Genetic Events in the Development of Renal Cell Carcinoma

描述（由申请人提供）：肾细胞癌是一种毁灭性的癌症，在美国每年影响36，600人，发病率稳步上升，但有效的治疗方法很少。冯希佩尔-林道（VHL）基因突变与大多数散发性肾癌相关，并与VHL疾病的遗传综合征相关，其中突变携带者有发生肾细胞癌、神经系统血管母细胞瘤和嗜铬细胞瘤的风险。个别错义突变可预测地使这些肿瘤中的每一个易于发生。VHL蛋白（pVHL）参与许多活动，最显著的是缺氧诱导因子HIF 1-α和HIF 2-α的氧依赖性调节，其转录调节大量缺氧应答基因。然而，pVHL的其他活性也是肿瘤促进的，因为与嗜铬细胞瘤相关的错义突变对缺氧反应基因的调节没有影响。然而，VHL突变与肾脏肿瘤发生的早期途径有关，可能起肿瘤起始作用。增强浸润性肾细胞癌发展的突变尚不清楚，可能导致这种肿瘤对常规治疗的难治性。了解VHL损失的致癌活性的完整谱以及补充肾脏中肿瘤进展的细胞事件是改善肾细胞癌治疗的使命的基本目标。该提案概述了一种综合和平衡的方法，以满足这一目标，通过开发与VHL疾病的完整谱相关的VHL突变的体外和体内模型，并利用小鼠模型系统中VHL疾病的强基因型：表型相关性。此外，我们提出了一种策略，诱导体细胞损失的VHL在肾小管模型VHL启动肾癌发生，以及体细胞激活的假定肾肿瘤的“进展”途径的背景下VHL突变。这些研究将提供一个独特的模型系统，其中VHL诱导的致癌作用的许多方面可以并将进行检查，以最终确定改善治疗肾细胞癌患者。

DESCRIPTION (provided by applicant): Renal cell carcinoma is a devastating cancer affecting 36,600 individuals per year in the US and rising steadily in incidence, but with few effective treatments. Mutations in the von Hippel-Lindau (VHL) gene have been associated with the majority of sporadic cancers of the kidney, and with the hereditary syndrome of VHL disease in which mutational carriers are at risk for development of renal cell carcinoma, as well as hemangioblastoma of the nervous system, and pheochromocytoma. Individual missense mutations predispose predictably to the penetrance of each of these tumors. VHL protein (pVHL) has been implicated in many activities, most notably the oxygen dependent regulation of the hypoxia inducible factors HIF1-alpha and HIF2-alpha which trancriptionally regulation a large cohort of hypoxia response genes. However, other activities of pVHL are also tumor-promoting, as missense mutations associated with exclusively pheochromocytoma have no effect on regulation of hypoxia response genes. VHL mutation, however, is implicated early in the pathway of tumorigenesis of the kidney, likely playing a tumor-initiating role. The mutations which augment the development of invasive renal cell carcinoma are not well-understood, and may contribute to the refractoriness of this tumor to conventional therapies. Understanding the complete spectrum of carcinogenic activities of VHL loss as well as the cellular events which supplement tumor progression in the kidney is an essential goal in a mission to improve treatments for renal cell carcinoma. This proposal outlines an integrated and balanced approach to meeting this goal by developing in vitro and in vivo models of VHL mutations associated with the complete spectrum of VHL disease, and exploiting the strong genotype:phenotype correlation of VHL disease in a mouse model system. Additionally, we propose a strategy to induce somatic loss of VHL in the kidney tubule to model VHL initiation of renal carcinogenesis, as well as somatic activation of putative renal tumor "progression" pathways in a background of VHL mutation. These investigations will provide a unique model system in which many aspects of VHL-induced carcinogenesis can and will be examined in order to ultimately identify improved treatments for patients with renal cell carcinoma.