Scientists discover a mechanism involved in the expansion processes of renal carcinoma

Von Hippel-Lindau syndrome is a rare genetic disorder that affects 1 in 36,000 people. The mutation of a gene, called VHL, predisposes the person to the development of multiple tumors and cysts throughout his or her life. While most are benign, one is malignant and is the leading cause of death among these patients: renal cell carcinoma.

Currently, there are no treatments to prevent the patient from developing tumors, but early detection would not only allow genetic counseling for the patients and their families but also generate treatment and intervention guidelines for tumors.

Researchers from the Biomedicine Research Institute of Buenos Aires (IBioBA, CONICET – Partner Institute of the Max Planck Society) and doctors from the Departments of Urology and Pathology of the Hospital Italiano [Italian Hospital] discovered that a protein, RSUME, plays a key role in the development of the pathology. The work was published in Cell Death & Disease, a publication of the Nature group.

“The concentration of RSUME increases in tissues when they are subject to low oxygen conditions, for instance when malignant cells divide uncontrollably and consume all the nutrients in the environment. We discovered that RSUME is present in greater concentrations when there are mutations in the VHL gene and in renal cell carcinoma. In those cases, RSUME promotes the formation of new blood vessels to feed the tumor”, explains María Belén Elguero, a postdoctoral fellow of CONICET at IBioBA, and one of the authors of the study.

Knowing that in malignant cells the levels or RSUME are very high, open a range of future therapeutic opportunities. “This molecule could become a marker for tumor aggressiveness in these patients with VHL mutations, and this would allow us to manage them differently”, says Patricio García Marchiñena, a physician in the Urology Department of the Hospital Italiano.

Currently, VHL patients are screened for kidney tumors, and their size is monitored on a regular basis to determine whether it increases or not. If the size is less than three centimeters then the physician suggests waiting because the chances of the tumor to metastasize are very low.

“Nowadays the approach is to conduct conservative surgeries, that is, to remove as little kidney as possible so that the person does not end up on dialysis. But with some patients this can be risky, because if the tumor is very aggressive it can metastasize before it reaches three centimeters. Thus, to have a marker of aggressiveness would allow us, from a biopsy, to determine the best course of action”, expands Mariana Isola, a member of the Pathology Department of the Hospital.

From bench to bedside

It all started with a question: is RSUME overexpressed – that is, produced in greater amounts – in patients with renal cell carcinoma? If so, why? From this, the team led by Eduardo Arzt at IBioBA started to unravel the causes.

They tested their hypothesis in vitro (in renal tumor cells) and saw that RSUME prevents the degradation of a molecule, called HIF, which plays a key role in the formation of new blood vessels. With this information they analyzed, in collaboration with the Bioinformatics Core Facility of IBioBA, a global database of patients with renal carcinoma and found that, indeed, the levels of RSUME correlate with more serious clinical manifestations in people who are in advanced stages of this disease.

Also, when they studied the data available in the Cancer Genome Atlas Research Network (TCGA), they realized that 20% of the people who suffered from this type of kidney cancer express high levels of RSUME and that this is associated with a reduction of 23% in the survival rate of patients.

The next question had to do with the mechanisms involved. How does RSUME work? “We found that it stops the protein produced by the VHL gene from degrading HIF. And with more HIF in the tumor, then more new vessels will appear to support the growth of the tumor”, adds Elguero.

Patients with Von Hippel-Lindau syndrome do not produce the VHL protein – or produce it with an aberrant structure. Thanks to the collaboration with the Hospital Italiano, researchers were able to verify in samples from these patients that – in renal cell carcinoma – there was indeed more RSUME than normal.

“This not only opens the possibility of using RSUME as an early marker of tumor aggressiveness in VHL patients but also proves that joint work between researchers and physicians is essential to allow basic science to reach the bedside”, adds Eduardo Arzt, Director of the IBioBA and leader of that research group.