Study shows huge effect of obesity on pancreatic cancer development

Pancreatic cancer is expected to become the second-deadliest cancer in the United States by 2030, driven in part by rising obesity rates. A new study led by Yale Cancer Center (YCC) researchers has demonstrated in mice that hormones released from the pancreas itself can advance pancreatic cancer -; and that weight loss can stop this process in its early stages. The research was published today in the journal Cell.

"These discoveries raise the hope of finding new ways to prevent both the growth and the spread of pancreatic cancer," said Mandar Muzumdar, M.D., assistant professor of genetics at Yale School of Medicine, a member of the Yale Cancer Biology Institute, and senior author of the paper.

Muzumdar and his collaborators, including a team from the Massachusetts Institute of Technology (MIT), began the project with a mouse model that was genetically modified to develop pre-cancerous pancreatic lesions with a mutation in the KRAS gene, which is mutated in most human pancreatic cancers. The mice were also genetically engineered both to become obese and to rapidly lose weight when scientists administered an additional form of genetic manipulation or limited their food intake.

Unlike mice of normal weight engineered with the KRAS mutation, obese mice with this mutation rapidly developed advanced pancreatic cancer. And unlike most humans diagnosed with the disease, tumors in the model mice did not present additional genetic mutations that would further enable tumor progression.

Just by making them obese, we could essentially simulate the effect of an additional mutation. That suggested that there is a huge effect of obesity on cancer development in mice."

Mandar Muzumdar, M.D., assistant professor of genetics at Yale School of Medicine

Next, he and his colleagues studied whether weight loss could slow the development of cancer in the mice who had developed pre-cancerous lesions. The results were dramatic. "We found that if we made the mice lose weight prior to advanced cancer development, we could essentially block the progression to advanced cancer almost as if they were never obese," Muzumdar said. "If we made the mice lose weight after advanced cancers had developed, the mice still succumbed to the disease within the same timeframe."

The finding suggested the possibility of intercepting tumor formation or progression by weight loss, or eventually using novel drugs that target the underlying biological pathways. Muzumdar noted that the result matches up well with clinical studies of people who are given weight-reducing bariatric surgery, which appears to lower the risk of developing pancreatic cancer.

To determine the cause of the tumors in these mice, the team looked at the genes being expressed in clusters of hormone-producing cells called "islets" in their pancreases. One type of pancreatic islet cell known as a "beta cell" normally produces insulin. In these mice, however, some beta cells were churning out a hormone called cholecystokinin (Cck), normally generated in the intestine to aid digestion. These beta cells also seemed to secrete less insulin. This finding interested Muzumdar and his team because they knew that the Cck hormone acts on the digestive enzyme-secreting cells where the predominant type of pancreatic cancer emerges.

They also discovered that Cck expression in the islets dropped when the obese mice lost weight. Additionally, other mouse models that were engineered with the KRAS mutation and forced to express Cck in beta cells, but were not obese, were more likely to form pancreatic tumors than mice engineered with the KRAS mutation alone.

Muzumdar's lab is now studying why beta cells switch from making insulin to Cck. Another key puzzle is how Cck can boost tumor formation and progression. "Our hope is that the underlying pathways and mechanisms we're identifying in obesity also may apply to those who develop pancreatic cancer in the absence of obesity," he added.


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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