Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Aug;1870(1):23-31.
doi: 10.1016/j.bbcan.2018.06.003. Epub 2018 Jun 28.

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

Danielle J Sanchez  1 , M Celeste Simon  2
Affiliations
Review

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

Danielle J Sanchez et al. Biochim Biophys Acta Rev Cancer. 2018 Aug.

Abstract

Clear cell renal cell carcinoma (ccRCC) is a malignancy characterized by deregulated hypoxia-inducible factor signaling, mutation of several key chromatin modifying enzymes, and numerous alterations in cellular metabolism. Pre-clinical studies have historically been limited to cell culture models, however, the identification of critical tumor suppressors and oncogenes from large-scale patient sequencing data has led to several new genetically engineered mouse models with phenotypes reminiscent of ccRCC. In this review, we summarize recent literature on these topics and discuss how they inform targeted therapeutic approaches for the treatment of ccRCC.

Keywords: Cancer; Genetics; Hypoxia-inducible factors; Lipid metabolism; Mouse models; Therapy.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.. Regulation of hypoxia-inducible factor (HIF) signaling by the von Hippel-Lindau (VHL) tumor suppressor.
Under oxygen-replete conditions, HIF-α subunits are hydroxylated by prolyl hydroxylases (PHDs) and then ubiquitinated by an E3-ubiquitin ligase complex containing pVHL, tagging them for proteasomal degradation. In hypoxia, or when VHL is inactivated (such as in ccRCC), HIF-α subunits escape degradation, translocate to the nucleus, and |heterodimerize with HIF-1β (ARNT). HIFs generally promote a transcriptional program favoring increased angiogenesis, glycolysis, and metastatic capabilities of ccRCC tumors. HRE = hypoxia response element.
Figure 2.
Figure 2.. Comparison of the metabolic state of renal epithelium and clear cell renal cell carcinoma (ccRCC).
Renal epithelial cells (of the proximal tubule, a proposed cell-of-origin of ccRCC) are characterized by high levels of glucose and fatty acid oxidation to serve their energetic needs. As these cells transition into ccRCC, they begin to store triglyceride and cholesterol ester in cytoplasmic lipid droplets. Furthermore, ccRCC have low levels of fatty acid oxidation and compromised mitochondrial architecture relative to healthy renal epithelium. Nuc = nucleus. Mito = mitochondria. LD = lipid droplet.
Figure 3.
Figure 3.. Select pharmacological approaches for the treatment of metastatic ccRCC.
Current and future therapeutic strategies for ccRCC include inhibition (denoted by red boxes) of mTOR signaling, angiogenesis, HIF-2α signaling, and immune checkpoint blockade. RTKi = receptor tyrosine kinase inhibitors. Rapalogs = rapamycin analogs. PD-1i = PD-1 inhibitor. PD- L1i = PD-L1 inhibitor.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Institute NC, SEER Cancer Stat Facts: Kidney and Renal Pelvis Cancer, 2018.
    1. Rini BI, Campbell SC, Escudier B, Renal cell carcinoma, The Lancet, 373 (2009) 1119–1132. - PubMed
    1. Wettersten HI, Aboud OA, Lara PN Jr, Weiss RH, Metabolic reprogramming in clear cell renal cell carcinoma, Nature Reviews Nephrology, 13 (2017) 410. - PubMed
    1. Linehan WM, Srinivasan R, Schmidt LS, The genetic basis of kidney cancer: a metabolic disease, Nature reviews urology, 7 (2010) 277. - PMC - PubMed
    1. Hakimi AA, Pham CG, Hsieh JJ, A clear picture of renal cell carcinoma, Nature genetics, 45 (2013) 849. - PubMed

Publication types

Supplementary concepts