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肿瘤在最初明显成功的治疗后复发。人们普遍认为，复发肿瘤可能源于少数在最初的治疗干预中幸存下来并具有再生肿瘤能力的“癌症干细胞”。然而，如果不对癌细胞进行体外操作，这一想法很难在体内进行测试。 动物的原生环境。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(“抗去势Nkx3.1表达细胞或CAN”和Bmi1+细胞)在小鼠雄激素消融后再生肿瘤的能力(目标1)。我们将进一步研究由特定致癌基因突变驱动的复发肿瘤是否优先来自退化性肿瘤内特定的干细胞样细胞群以及雄激素受体的作用(目标2)。最后，我们将使用退化肿瘤中特定细胞类型的谱系消融来评估特定干细胞样细胞(CANS和Bmi1+细胞)在前列腺癌复发中的相对贡献(目标3)。在这些研究中，将使用新的方法来确定特定的前列腺细胞类型在雄激素治疗后肿瘤复发中的重要性。这项建议如果成功，将对我们了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.