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Von Hippel-Lindau tumor suppressor pathways & corresponding therapeutics in kidney cancer
Maxwell Shulman1, Rachel Shi1, Qing Zhang1
1Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Abstract:
The identification and application of the Von Hippel-Lindau (VHL) gene is a seminal breakthrough in kidney cancer research. VHL and its protein pVHL are the root cause of most kidney cancers, and the cascading pathway below them is crucial for understanding hypoxia, in addition to the aforementioned tumorigenesis routes and treatments. We reviewed the history and functions of VHL/pVHL and Hypoxia-inducible factor (HIF), their well-known activities under low-oxygen environments as an E3 ubiquitin ligase and as a transcription factor, respectively, as well as their non-canonical functions revealed recently. Additionally, we discussed how their dysregulation promotes tumorigenesis: beginning with chromosome 3 p-arm (3p) loss/epigenetic methylation, followed by two-allele knockout, before the loss of complimentary tumor suppressor genes leads cells down predictable oncological paths. These different pathways can ultimately determine the grade, outcome, and severity of the deadliest genitourinary cancer. We finished by investigating current and proposed schemes to therapeutically treat clear cell renal cell carcinoma (ccRCC) by manipulating the hypoxic pathway utilizing Vascular Endothelial Growth Factor (VEGF) inhibitors, mammalian target of rapamycin complex 1 (mTORC1) inhibitors, small molecule HIF inhibitors, immune checkpoint blockade therapy, and synthetic lethality.
Insights
The Von Hippel-Lindau (VHL) gene and its protein pVHL are central to kidney cancer. Understanding their role in hypoxia and tumorigenesis informs new treatments for clear cell renal cell carcinoma (ccRCC).
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The Von Hippel-Lindau (VHL) gene and its protein pVHL are implicated in the majority of kidney cancers.
- Dysregulation of VHL/pVHL and Hypoxia-inducible factor (HIF) pathways are critical in tumorigenesis and response to low-oxygen environments.
Purpose of the Study:
- To review the history and functions of VHL/pVHL and HIF, including their canonical and non-canonical roles.
- To elucidate how VHL/pVHL dysregulation contributes to clear cell renal cell carcinoma (ccRCC) development.
- To investigate therapeutic strategies targeting the hypoxic pathway in ccRCC.
Main Methods:
- Literature review of VHL/pVHL and HIF functions and dysregulation in tumorigenesis.
- Analysis of genetic alterations, including chromosome 3p loss and epigenetic methylation.
- Examination of current and proposed therapeutic interventions for ccRCC.
Main Results:
- VHL/pVHL acts as an E3 ubiquitin ligase, while HIF functions as a transcription factor, both crucial in low-oxygen responses.
- Tumorigenesis involves VHL inactivation, leading to HIF stabilization and activation of oncogenic pathways.
- Genetic alterations in VHL influence ccRCC grade, outcome, and severity.
Conclusions:
- VHL/pVHL and HIF pathways are fundamental to understanding ccRCC pathogenesis.
- Targeting the hypoxic pathway, through agents like VEGF inhibitors, mTORC1 inhibitors, HIF inhibitors, and immunotherapy, offers promising therapeutic avenues for ccRCC.
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