Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892-1107, USA.
Nat Rev Urol. 2010 May;7(5):277-85. doi: 10.1038/nrurol.2010.47.
Kidney cancer is not a single disease but comprises a number of different types of cancer that occur in the kidney, each caused by a different gene with a different histology and clinical course that responds differently to therapy. Each of the seven known kidney cancer genes, VHL, MET, FLCN, TSC1, TSC2, FH and SDH, is involved in pathways that respond to metabolic stress or nutrient stimulation. The VHL protein is a component of the oxygen and iron sensing pathway that regulates hypoxia-inducible factor (HIF) levels in the cell. HGF-MET signaling affects the LKB1-AMPK energy sensing cascade. The FLCN-FNIP1-FNIP2 complex binds AMPK and, therefore, might interact with the cellular energy and nutrient sensing pathways AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR. TSC1-TSC2 is downstream of AMPK and negatively regulates mTOR in response to cellular energy deficit. FH and SDH have a central role in the mitochondrial tricarboxylic acid cycle, which is coupled to energy production through oxidative phosphorylation. Mutations in each of these kidney cancer genes result in dysregulation of metabolic pathways involved in oxygen, iron, energy or nutrient sensing, suggesting that kidney cancer is a disease of cell metabolism. Targeting the fundamental metabolic abnormalities in kidney cancer provides a unique opportunity for the development of more-effective forms of therapy for this disease.
肾细胞癌不是一种单一的疾病，而是由发生在肾脏中的多种不同类型的癌症组成，每种癌症都是由不同的基因引起的，具有不同的组织学和临床过程，对治疗的反应也不同。已知的七种肾癌基因，VHL、MET、FLCN、TSC1、TSC2、FH 和 SDH，都参与了对代谢应激或营养刺激做出反应的途径。VHL 蛋白是氧和铁感应途径的一个组成部分，该途径调节细胞中的低氧诱导因子 (HIF) 水平。HGF-MET 信号影响 LKB1-AMPK 能量感应级联。FLCN-FNIP1-FNIP2 复合物结合 AMPK，因此可能与细胞能量和营养感应途径 AMPK-TSC1/2-mTOR 和 PI3K-Akt-mTOR 相互作用。TSC1-TSC2 是 AMPK 的下游，对细胞能量不足做出反应，负调节 mTOR。FH 和 SDH 在三羧酸循环中具有核心作用，三羧酸循环通过氧化磷酸化与能量产生相耦合。这些肾癌基因中的每一个基因突变都会导致参与氧、铁、能量或营养感应的代谢途径失调，这表明肾细胞癌是一种细胞代谢疾病。针对肾细胞癌的基本代谢异常为这种疾病的发展提供了更有效的治疗方法的独特机会。
