Genetic and metabolic hallmarks of clear cell renal cell carcinoma

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.

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.. 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.. 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.