Study of cell-of-origin and cancer stem cells in prostatic adenocarcinoma

描述（由申请人提供）：我们对Pten缺失前列腺癌模型的描述令人信服地证明，突变小鼠模拟了人类前列腺癌发展的关键特征，是研究前列腺癌细胞起源和癌症干细胞的合适模型。这项拨款申请的目的是验证一种假设，即特定的前列腺细胞类型对癌性转化敏感，因此可以作为前列腺癌的起源细胞。这些研究的优势在于，在Pten小鼠模型中，前列腺癌的发生和发展在一个浓缩的框架内是可预测的，从而允许对与肿瘤发展相关的细胞、分子和遗传事件进行快速和系统的研究。Pten模型也对激素消融治疗有反应，并在长期雄激素消耗后发展为激素难治性前列腺癌（HRPC）。我们将首先破译正常生理条件下的前列腺上皮干细胞-祖细胞结构，然后利用该结构图谱在小鼠前列腺癌模型和人类前列腺癌样本中鉴定癌症干细胞（Aim 1）。我们将进一步探讨HRPC的细胞和分子基础。特别是，将仔细研究雄激素非依赖性生长与癌症干细胞之间的联系。有了特征性的癌症干细胞，我们将研究前列腺癌干细胞发育的分子机制，包括控制干细胞自我更新和分化的途径，并测试小途径特异性抑制剂对癌症干细胞和HRPC发育的影响（目的2）。我们期望前列腺癌细胞起源的鉴定和功能特征以及失调的信号通路将为改进这种疾病的检测、诊断和治疗提供必要的信息。尽管主要针对前列腺癌，但这里概述的研究和本提案阐明的机制将具有广泛的相关性，因为PTEN在人体所有细胞类型中表达，并且在多种人类癌症中都观察到PTEN突变。公共卫生相关性：尽管前列腺癌对男性健康有巨大影响，但其发病机制的分子机制仍未得到解决。本应用的中心焦点是前列腺癌干细胞的特征，并测试干细胞特性的改变是否有助于前列腺癌的发展和激素难治性前列腺癌的发展。这将有助于了解疾病的起源，并为新的干细胞靶向治疗提供依据。

DESCRIPTION (provided by applicant): Our characterization of the Pten null prostate cancer model makes a compelling case that the mutant mouse mimics key features of human prostate cancer development and is a suitable model for investigating the cell- of-origin and cancer stem cells in prostate adenocarcinoma. The goal of this grant application is to test the hypothesis that a specific prostatic cell type is sensitive to the oncogenic transformation and therefore serves as the cell-of-origin of prostate cancer. To the advantage of these investigations, prostate cancer initiation and progression in the Pten mouse model is predictable within a condensed frame, thereby permitting a rapid and systematic study of the cellular, molecular and genetic events linked to tumor development. The Pten model also responds to hormone ablation therapy and develops hormone refractory prostate cancer (HRPC) following prolonged androgen depletion. We will first decipher the prostate epithelial stem-progenitor cell hierarchy under normal physiological conditions and then use this hierarchy map to identify cancer stem cells in the murine prostate cancer models and human prostate cancer samples (Aim 1). We will further address the cellular and molecular basis of HRPC. In particular, the link between androgen-independent growth and cancer stem cells will be carefully examined. With characterized cancer stem cells in hand, we will then investigate the molecular mechanisms underlying prostate cancer stem cell development, including pathways controlling stem cell self- renewal and differentiation, and test the effects of small pathway-specific inhibitors on cancer stem cells and HRPC development (Aim 2). We expect that the identification and functional characterization of both the cell- of-origin of prostate cancer as well as dysregulated signaling pathways will provide essential information for improved detection, diagnosis, and therapy of this disease. Although focused on prostate cancer, the studies outlined here and the mechanisms elucidated in this proposal will be broadly relevant, since PTEN is expressed in all cell types in the human body and PTEN mutations are observed in a variety of human cancers. PUBLIC HEALTH RELEVANCE: Despite its enormous impact on male health, the molecular mechanisms underlying the pathogenesis of prostate cancer remain unsolved. A central focus of this application is to characterize the prostate cancer stem cells and to test whether altered stem cell properties may contribute to prostate cancer development and hormone refractory prostate cancer development. This will help in understanding the origin of the disease and provide rationales for novel, stem cell-targeted treatment.