastic transformation and Specific Aims 3 and 4 will evaluate the role of the prostate tumor stem cell in the transition from androgen-dependent to androgen-independent growth. Specific Aim 1 will isolate and characterize stem-like cell lines from the regenerating rat prostate. The goal of these studies is to isolate stem-like ells at different stages of differentiation, contrast the expression of basal cell and secretory cell specific genes in these cell lines, end evaluate the capacity of these stem-like cells to differentiated into mature prostatic epithelial when co-transplanted with normal prostatic stromal cells or when transplanted into the urogenital sinus. Specific Aim 2 will derived and characterize a cohort of androgen-dependent and androgen- independent prostatic epithelial tumor cell lines derived from a subset of the stem-like cell lines established in aim 1. The goal of these studies is to generate spontaneous neoplastic transformants; characterize their expression of the basal cell and secretory cell specific markers; isolate androgen-independent variants of the tumor cell lines; and determine if expression of the androgen receptor is required to maintain tumorigenic potential. Specific Aim 3 will compared the tumor stem cell components of the androgen-dependent Dunning H Tumor and CWR-22 tumors. The goals of these studies are to establish the methodology to identify and characterize the tumor stem cells in xenografts, establish tumor stem-like cells in culture, and compare their phenotype to recurrent versions of the xenografts. Based upon the methodologies and markers established in aims 1-3, Specific Aim 4 will characterize the stem cell and tumor stem cell components in histologic sections of androgen-dependent and androgen-independent human prostate cancers and in transient xenografts to be established from normal human prostate and CaP. The goals of these studies are to determine if a tumor stem cell compartment exists in human CaP, if it could contribute to the evolution of recurrent CaP and if there are racial differences in the stem cell and tumor cell compartments between African Americans and Caucasians.

在雄激素剥夺中生存的前列腺癌细胞是雄激素独立帽的潜在来源。复发帽具有许多表型特征与所谓的前列腺上皮干细胞相结合，这表明可能从未分化的前列腺干细胞中发生线性进化，尽管具有阻碍分化的肿瘤干细胞，并且对雄激素缺乏症诱导的凋亡的抗性，从而反复出现与雄激素独立依赖性依赖性依赖型雄激素。因此，在该提案中要检验的假设是，前列腺中的茎样细胞经历遗传变化，并引起恶性肿瘤干细胞，该细胞响应于雄激素，使雄激素剥夺源凋亡，并且是依赖雄激素依赖性帽的来源。检验该假设的实验计划分为两种策略：具体目的1和2将集中于前列腺干细胞作为肿瘤转化的靶标，而具体目的3和4将评估前列腺肿瘤干细胞在从雄激素依赖于雄激素无关的生长的过渡中的作用。特定的目标1将从再生大鼠前列腺中隔离并表征茎状细胞系。这些研究的目的是在分化的不同阶段分离出类似茎状的ELL，对比这些细胞系中基底细胞和分泌细胞特异性基因的表达，结束与正常前列腺脊髓细胞共同移植时，这些类似茎样细胞的能力分化为成熟的前列腺上皮分化，或者当泌尿生成丝中的正常细胞中。具体目标2将得出并表征雄激素依赖性和雄激素独立的前列腺上皮肿瘤细胞系，这些细胞系来自AIM 1中建立的茎状细胞系的子集。这些研究的目的是产生自发性肿瘤转化剂；表征它们的基础细胞和分泌细胞特异性标记的表达；肿瘤细胞系的分离雄性雄激素非依赖性变体；并确定是否需要雄激素受体的表达来维持肿瘤性潜能。特定的目标3将比较依赖雄激素的邓宁H肿瘤和CWR-22肿瘤的肿瘤干细胞成分。这些研究的目标是建立方法，以识别和表征异种移植物中的肿瘤干细胞，在培养中建立肿瘤干细胞，并将其表型与异种移植物的复发版本进行比较。基于目标1-3中建立的方法和标记，特定的目标4将表征干细胞和肿瘤干细胞成分在雄激素依赖性和雄激素独立的人类前列腺癌的组织学切片中，以及在正常的人类前列腺和帽子中确定的短暂性异种移植物中。这些研究的目标是确定肿瘤干细胞室是否存在于人帽中，是否有助于复发帽的演变，以及非裔美国人和高加索人之间的干细胞和肿瘤细胞室的种族差异。