TGF Beta receptor biology in human renal cell carcinoma

人肾细胞癌中的 TGF Beta 受体生物学

• 批准号: 7111717
• 负责人: John A. Copland
• 金额: $ 24.11万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-10 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111717
• 关键词: Adenoviridae; athymic mouse; biological signal transduction; carcinogenesis; cell line; clinical research; gene deletion mutation; gene therapy; genetic promoter element; genetic regulation; genetic transcription; growth factor receptors; human tissue; metastasis; molecular oncology; neoplasm /cancer genetics; nonhuman therapy evaluation; point mutation; protein protein interaction; protein structure function; receptor expression; renal cell carcinoma; transcription factor; transfection /expression vector; transforming growth factors

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.

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。治疗方法的发展有待对 RCC 癌变分子途径的了解。通过对传统 RCC 患者匹配样本进行基因组分析，我们发现了转化生长因子 β (TGFbeta) 通路中的畸变。我们在所有样本中观察到 III 型 TGFbeta 受体 (TbetaR3) 的丢失。这表明 TbetaR3 的缺失是 RCC 发生过程中的一个早期哨兵事件。这是首次明确证明 TbetaR3 缺失与疾病状态有关。我们还观察到转移性肾细胞癌中 II 型 TGFbeta 受体 (TbetaR2) 的缺失。这些数据表明 TGFbeta 信号传导的异常在 RCC 癌变和进展中很重要，并且是通过 TbetaR 的下调介导的。我们假设 TbetaR3 的缺失通过 Smad 依赖和/或独立机制介导的 TGFbeta 信号调节失调促进 RCC 肿瘤发生。我们的初步数据也支持这样的假设：TbetaR3 具有独立于 TGFbeta 信号传导和 TbetaR2 的生长抑制活性。这些假设将通过以下具体目标在体外和体内 RCC 模型中进行测试：1）我们将在体外测试 TbetaR3 通过 Smad 依赖和独立机制抑制 RCC 细胞增殖的假设。我们将进一步测试 TbetaR3 生长抑制是否是通过 TGFbeta/TbetaR2 独立途径通过与迄今未知的细胞内蛋白质相互作用介导的。 2）我们将使用相关的肾细胞癌动物模型来检验TbetaR3在体内抑制致瘤性的假设。我们将测试针对 TbetaR 的腺病毒基因治疗的功效。 3）我们将测试 TbetaR3 通过 TbetaR3 启动子的转录调控在 RCC 中沉默的假设。这些研究的完成将明确TbetaR3缺失在RCC致癌过程中的作用、TbetaR3在正常肾脏生物学和致癌过程中的功能以及TbetaR3在RCC生物学中的调节机制。