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The genetic basis of kidney cancer: a metabolic disease

Nature Reviews Urology volume 7, pages 277–285 (2010)Cite this article

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Abstract

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.

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Figure 1: The genetic basis of kidney cancer.
Figure 2: Abnormal VHL activity leads to HIF accumulation.
Figure 3: Birt–Hogg–Dubé syndrome.
Figure 4: The putative FLCN pathway.
Figure 5: Hereditary leiomyomatosis renal cell cancer.
Figure 6: FH-deficient and SDH-deficient kidney cancer: the Warburg effect.

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Acknowledgements

This research was supported in part by the Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research and funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Heath and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The authors acknowledge the outstanding editorial and graphics support by Georgia Shaw.

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    W. Marston Linehan, Ramaprasad Srinivasan & Laura S. Schmidt

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Linehan, W., Srinivasan, R. & Schmidt, L. The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol 7, 277–285 (2010). https://doi.org/10.1038/nrurol.2010.47

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