INDIANAPOLIS—A team of all Indiana University School of Medicine researchers have discovered a novel drug target to treat involuntary muscle and fat wasting – known as cachexia - in people with pancreatic cancer. They’ve also identified the way muscle and fat are communicating with one another in the presence of a pancreatic tumor, which could prove important to extending overall pancreatic cancer patient survival in those suffering from cachexia. Their findings were recently published in the Journal of Experimental Medicine, a scientific journal focused on publishing outstanding studies in medical biology.
Pancreatic cancer is one of the deadliest cancers, with only a 10% survival rate beyond five years. Alex Trebek, host of popular TV show "Jeopardy, was diagnosed with stage four pancreatic cancer. He lived for two years following his diagnosis. Pancreatic cancer patients experience some of the highest rates of cachexia at 85%. Cachexia causes morbidity, treatment toxicity and low quality of life. Moreover, researchers estimate cachexia is the cause of death in more than a third of all patients with any type of cancer.
Interleukin 6, more commonly referred to as “IL-6” is a protein in the human body, which is necessary for maintaining good overall health. However, when overexpressed it’s known to be associated with cachexia. The role of IL-6 expressed from tumor cells was unknown until now.
"We took the path less traveled," said Joe Rupert, PhD, Biochemistry and Molecular Biology and lead author of the study. “Broadly, a tumor includes two types of compartments; stromal and epithelial. While a lot of research has been done on the idea that the stromal cells are producing IL-6, we focused instead on the epithelial cells. When we removed IL-6 from the tumor’s epithelial cells, significantly less fat and muscle wasting occurred and overall survival increased.”
The research team also discovered the fat and muscle are talking with one another. And, when the researchers deleted IL-6 from the tumor, the cross-talk was greatly diminished.
“We found that tumor-derived IL-6 in turn induced IL-6 expression in fat and IL-6 receptor expression in muscle, resulting in a feed-forward vicious cycle of IL-6 trans-signaling leading to fat and muscle wasting”, said Teresa Zimmers, PhD, H.H. Gregg Professor of Cancer Research and Professor of Surgery at IU School of Medicine and senior author of the study. “We believe that if you can stop this crosstalk you can block cachexia and increase survival.”
The team also discovered lipid accumulation increases in muscle with cachexia.
“Increases in IL-6 signaling largely increases fat wasting, which dumps lipids and fatty acids into blood that the muscle picks up, leading it to become overloaded. This increases muscle stress and promotes more muscle wasting,” said Rupert.
Going forward, the team is investigating several approaches to stopping the crosstalk among fat and muscle through lipid and IL-6 neutralization.
This research was funded in part by grants from the National Institutes of Health (grants R01CA122596, R01CA194593, and R01GM137656), the Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Lilly Endowment, the Bioinformatics analysis was supported by the Purdue University Center for Cancer Research (grant P30CA023168), the Walther Cancer Foundation, and the Indiana University (IU) Melvin and Bren Simon Comprehensive Cancer Center (grant P30CA082709), the last of which also supports the IU Melvin and Bren Simon Comprehensive Cancer Center Tissue Procurement and Distribution Core, In Vivo Therapeutics Core, Flow Cytometry Core, and Genomics Core.
About IU School of Medicine IU School of Medicine is the largest medical school in the U.S. and is annually ranked among the top medical schools in the nation by U.S. News & World Report. The school offers high-quality medical education, access to leading medical research and rich campus life in nine Indiana cities, including rural and urban locations consistently recognized for livability.