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; 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。虽然可以通过手术治愈局部疾病，但没有有效的转移性疾病治疗。疗法的发展等待对RCC致癌基础​​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（TGFBETA）途径中的畸变。我们观察到所有样品中III型TGFBETA受体（TBETAR3）的丧失。这表明TBETAR3的丧失是RCC起源中的早期，前哨事件。这是将TBETAR3与疾病状态联系起来的第一个明确的示范。我们还观察到转移性RCC中II型TGFBETA受体（TBETAR2）的损失。这些数据表明，TGFBETA信号传导中的像差在RCC的癌变和进展中很重要，并且通过下调TBETAR介导。我们假设TBETAR3的丧失通过TGFBETA信号传导失调促进RCC肿瘤发生，这是通过SMAD依赖和/或独立机制介导的。我们的初步数据还支持以下假设：TBETAR3具有与TGFBETA信号传导和TBETAR2无关的生长抑制活性。这些假设将通过以下特定目的在RCC，体外和体内模型中进行测试：1）我们将通过SMAD依赖性和独立机制来测试TBETAR3抑制RCC的细胞增殖的假设。我们将进一步测试TBETAR3生长抑制是否通过TGFBETA/TBETAR2独立途径介导，但与未知的细胞内蛋白相互作用。 2）我们将使用相关的RCC动物模型来测试TBETAR3在体内抑制肿瘤性的假设。我们将测试针对TBETAR的腺病毒基因疗法的功效。 3）我们将通过TBETAR3启动子的转录调控来测试TBETAR3在RCC中沉默的假设。这些研究的完成将定义TBETAR3损失在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生物学中调节的机理。