PTEN and Prostate Cancer Progression

PTEN 和前列腺癌进展

• 批准号: 7032347
• 负责人: HONG WU
• 金额: $ 30.67万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-07 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032347
• 关键词: androgen receptor; androgens; biomarker; charge coupled device camera; comparative genomic hybridization; flow cytometry; gene expression; genetically modified animals; green fluorescent proteins; hormone sensitivity /resistance; laboratory mouse; loss of heterozygosity; metastasis; microarray technology; neoplasm /cancer genetics; neoplastic process; neoplastic transformation; prostate neoplasms; tumor suppressor genes

DESCRIPTION (provided by applicant): Prostate cancer is the most common cancer in men and is the second leading cause of cancer deaths in men in the United States. Despite its enormous impact on male health, the molecular mechanisms underlying the pathogenesis of prostate cancer, especially issues related to metastasis and resistance to androgen ablation therapy, remain relatively unknown in comparison with other common cancers. The PTEN tumor suppressor gene is deleted in 30% of primary prostate cancers and 63% of prostate metastatic lesions, placing PTEN loss among the most common genetic alterations in human prostate cancers. The long term objective of this application is to understand the molecular mechanisms underlying prostate tumor initiation, progression, metastasis, and hormone resistance, and to identify new targets for drug development as well as new biomarkers for monitoring treatment, using our genetically defined murine Pten conditional knock-out model. Aim 1 will focus on characterization of the course of the disease in this model and on the location and the cell types associated with prostate cancer metastasis. "Reporter mice" have been generated for this purpose for in vivo, non-invasive imaging and for tracking specific cell types during tumor progression and metastasis. We will directly test the hypothesis that prostate cancer may arise from dysregulated stem/progenitor cells. Since the murine Pten prostate cancer model is the only model currently available in which the primary tumorigenic lesion is not regulated by androgen, Aim 2 will dissect hormone resistant mechanisms and identify the cellular origin of hormone refractory prostate cancer. Finally, tumor tissues and cell lines will be used for genome-wide microarray analyses and comparative genome hybridization analyses. This dataset will be compared with similar datasets from human prostate cancers to identify key molecular events in prostate cancer progression, metastasis, and hormone resistance. Candidate genes will be further evaluated biochemically and genetically for their contributions to prostate cancer development. Although focused on prostate cancer, the studies outlined here and the mechanisms elucidated in this proposal will be broadly relevant to cancers associated with PTEN loss in general, since PTEN is expressed in all cell types in our body and PTEN mutations are observed in many human cancers.

描述（由申请人提供）：前列腺癌是男性最常见的癌症，是美国男性癌症死亡的第二大原因。尽管对男性健康的影响很大，但与其他普通癌症相比，前列腺癌发病机理的分子机制，尤其是与转移和对雄激素消融疗法的耐药性有关的问题，尤其是与雄激素消融疗法有关的问题。 PTEN肿瘤抑制基因在30％的原发前列腺癌和63％的前列腺转移性病变中被删除，在人类前列腺癌中最常见的遗传改变之一。该应用的长期目标是了解前列腺肿瘤起始，进展，转移和激素耐药性的分子机制，并使用我们的基因定义的鼠类PTEN PTEN条件敲除模型来确定药物开发的新靶标以及用于监测治疗的新生物标志物。 AIM 1将重点介绍该模型以及与前列腺癌转移相关的位置和细胞类型的表征。为此目的生成了“记者小鼠”，用于体内，非侵入性成像以及在肿瘤进展和转移过程中跟踪特定细胞类型。我们将直接检验以下假设，即前列腺癌可能是由茎/祖细胞失调的。由于鼠PTEN前列腺癌模型是当前可用的唯一可用的原发性肿瘤性病变的模型，因此AIM 2将剖析激素耐药机制并确定激素耐火前列腺癌的细胞起源。最后，肿瘤组织和细胞系将用于全基因组微阵列分析和比较基因组杂交分析。该数据集将与人类前列腺癌的类似数据集进行比较，以鉴定前列腺癌进展，转移和激素耐药性中的关键分子事件。候选基因将在生化和遗传上进一步评估，以促进其对前列腺癌发展的贡献。尽管专注于前列腺癌，但此处概述的研究和该提案中阐明的机制将与一般的PTEN损失相关的癌症广泛相关，因为PTEN在我们体内的所有细胞类型中都表达，并且在许多人类癌症中都观察到PTEN突变。