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The metabolic basis of kidney cancer

https://doi.org/10.1016/j.semcancer.2012.06.002Get rights and content

Abstract

Kidney cancer is not a single disease; it is made up of a number of different types of cancer that occur in the kidney. Each of these different types of kidney cancer can have a different histology, have a different clinical course, can respond differently to therapy and is caused by a different gene. Kidney cancer is essentially a metabolic disease; each of the known genes for kidney cancer, VHL, MET, FLCN, TSC1, TSC2, TFE3, TFEB, MITF, fumarate hydratase (FH), succinate dehydrogenase B (SDHB), succinate dehydrogenase D (SDHD), and PTEN genes is involved in the cells ability to sense oxygen, iron, nutrients or energy. Understanding the metabolic basis of kidney cancer will hopefully provide the foundation for the development of effective forms of therapy for this disease.

Section snippets

An introduction to kidney cancer

It is now known that kidney cancer is not a single uniform disease; it is in fact a number of different and specific types of cancers that can occur within the kidney. Each of these different types of kidney cancer can be characterized by differing histologies, different clinical courses, differing responses to a number of varied therapies and association with alterations to different tumor suppressor genes or oncogenes. Currently there are at least twelve different genes associated with the

Hereditary kidney cancer

Much of what we know about the genetic basis of kidney cancer was learned from the study of inherited forms of kidney cancer. There are a number of familial forms of kidney cancer, including von Hippel–Lindau (VHL), Hereditary Papillary Renal Carcinoma (HPRC), Birt–Hogg–Dubé (BHD), Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC), Succinate Dehydrogenase Renal Cell Carcinoma (SDH-RCC), Tuberous Sclerosis (TS), and Cowden's Disease (Fig. 1) [1], [2]. All these syndromes are associated with

Von Hippel–Lindau (VHL): clear cell kidney cancer

Von Hippel–Lindau (VHL) is a hereditary kidney cancer syndrome in which affected individuals are at risk for the development of tumors in a number of organs, including the kidneys [3]. It represents a well studied form of inherited cancer risk syndrome, which has additionally provided invaluable insight into the study of non-familial, sporadic kidney cancer.

Hereditary papillary renal carcinoma (HPRC): type 1 papillary kidney cancer

Hereditary papillary renal carcinoma (HPRC) is an autosomal dominant hereditary cancer syndrome in which affected individuals are at risk for the development of bilateral, multifocal type 1 papillary kidney cancer (Fig. 3) [33], [34]. It is estimated that patients affected with HPRC are at risk for the development of up to 1100 tumors per kidney throughout their lifetime [35].

Clinical management, like in patients with VHL-associated kidney tumors, involves active surveillance until the largest

Birt–Hogg–Dubé (BHD): chromophobe kidney cancer

Birt–Hogg–Dubé is an autosomal dominant, hereditary cancer syndrome in which affected individuals are at risk for the development of cutaneous fibrofolliculomas [41], pulmonary cysts [42] and kidney cancer [43]. BHD-associated kidney cancers can be multifocal, bilateral and they can metastasize. Patients affected with BHD are at risk for the development of chromophobe, hybrid oncocytic, and clear cell kidney cancer and oncocytoma (Fig. 4) [44]. Like VHL and HPRC, BHD-associated kidney cancers

MiT transcription factor associated kidney cancer

The MiT family of transcription factors includes TFE3, TFEB, MITF, and TFEC, a family of transcription factors that share a highly homologous basic-helix-loop-helix-leucine zipper DNA binding and dimerization domain. These proteins can produce both hetero- and homodimers and bind identical DNA response elements, suggesting that they may have common downstream targets and a degree of functional redundancy. In tumors, these genes are mainly over expressed due to somatic translocations that create

Tuberous sclerosis complex: regulation of the mTOR pathway

The tuberous sclerosis complex (TSC) is an autosomal dominant disorder in which affected individuals are at risk for the development of manifestations involving multiple organs, including cutaneous angiofribroma, pulmonary lymphangiomyomatosis and renal tumors [68]. Although angiomyolipoma is the most common type of renal tumor found in TSC patients, other types of tumors have been identified, including clear cell kidney cancer [69].

Cowden syndrome: PTEN and the regulation of the mTOR pathway

Cowden syndrome is an autosomal dominant disorder that results from germline mutation of the PTEN gene, in which affected individuals are at risk for manifestations in a number of organs, including tumors of the breast, thyroid, endometrium and kidney [73], [74], [75]. The protein product of the PTEN gene, PTEN, is a phosphatase that catalyzes the conversion of PIP3 (phosphatidylinositol 3,4,5 triphosphate) to PIP2 (phosphatidylinositol 4,5 biphosphate). In response to growth factor receptor

Tricarboxylic acid mutation kidney cancers: exemplifying the Warburg effect

In the 1920s Otto Warburg proposed that a basic characteristic of cancer would be that it is characterized by aerobic glycolysis [77], [78]. Subsequently, this has been shown to be true to a greater and lesser extent in nearly all general cancer types, including kidney cancer. There are two types of inherited kidney cancer that are unique examples of the Warburg effect in cancer driven by specific gene mutation; fumarate hydratase-deficient kidney cancer and succinate dehydrogenase deficient

Conclusion – kidney cancer is a metabolic disease

Kidney cancer is fundamentally a metabolic disease. The known genes for kidney cancer, VHL, MET, FLCN, MITF, TFE3, TFEB, TSC1, TSC2, PTEN, FH, SDHB and SDHD are involved in the cell's ability to sense oxygen, iron, nutrients, and, particularly in the TCA cycle enzymes, energy (Fig. 7). Although significant progress has been made targeting, we still have a long way to go. Most patients treated with the approved drugs targeting the VHL gene pathway, such as sunitinib, sorafenib, bevacuzimab,

Acknowledgements

This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

The authors thanks Georgia Shaw for the outstanding editorial and graphics support.

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