Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers

Abstract

The field of hereditary kidney cancer has begun to mature following the identification of several germline syndromes that define genetic and molecular features of this cancer. Molecular defects within these hereditary syndromes demonstrate consistent deficits in angiogenesis and metabolic signaling, largely driven by altered hypoxia signaling. The classical mutation, loss of function of the von Hippel-Lindau (VHL) tumor suppressor, provides a human pathogenesis model for critical aspects of pseudohypoxia. These features are mimicked in a less common hereditary renal tumor syndrome, known as hereditary leiomyomatosis and renal cell carcinoma. Here, we review renal tumor angiogenesis and metabolism from a HIF-centric perspective, considering alterations in the hypoxic landscape, and molecular deviations resulting from high levels of HIF family members. Mutations underlying HIF deregulation drive multifactorial aberrations in angiogenic signals and metabolism. The mechanisms by which these defects drive tumor growth are still emerging. However, the distinctive patterns of angiogenesis and glycolysis-/glutamine-dependent bioenergetics provide insight into the cellular environment of these cancers. The result is a scenario permissive for aggressive tumorigenesis especially within the proximal renal tubule. These features of tumorigenesis have been highly actionable in kidney cancer treatments, and will likely continue as central tenets of kidney cancer therapeutics.

Figure 1. Common themes in hereditary kidney cancer syndromes.

The two dominant forms of hereditary (and sporadic) RCC derive from cells in the proximal tubule. In spite of their common or similar origin, these tumor types have distinct genetics and biological characteristics. Although both VHL mutation, which is associated with clear cell type RCC, and FH mutation, which is associated with papillary-type 2 RCC, can deregulate HIF expression, these factors drive a differing balance of angiogenic and metabolic features, contributing to the overall pattern of the distinct diseases.

Figure 2. HIF-mediated metabolic reprogramming in VHL-deficient RCC.

Germline mutations that render the tumor suppressor gene VHL defective, as observed in a majority of clear cell renal carcinoma cells (ccRCC), interfere with pVHL-mediated proteolysis of HIFα (compare a classic model of cellular metabolism in A, with pseudohypoxic HIF-driven RCC metabolic reprogramming in B). Stabilized HIFα translocates to the nucleus, where it dimerizes with HIFβ and directly upregulates transcription of genes related to cellular metabolism, among hundreds of others. HIF reprograms metabolism away from aerobic respiration and toward aerobic glycolysis by increasing conversion from pyruvate to lactate (via upregulation of LDHA) and by blocking pyruvate conversion to acetyl-CoA by PDH (via upregulation of PDK1). HIF increases metabolic nutrients by upregulating transporters for both glucose (GLUT1 and GLUT3) and glutamine (SLCA1 and SLCA3), thereby increasing rates of glycolytic and reductive carboxylation pathways, respectively. In addition, HIF mediates a reduction in aerobic respiration by upregulating BNIP3 and BNIP3L, which leads to selective mitochondrial degradation. HIF interferes with TCA cycle enzymes via miR-210, which disrupts formation of Fe-S clusters necessary for catalysis. Upregulation of the transcription suppressor MXI1 represses c-MYC expression that greatly facilitates the metabolic shift in cancer cells. HIF amplifies its own transcriptional activity by upregulating the HIFα cofactor PKM2. Ub, ubiquitin. α-KG, α-ketoglutarate.

Figure 3. Vascular dysmorphogenesis during VHL mutations.

Inducing VHL mutations experimentally (compare WT conditions in A with VHL mutant condition in B) leads to vascular abnormalities characterized by an ectopic expression of smooth muscle α-actin (α-SMA; green) by vascular pericytes and vascular patterning defects, including elevated vessel density and the development of arteriovenous shunts spanning major arteries/arterioles (light red) and venules/veins (light blue).