TGF Beta receptor biology in human renal cell carcinoma

描述（申请人提供）：肾细胞癌（RCC）是一个主要的健康问题。虽然局部疾病可以通过手术治愈，但对于转移性疾病没有有效的治疗方法。治疗的发展有待于对肾癌发生的分子途径的理解。利用常规RCC患者匹配标本的基因组分析，我们确定了转化生长因子β (tgfβ)途径的畸变。我们在所有样本中观察到III型tgf - β受体（TbetaR3）的缺失。这表明，在RCC的发生过程中，TbetaR3的缺失是一个早期的哨兵事件。这是第一个将TbetaR3缺失与疾病状态联系起来的明确证据。我们还观察到转移性RCC中II型tgf - β受体（TbetaR2）的缺失。这些数据表明，tgf - β信号的畸变在RCC的癌变和进展中很重要，并通过下调TbetaR介导。我们假设TbetaR3的缺失通过Smad依赖和/或独立机制介导的tgfβ信号失调促进了RCC的肿瘤发生。我们的初步数据也支持了TbetaR3具有独立于TGFbeta信号和TbetaR2的生长抑制活性的假设。这些假设将在体外和体内的RCC模型中进行验证，具体目的如下：1)我们将在体外通过Smad依赖和独立的机制来验证TbetaR3抑制RCC细胞增殖的假设。我们将进一步测试TbetaR3生长抑制是否通过TGFbeta/TbetaR2独立通路通过与未知的细胞内蛋白相互作用介导。2)我们将使用相关的RCC动物模型来验证TbetaR3在体内抑制肿瘤发生的假设。我们将测试针对TbetaR的腺病毒基因治疗的疗效。3)我们将通过对TbetaR3启动子的转录调控来验证TbetaR3在RCC中沉默的假设。这些研究的完成将明确TbetaR3丢失在RCC癌变中的作用，TbetaR3在正常肾脏生物学和癌变中的功能，以及TbetaR3在RCC生物学中的调控机制。

DESCRIPTION (provided by applicant): Renal cell carcinoma (RCC) is a major health issue. While localized disease can be cured surgically, there is no effective treatment for metastatic disease. The development of therapy awaits understanding of the molecular pathways that underlie RCC carcinogenesis. Using genomic profiling of conventional RCC patient matched specimens, we identified aberrations in the transforming growth factor beta (TGFbeta) pathway. We observed loss of type III TGFbeta receptor (TbetaR3) in all samples. This suggests that loss of TbetaR3 is an early, sentinel event in the genesis of RCC. This is the first clear demonstration linking loss of TbetaR3 to a disease state. We also observed loss of type II TGFbeta receptor (TbetaR2) in metastatic RCC's. These data suggest that aberrations in TGFbeta signaling are important in RCC carcinogenesis and progression, and are mediated through down regulation of TbetaR. We hypothesize that loss of TbetaR3 promotes RCC tumorigenesis through dysregulation of TGFbeta signaling, mediated through Smad dependent and/or independent mechanisms. Our preliminary data also support the hypothesis that TbetaR3 has growth inhibitory activity independent of TGFbeta signaling and TbetaR2. These hypotheses will be tested in models of RCC, in vitro and in vivo, through the following specific aims: 1) We will test the hypothesis that TbetaR3 inhibits cell proliferation in RCC, in vitro, through both Smad dependent and independent mechanisms. We will further test whether TbetaR3 growth inhibition is mediated through TGFbeta/TbetaR2 independent pathways through interaction with, as yet, unknown intracellular proteins. 2) We will test the hypothesis that TbetaR3 inhibits tumorigenicity in vivo, using relevant animal models of RCC. We will test the efficacy of adenoviral gene therapy targeting TbetaR. 3) We will test the hypothesis that TbetaR3 is silenced in RCC through transcriptional regulation of the TbetaR3 promoter. Completion of these studies will define the role of TbetaR3 loss in RCC carcinogenesis, the function of TbetaR3 in normal renal biology and carcinogenesis, and the mechanism of regulation of TbetaR3 in RCC biology.