The genetic basis of kidney cancer: a metabolic disease.
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.
Linehan
W Marston
WM
Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892-1107, USA. wml@nih.gov <wml@nih.gov>
Srinivasan
Ramaprasad
R
Schmidt
Laura S
LS
D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics; D002952:Citric Acid Cycle / Q000235:genetics; D005649:Fumarate Hydratase / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000235:genetics; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D013385:Succinate Dehydrogenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D005649:Fumarate Hydratase; C497446:VHL protein, human
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