The role of VHL in clear-cell renal cell carcinoma and its relation to targeted therapy.
The role of VHL in clear-cell renal cell carcinoma and its relation to targeted therapy.
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DOI：
10.1038/ki.2009.296
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发表时间：
2009-11
影响因子：
19.6
通讯作者：
Clark, Peter E.
中科院分区：
文献类型：
--
作者：
Clark, Peter E.
透明细胞肾细胞癌（ccRCC）发展的基础生物学关键依赖于von Hippel-Lindau基因（VHL），其蛋白质产物在细胞对缺氧的正常反应中很重要。VHL的功能异常，无论是通过突变或启动子高甲基化，导致转录调节分子，缺氧诱导因子α（HIFα）的积累。然后HIFα可以与HIFβ二聚化并转移到细胞核，在那里它将转录上调一系列缺氧反应基因，包括血管内皮生长因子（VEGF），血小板衍生生长因子（PDGF）等。这些配体与其同源受体的结合激活了一系列激酶依赖性信号传导途径，包括RAF-MEK-ERK和磷脂酰肌醇-3激酶-AKT-mTOR途径。开发并现已批准用于晚期ccRCC的靶向药物包括针对VEGF的人源化单克隆抗体、小分子酪氨酸激酶抑制剂和mTOR抑制剂。了解ccRCC的生物学对于了解该疾病的当前疗法和未来开发新疗法至关重要。本综述将概述ccRCC的遗传学，重点是如何为这种疾病的靶向治疗提供信息。
The basic biology underlying the development of clear-cell renal cell carcinoma (ccRCC) is critically dependent on the von Hippel–Lindau gene (VHL), whose protein product is important in the cell’s normal response to hypoxia. Aberrations in VHL’s function, either through mutation or promoter hypermethylation, lead to accumulation of the transcriptional regulatory molecule, hypoxia-inducible factor alpha (HIFα). HIFα can then dimerize with HIFβ and translocate to the nucleus, where it will transcriptionally upregulate a series of hypoxia-responsive genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and others. Binding of these ligands to their cognate receptors activates a series of kinase–dependent signaling pathways, including the RAF–MEK–ERK and phosphatidylinositol-3 kinase–AKT–mTOR pathways. Targeted agents developed and now approved for use in advanced ccRCC include humanized monoclonal antibodies against VEGF, small-molecule tyrosine kinase inhibitors, and inhibitors of mTOR. Understanding the biology of ccRCC is critical in understanding the current therapy for the disease and in developing novel therapeutics in the future. This review will provide an overview of the genetics of ccRCC, with an emphasis on how this has informed the development of the targeted therapeutics for this disease.
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