Breaking the Link Between Alcohol Use and Pancreatic Cancer
Summary
- A new study by researchers at Sylvester Comprehensive Cancer Center provides insight into the mechanisms that link alcohol and pancreatic cancer.
- The new findings suggest that inhibiting the cellular molecule CREB might thwart pancreatic tumor development in response to alcohol.
- The study hints that inhibitors of CREB might have therapeutic potential in people who have high alcohol use.
The U.S. surgeon general recently declared alcohol the third-leading preventable cause of cancer. Yet, despite increasing evidence linking alcohol consumption to the disease, little is known about the biological mechanisms behind the association.
A new study by researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, provides insight into these mechanisms in pancreatic cancer.
The new findings delved into the role of a cellular molecule called CREB. CREB seems to mediate an inflammatory condition in the pancreas caused by high alcohol use that increases the risk of developing cancer. Inhibiting CREB might thwart pancreatic tumor development in response to alcohol.
“Our model serves as an important platform for understanding how chronic inflammation related to alcohol consumption accelerates the development of pancreatic cancer,” said Sylvester scientist Siddharth Mehra, Ph.D., who is the study’s first author.
The Alcohol-Cancer Connection
Chronic, high alcohol use damages the acinar cells in the pancreas that produce digestive enzymes. The damage in turn causes the cells’ enzymes to increase inflammation in the tissue, exacerbating damage to the pancreas.
Over time, precancerous lesions can develop, increasing the risk for full-blown pancreatic cancer, one of the deadliest types of tumors. Previous studies have implicated CREB, a DNA-binding protein that regulates gene activity, and associated molecules in helping to mediate this process.
Progression to cancer also generally requires other cellular events, such as a mutation in a pro-cancerous gene called Ras, which commonly occurs in pancreatic tumors.
In the new study, the researchers developed a model that recapitulated alcohol-induced inflammation, the development of pre-cancerous lesions and progression to cancer. The model contained Ras mutations in acinar cells, and it also had an intact CREB gene that could be experimentally knocked out in these cells.
A Molecular Orchestrator
The researchers found that exposure to alcohol and a pro-inflammatory molecule caused the development of symptoms similar to alcohol-induced pancreatitis, an inflammatory condition. Inflammation in turn prompted the development of precancerous lesions and, later, cancer. Consistent with previous studies, CREB was highly activated throughout this transition process.
The researchers next knocked out CREB and found they could quell the development of precancerous and cancerous lesions, even in the continued presence of alcohol. Knocking out CREB also relieved damage to acinar cells.
We believe this study lays the groundwork for future translational efforts targeting CREB as a therapeutic vulnerability in inflammation-associated pancreatic cancer.
Dr. Nipun Merchant
The findings hint that inhibitors of CREB might have therapeutic potential in people who have high alcohol use. Such inhibitors could potentially relieve damage to the pancreas and thwart tumor development, said the researchers.
“We found that CREB is not just a mediator of inflammation. It is a molecular orchestrator that permanently converts acinar cells into precancerous cells, which ultimately progress to high-grade neoplasia,” said senior author Nagaraj Nagathihalli, Ph.D., associate professor in the DeWitt Daughtry Family Department of Surgery and assistant director of the Sylvester Pancreatic Cancer Research Institute at the University of Miami.
The findings appeared Aug. 12 in the journal, Cellular and Molecular Gastroenterology and Hepatology. The research was funded in part by the U.S. National Institutes of Health as part of an effort to probe the biology behind alcohol use and cancer.
Setting the Stage
Future studies should help provide additional information about how alcohol use promotes pancreatic cancer development.
Points of investigation include whether similar events occur in human cells and tissues and what other molecules and cells play a role in the process. CREB activation may also be involved in other alcohol-linked cancers.
Dr. Nagathihalli and his colleagues are also leveraging the model to investigate the potential of CREB inhibitors, which are under development as potential cancer therapeutics.
“We believe this study lays the groundwork for future translational efforts targeting CREB as a therapeutic vulnerability in inflammation-associated pancreatic cancer,” said study co-author Nipun Merchant, M.D., Sylvester associate director of translational science and chief of the Division of Surgical Oncology at the Miller School.
Tags: alcohol, cancer research, DeWitt Daughtry Family Department of Surgery, Dr. Nagaraj Nagathihalli, Dr. Siddarth Mehra, pancreatic cancer, Sylvester Comprehensive Cancer Center