Altered cellular energetics, a hallmark of cancers, has been associated with obesity. However, links between systemic energy regulation and aberrant cancer cell metabolism have been lacking. A group of researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, led by Scott Welford, Ph.D., has published a paper in Cancer Discovery describing a mechanistic link in kidney cancer between fat metabolism and obesity that holds promise to be a novel renal cancer biomarker and drug target.
Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer and is identified by its robust lipid storage behavior by histology. What makes these tumors store fat, and whether this matters for the behavior of the cancer has long been unknown. Additionally, the realization that obesity associates with renal cancer has led to speculation about how systemic changes in fat production could contribute to a cancer that is known for its excess fat accumulation.
Dr. Welford's group made the leap that kidney cancer and systemic fat could be talking to each other through a group of signaling proteins called adipokines; and if they were, this would set up a situation where a factor in the blood could be detectable and possibly blocked to reduce cancer burden. The hypothesis turned out to be true.
The researchers found that a protein named chemerin is present in higher quantities in the blood of obese individuals and plays an essential role in controlling fat metabolism in kidney cancer cells. Furthermore, kidney cancers also produce chemerin as a way to promote themselves, and thus even higher levels can be seen in patients with kidney cancer as opposed to those without.
There is also a possibility that the implications of the findings go beyond kidney cancer. Altered lipid biology is present in many cancers. We are hoping the link between obesity and cancer through chemerin can be extended to other cancers as well."
Dr. Scott Welford, Ph.D., Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine
Strikingly, inhibition of chemerin dramatically reduces cancer growth. Together the study leads to the exciting possibilities of using chemerin as a new biomarker to assess prognosis or disease recurrence, and the concept of targeting fat metabolism to improve patient outcomes.
"This research provides a biological link between obesity and kidney cancer suggesting a molecular marker and therapeutic target that can be used to improve the way we currently treat this disease. Targeting this pathway represents an exciting area for future pharmacologic research and development of clinical trials to provide patients with additional treatment options" said Mark Gonzalgo,M.D.,Ph.D., a urologic oncologist at Sylvester an a co-author of this paper.
Sze Kiat Tan (Owen), a current MD/PhD student and the first author of the paper, added, "Our multi-modal approach to delineating the chemerin pathway in kidney cancer is just the beginning."
Tan, S.K., et al. (2021) Obesity-Dependent Adipokine Chemerin Suppresses Fatty Acid Oxidation to Confer Ferroptosis Resistance. Cancer Discovery. doi.org/10.1158/2159-8290.CD-20-1453.