Prostate Cancer Recurrence: models and mechanisms

描述（由申请人提供）：前列腺癌的一个主要临床问题是在最初明显成功的治疗后肿瘤复发。人们普遍认为，复发肿瘤可能是由少数“癌症干细胞样细胞”引起的，这些细胞在最初的治疗干预中存活下来，并具有再生肿瘤的能力。然而，这个想法很难在体内测试，如果不操纵癌细胞的外部

DESCRIPTION (provided by applicant): A major clinical problem in prostate cancer is that of tumor recurrence following initial apparently successful therapy. It is widely believed that recurrent tumors may arise from a small number of "cancer stem-like cells" that survive the initial therapeutic intervention and which have the capacity to regenerate the tumor. However, this idea has been difficult to test in vivo without manipulation of the cancer cells outside their native environment in the animal. Here we propose a lineage-tracing strategy to examine the competence of specific prostate epithelial cell types ("castration-resistant Nkx3.1-expressing cells or CARNs" and Bmi1+ cells) to regenerate tumors following androgen ablation in mice (Aim 1). We will further examine whether recurrent tumors driven by specific oncogenic mutations preferentially arise from particular cell populations of stem-like cells within a regressed tumor and the role of the androgen receptor (Aim 2). Finally, we will employ lineage ablation of specific cell types within a regressed tumor to assess the relative contributions of specific stem-like cells (CARNs and Bmi1+ cells) to prostate cancer relapse (Aim 3). In these studies will use novel approaches to define the significance of specific prostate cell types in tumor relapse following androgen ablation. This proposal if successful will have a major impact on our understanding of the cellular origins of recurrent prostate cancer and will facilitate effors aimed at successfully eradicating the tumor.