HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron

Cancer Cell. 2002 Jun;1(5):459-68. doi: 10.1016/s1535-6108(02)00071-5.

Abstract

Mutations in the von Hippel-Lindau (VHL) gene are associated with hereditary and sporadic clear cell renal carcinoma. VHL acts in a ubiquitin ligase complex regulating hypoxia-inducible factor-1 (HIF-1), but the link between this function and cancer development is unclear. Here we show that in the kidneys of patients with VHL disease, HIF activation is an early event occurring in morphologically normal single cells within the renal tubules. In comparison, dysplastic lesions, cystic lesions, and tumors showed evidence of additional mechanisms that amplify HIF activation. Detection of cells with constitutive HIF activation identified a large number of previously unrecognized foci of VHL inactivation. In proximal tubules these were almost entirely unicellular, whereas multicellular foci were almost exclusively seen in the distal nephron.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Clear Cell / genetics
  • Adenocarcinoma, Clear Cell / metabolism*
  • Adenocarcinoma, Clear Cell / pathology
  • Adult
  • Antigens, CD / metabolism
  • Antigens, Neoplasm*
  • Apoptosis / physiology
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases / metabolism
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • DNA-Binding Proteins / metabolism*
  • Genes, Tumor Suppressor / physiology*
  • Glucose Transporter Type 1
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunoenzyme Techniques
  • In Situ Hybridization
  • In Situ Nick-End Labeling
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Middle Aged
  • Monosaccharide Transport Proteins / metabolism
  • Neoplasm Proteins / metabolism
  • Nephrectomy
  • Nephrons / metabolism*
  • Nuclear Proteins / metabolism*
  • RNA Probes
  • Transcription Factors*
  • von Hippel-Lindau Disease / genetics
  • von Hippel-Lindau Disease / metabolism*
  • von Hippel-Lindau Disease / pathology

Substances

  • Antigens, CD
  • Antigens, Neoplasm
  • DNA-Binding Proteins
  • Glucose Transporter Type 1
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Monosaccharide Transport Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • RNA Probes
  • SLC2A1 protein, human
  • Transcription Factors
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases