TGF Beta receptor biology in human renal cell carcinoma

描述（由申请人提供）：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RCC致癌的分子途径的理解。使用常规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（TGF β）途径中的畸变。我们在所有样品中观察到III型TGF β受体（TbetaR 3）的损失。这表明TbetaR 3的丢失是RCC发生中的早期哨兵事件。这是第一次明确证明TbetaR 3的丢失与疾病状态有关。我们还观察到转移性RCC中II型TGF β受体（TbetaR 2）的丢失。这些数据表明，TGF β信号传导的异常在RCC癌发生和进展中是重要的，并且通过下调TbetaR介导。我们假设TbetaR 3的缺失通过TGF β信号的失调促进RCC肿瘤发生，其通过Smad依赖性和/或非依赖性机制介导。我们的初步数据也支持TbetaR 3具有独立于TGF β信号和TbetaR 2的生长抑制活性的假设。这些假设将通过以下具体目的在体外和体内RCC模型中进行测试：1）我们将测试TbetaR 3通过Smad依赖性和非依赖性机制在体外抑制RCC中的细胞增殖的假设。我们将进一步测试TbetaR 3生长抑制是否通过TGF β/TbetaR 2独立途径介导，通过与未知的细胞内蛋白质相互作用。2)我们将使用RCC的相关动物模型来检验TbetaR 3抑制体内致瘤性的假设。我们将测试靶向TbetaR的腺病毒基因治疗的功效。3)我们将测试TbetaR 3在RCC中通过TbetaR 3启动子的转录调节而沉默的假设。这些研究的完成将确定TbetaR 3丢失在RCC致癌中的作用，TbetaR 3在正常肾脏生物学和致癌中的功能，以及TbetaR 3在RCC生物学中的调节机制。

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.