The von Hippel-Lindau (VHL) protein is produced within human cells, with the VHL gene providing the instructions for its creation. It functions as part of a protein complex involved in several cellular processes, including the formation of the extracellular matrix.
A primary responsibility of the VHL protein is participating in the breakdown and removal of other proteins that are damaged or no longer needed. This protein degradation is a maintenance function that helps ensure proper cell operation. It works by identifying specific proteins and marking them for disposal, which also helps regulate genes and control cell division.
The VHL Protein’s Role as a Tumor Suppressor
Tumor suppressors are proteins that act as a control system, preventing cells from growing and dividing in a rapid or uncontrolled manner. By applying a brake to cell proliferation, they ensure that new cells are produced only when necessary for growth or to replace old and damaged cells.
The VHL protein is a tumor suppressor because it helps restrain unchecked cell growth. It participates in the targeted degradation of specific proteins that promote proliferation. This action helps to halt the process that can lead to tumor formation and is a widespread mechanism throughout the body.
A mutation in the VHL gene can produce an altered or non-functional VHL protein. Without the VHL protein’s braking action, cells can begin to divide without restraint, leading to the development of benign and malignant tumors. The loss of VHL function is associated with non-inherited forms of a kidney cancer known as clear cell renal cell carcinoma.
Regulating Cellular Response to Oxygen
The VHL protein’s tumor suppression function is linked to its ability to respond to cellular oxygen levels. This process involves a family of proteins called Hypoxia-Inducible Factors (HIFs). HIFs are transcription factors that can activate genes involved in cell division, metabolism, and the formation of new blood vessels (angiogenesis).
When oxygen is available, the VHL protein is active. It recognizes and binds to the HIF-alpha subunit after it has been chemically modified by oxygen-dependent enzymes. Once bound, the VHL protein complex tags HIF-alpha for destruction by the cell’s proteasome. This action keeps HIF levels low, preventing the activation of its target genes.
In a low-oxygen environment (hypoxia), the enzymes that modify HIF-alpha cannot function. As a result, HIF-alpha is not modified, and the VHL protein cannot bind to it. This allows HIF-alpha to accumulate inside the cell, travel to the nucleus, and activate genes. These genes help the cell adapt by promoting the growth of new blood vessels to increase oxygen supply.
This regulatory system functions like a switch. With sufficient oxygen, VHL keeps HIF inactive. When oxygen levels drop, VHL allows HIF to mobilize the cell’s survival mechanisms. This regulation of HIF levels is the basis of the VHL protein’s role as a tumor suppressor.
Consequences of a Faulty VHL Protein
A mutated VHL gene produces a faulty or absent protein, disrupting the cell’s oxygen-sensing machinery. The VHL protein can no longer target HIF-alpha for destruction, even when oxygen is normal. Consequently, HIF proteins accumulate to high levels, creating a false state of hypoxia. This triggers a continuous signal for survival pathways as if the cell were starved of oxygen.
This persistent HIF activation leads to the uncontrolled expression of genes that drive cell growth and angiogenesis. The constant signal to create new blood vessels results in highly vascularized (blood-vessel-rich) tumors. The genetic condition caused by an inherited VHL gene mutation is Von Hippel-Lindau disease. Individuals with this disease are predisposed to developing various benign and malignant tumors.
Characteristic tumors associated with VHL disease include hemangioblastomas, benign tumors of new blood vessels that develop in the brain, spinal cord, and retina, where they can cause neurological symptoms or vision loss. Patients are also at an increased risk of developing clear cell renal cell carcinoma (ccRCC), a type of kidney cancer that occurs in up to 70% of individuals with VHL. Other associated growths include tumors of the adrenal gland (pheochromocytomas) and pancreatic cysts and tumors.
Therapeutic Approaches Targeting the VHL Pathway
Understanding the VHL-HIF pathway has led to targeted cancer therapies. Since the problem in VHL-related cancers is excessive HIF protein accumulation, research has focused on drugs that block HIF activity. This strategy aims to shut down the signals that fuel tumor growth and angiogenesis. It differs from traditional chemotherapy by targeting the specific molecular driver of the disease.
An advancement in this area is the creation of drugs that inhibit HIF-2α, an oncogenic driver in many VHL-defective tumors. These HIF-2α inhibitors are small molecules that bind to the HIF-2α protein, preventing it from activating gene expression. By blocking HIF-2α, these drugs slow or stop tumor growth by cutting off signals for cell proliferation and new blood vessel formation.
The HIF-2α inhibitor belzutifan is an approved treatment for patients with VHL disease-associated tumors, including renal cell carcinoma. Clinical trials have shown this targeted therapy can lead to tumor regression and provide a durable response. Research continues to explore combining these inhibitors with other treatments to improve outcomes.