Hypoxia, Hypoxia-inducible Transcription Factors, and Renal Cancer

Abstract

Context: Renal cancer is a common urologic malignancy, and therapeutic options for metastatic disease are limited. Most clear cell renal cell carcinomas (ccRCC) are associated with loss of von Hippel-Lindau tumor suppressor (pVHL) function and deregulation of hypoxia pathways.

Objective: This review summarizes recent evidence from genetic and biological studies showing that hypoxia and hypoxia-related pathways play critical roles in the development and progress of renal cancer.

Evidence acquisition: We used a systematic search for articles using the keywords hypoxia, HIF, renal cancer, and VHL.

Evidence synthesis: Identification of the tumor suppressor pVHL has allowed the characterization of important ccRCC-associated pathways. pVHL targets α-subunits of hypoxia-inducible transcription factors (HIF) for proteasomal degradation. The two main HIF-α isoforms have opposing effects on RCC biology, possibly through distinct interactions with additional oncogenes. Furthermore, HIF-1α activity is commonly diminished by chromosomal deletion in ccRCCs, and increased HIF-1 activity reduces tumor burden in xenograft tumor models. Conversely, polymorphisms at the HIF-2α gene locus predispose to the development of ccRCCs, and HIF-2α promotes tumor growth. Genetic studies have revealed a prominent role for chromatin-modifying enzyme genes in ccRCC, and these may further modulate specific aspects of the HIF response. This suggests that, rather than global activation of HIF, specific components of the response are important in promoting kidney cancer. Some of these processes are already targets for current therapeutic strategies, and further dissection of this pathway might yield novel methods of treating RCC.

Conclusions: In contrast to many tumor types, HIF-1α and HIF-2α have opposing effects in ccRCC biology, with HIF-1α acting as a tumor suppressor and HIF-2α acting as an oncogene. The overall effect of VHL inactivation will depend on fine-tuning of the HIF response.

Patient summary: High levels of hypoxia-inducible transcription factors (HIF) are particularly important in the clear cell type of kidney cancer, in which they are no longer properly regulated by the von Hippel-Lindau protein. The two HIF-α proteins have opposing effects on tumor evolution.

Keywords: Clear cell renal cell carcinoma; Hypoxia; Hypoxia-inducible transcription factors; von Hippel-Lindau.

Fig. 1

Subtypes of von Hippel-Lindau disease. Phenotypic characteristics correlate with the degree of hypoxia-inducible transcription factor dysregulation. HIF = hypoxia-inducible transcription factors; VHL = von Hippel-Lindau protein.

Fig. 2

The hypoxia-inducible transcription factor (HIF) pathway in clear cell renal cancer. In normal epithelial cells, ubiquitination of HIF-α by the E3 ubiquitin ligase leads to degradation via the 26 proteasome. In precancerous cells, defective tumor suppressor pVHL or elongin C results in stabilization of both HIF-α isoforms. Subsequent deletions of HIF-1α and/or chromatin-modifying enzymes as well as somatic mutations in HIF DNA-binding sites can affect the transcriptional program of HIF and eventually lead to a tumorigenic phenotype. eloB = elongin B; eloC = elongin C; HIF = hypoxia-inducible transcription factors; VHL = von Hippel-Lindau protein.