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Updated: Jul 17, 2026
Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma
1Howard Hughes Medical Institute, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. William_kaelin@dfci.harvard.edu
Abstract:
Germ line VHL tumor suppressor gene loss-of-function mutations cause von Hippel-Lindau disease, which is associated with an increased risk of central nervous system hemangioblastomas, clear cell renal carcinomas, and pheochromocytomas. Somatic VHL mutations are also common in sporadic clear cell renal carcinomas. The VHL gene product, pVHL, is part of a ubiquitin ligase complex that targets the alpha-subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for polyubiquitylation, and hence, proteasomal degradation, when oxygen is available. pVHL-defective clear cell renal carcinomas overproduce a variety of mRNAs that are under the control of HIF, including the mRNAs that encode vascular endothelial growth factor, platelet-derived growth factor B, and transforming growth factor alpha. In preclinical models, down-regulation of HIF-alpha, especially HIF-2alpha, is both necessary and sufficient for renal tumor suppression by pVHL. These observations are probably relevant to the demonstrated clinical activity of vascular endothelial growth factor antagonists in clear cell renal carcinoma and form a foundation for the testing of additional agents that inhibit HIF, or HIF-responsive gene products, in this disease.
Insights
Loss of the VHL tumor suppressor gene leads to von Hippel-Lindau disease and clear cell renal carcinoma. Inhibiting hypoxia-inducible factor (HIF) shows promise for treating these VHL-defective cancers.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Germline mutations in the VHL tumor suppressor gene cause von Hippel-Lindau (VHL) disease, increasing risks for central nervous system hemangioblastomas, clear cell renal carcinomas, and pheochromocytomas.
- Somatic VHL mutations are frequently observed in sporadic clear cell renal carcinomas.
- The VHL gene product, pVHL, functions within a ubiquitin ligase complex, targeting hypoxia-inducible factor (HIF) alpha-subunits for degradation under oxygen-rich conditions.
Purpose of the Study:
- To investigate the role of pVHL in regulating HIF and its implications for clear cell renal carcinoma (ccRCC) development.
- To explore the therapeutic potential of targeting HIF or HIF-regulated genes in VHL-defective cancers.
Main Methods:
- Analysis of VHL gene mutations in VHL disease and sporadic ccRCC.
- Biochemical characterization of the pVHL-containing ubiquitin ligase complex.
- Assessment of HIF-alpha subunit regulation by pVHL.
- Examination of HIF-regulated gene expression in pVHL-defective ccRCC.
- Preclinical studies evaluating the effects of HIF down-regulation on renal tumor suppression.
Main Results:
- pVHL-defective ccRCC exhibits overexpression of HIF-controlled genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor B (PDGFB), and transforming growth factor alpha (TGF-α).
- Down-regulation of HIF-alpha, particularly HIF-2alpha, was found to be both necessary and sufficient for renal tumor suppression mediated by pVHL in preclinical models.
- These findings correlate with the clinical efficacy of VEGF antagonists in ccRCC.
Conclusions:
- pVHL loss-of-function mutations drive ccRCC by stabilizing HIF.
- Targeting HIF or its downstream effectors represents a promising therapeutic strategy for VHL-associated and sporadic clear cell renal carcinomas.
- Further clinical investigation of HIF-inhibiting agents is warranted for ccRCC treatment.
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