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，复发性肿瘤可能是由少量的“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，并且具有再生肿瘤的能力。然而，如果不操纵癌细胞外的癌细胞，这种想法很难在体内进行测试。 动物的自然环境。在这里，我们提出了一种谱系追踪策略，以检查特定的前列腺上皮细胞类型（“去势抵抗性Nkx3.1表达细胞或CARN”和Bmi 1+细胞）在小鼠雄激素消融后再生肿瘤的能力（目的1）。我们将进一步研究由特定致癌突变驱动的复发性肿瘤是否优先来自消退肿瘤内的干细胞样细胞的特定细胞群以及雄激素受体的作用（Aim 2）。最后，我们将采用消退肿瘤内特定细胞类型的谱系消融来评估特定干细胞样细胞（CARN和Bmi 1+细胞）对前列腺癌复发的相对贡献（目的3）。在这些研究中，将使用新的方法来确定特定前列腺细胞类型在雄激素消融后肿瘤复发中的意义。如果成功，这一提议将对我们理解复发性前列腺癌的细胞起源产生重大影响，并将促进旨在成功根除肿瘤的努力。

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.