Role of Rb and E2Fs in Regulating Stromal/Epithelial

虽然从历史上看，人类的肿瘤发生过程被认为是遗传和/或体细胞突变在‘肿瘤细胞’内连续积累的结果(71)，但很明显，间质是肿瘤不可分割的一部分，它促成了一些最具破坏性的恶性细胞特征。了解肿瘤细胞和间质细胞中发生的遗传异常，并阐明由于这些异常而改变的分子通路的细节，将是我们全面理解人类癌症的关键。 细胞增殖失控是癌症的标志之一，上皮性肿瘤细胞和间质成纤维细胞都获得了直接调节细胞周期的基因的遗传和/或表观遗传变化。进入细胞周期和刺激细胞增殖包括立即诱导早期基因产物如Myc以及激活Rb通路，该通路对于G1期到S期的进展至关重要。 我们最近的研究表明，E2F1、E2F2和E2F3在体内介导了Rb的功能，并且这三种活性是Myc通路中的重要组成部分，Myc通路控制着上皮和间质成纤维细胞的细胞增殖和细胞命运决定。我们接受这样的假设，即特定组织的微环境强烈地受到Rb功能的影响，而间质成纤维细胞中这一肿瘤抑制通路的失活对肿瘤的演变有很大的贡献。拟议的研究将采用转基因和条件基因敲除策略，以解决以下三个具体目标： 具体目的1：研究乳腺间质成纤维细胞中的肿瘤抑制和致癌途径对正常上皮细胞增殖的影响。 具体目的2：研究乳腺间质成纤维细胞中的肿瘤抑制和致癌途径在调节癌基因诱导的上皮细胞致瘤性中的作用。 具体目的3：在体内评价乳腺间质成纤维细胞中Rb在Myc诱导的乳腺上皮性肿瘤发生中的作用

While historically, the process of tumorigenesis in humans was considered to result from the sequential accumulation of inherited and/or somatic mutations within the 'tumor cell '(71),it is clear that the stroma is an integral part of the tumor and that it contributes to some of the most destructive characteristics of malignant cells. Understanding the genetic aberrations that occur in both tumor cells and stromal cells, and elucidating the details of the molecular pathways that are altered as a result of these aberrations, will be key to our overall understanding of human cancer. Uncontrolled cell proliferation is one of the hallmarks of cancer, and both epithelial tumor cells and stromal fibroblast cells have acquired genetic and/or epigenetic changes to genes that directly regulate their cell cycles. Entry into the cell cycle and stimulation of cell proliferation involves the induction of immediate early gene products such as Myc as well as the activation of the Rb pathway that is critical for G1 to S phase progression. Our recent studies demonstrate that E2F1, E2F2 and E2F3 mediate Rb function in vivo and that these three activities are essential components in the Myc pathway that controls cell proliferation and cell fate decisions of both epithelial and stromal fibroblasts. We entertain the hypothesis that the microenvironment of a given tissue is strongly influenced by the function of Rb, and inactivation of this tumor suppressor pathway within stromal fibroblasts contributes strongly to the evolution of neoplasm. The proposed studied will employ transgenic and conditional gene knock-out strategies in order to address the following three specific aims: Specific Aim 1: To examine the role of tumor suppressor and oncogenic pathways, operating within mammary stromal fibroblasts, on the proliferation of normal epithelial cells. Specific Aim 2: To examine the role of tumor suppressor and oncogenic pathways, operating within mammary stromal fibroblasts, in moderating the tumorigenicity of oncogene-primed epithelial cells. Specific Aim 3: To assess in vivo the contributions made by Rb within mammary stromal fibroblasts, towards the development of Myc-induced mammary epithelial tumors