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。治疗的发展还有待于了解肾细胞癌发生的分子途径。利用常规肾癌患者配对标本的基因组图谱，我们鉴定了转化生长因子β(TGFbeta)途径中的异常。我们观察到所有样本中都有III型转化生长因子β受体(TbetaR3)的丢失。这表明TbetaR3的缺失是肾细胞癌发生的早期前哨事件。这是第一个将TbetaR3的缺失与疾病状态联系起来的明确演示。我们还观察到转移性肾细胞癌中II型转化生长因子β受体(TbetaR2)的缺失。这些数据表明，转化生长因子β信号的异常在肾癌的发生和发展中起重要作用，并通过TbetaR的下调而介导。我们假设，TbetaR3的缺失通过Smad依赖和/或独立的机制调节TGFbeta信号，促进肾细胞癌的发生。我们的初步数据也支持这样的假设，即TbetaR3具有独立于TGFbeta信号和TbetaR2的生长抑制活性。这些假说将通过以下特定目的在体外和体内肾癌模型中得到验证：1)我们将通过Smad依赖和独立的机制在体外检验TbetaR3抑制肾癌细胞增殖的假说。我们将进一步测试TbetaR3生长抑制是否通过TGFbeta/TbetaR2独立途径通过与未知的细胞内蛋白相互作用而介导。2)利用肾癌相关动物模型，对TbetaR3抑制体内致瘤性的假说进行验证。我们将测试针对TbetaR的腺病毒基因治疗的效果。3)我们将验证TbetaR3在肾癌中通过TbetaR3启动子的转录调控而沉默的假设。这些研究的完成将明确TbetaR3缺失在肾癌发生中的作用，TbetaR3在正常肾脏生物学和肿瘤发生中的作用，以及TbetaR3在肾癌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.