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Updated: Jul 9, 2026
Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
VHL inactivation in renal cell carcinoma: implications for diagnosis, prognosis and treatment
W Kimryn Rathmell1, Shufen Chen
1The University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, 450 West Drive, Campus Box 7295, Chapel Hill, NC 27599-7295, USA. rathmell@med.unc.edu
Abstract:
Clear cell renal cell carcinoma (ccRCC) provides a tumor paradigm for the integration of genetics, molecular biology, therapeutic target validation and the introduction of high-impact treatment strategies. Most cases of sporadic as well as familial ccRCC acquire somatic inactivating mutations of the von Hippel-Lindau tumor-suppressor gene, VHL. pVHL, VHL gene product and a protein member of the E3 ubiquitin ligase family, acts in normal cells to direct the degradation and clearance of the hypoxia inducible factor (HIF)alpha transcription factor family, such that in its absence, as in ccRCC, the HIF proteins stabilize, accumulate to supraphysiologic levels and activate the transcription of genes such as VEGF and PDGF, which contributes substantially to the physiology of the tumor, and has been assessed indirectly as a prognostic factor. Molecularly targeted therapy blocking components of this pathway has been successfully introduced to the clinic with a substantive impact on clinical parameters of RCC. This review will examine the regulation of these molecular pathways in RCC and discuss the impact on the clinical management of patients with RCC.
Insights
Clear cell renal cell carcinoma (ccRCC) is linked to VHL gene mutations that stabilize hypoxia-inducible factors (HIFs). Targeting this pathway offers effective treatment strategies for kidney cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Clear cell renal cell carcinoma (ccRCC) is a significant cancer model for integrating genetics and molecular biology.
- The von Hippel-Lindau (VHL) tumor-suppressor gene is frequently inactivated in sporadic and familial ccRCC.
- Loss of VHL function leads to the stabilization and accumulation of hypoxia-inducible factors (HIFs).
Purpose of the Study:
- To review the molecular pathways regulating ccRCC, focusing on the VHL-HIF axis.
- To discuss the impact of understanding these pathways on the clinical management of renal cell carcinoma.
- To examine the role of HIFs in ccRCC pathogenesis and as therapeutic targets.
Main Methods:
- Literature review of studies on ccRCC genetics, molecular biology, and targeted therapies.
- Analysis of the VHL gene, its product (pVHL), and its role in HIF regulation.
- Examination of the downstream effects of HIF stabilization, including VEGF and PDGF signaling.
Main Results:
- Inactivation of the VHL gene is a key event in ccRCC development.
- Stabilized HIF proteins promote tumor physiology by activating pro-angiogenic and growth factor genes.
- Molecularly targeted therapies inhibiting the VHL-HIF pathway have shown clinical efficacy in RCC.
Conclusions:
- The VHL-HIF pathway is central to ccRCC pathogenesis.
- Targeting this pathway represents a successful therapeutic strategy for managing renal cell carcinoma.
- Further understanding of these molecular mechanisms can refine clinical treatment approaches for ccRCC patients.
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