Obesity is a driver of pancreatic cancer, new study shows

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Pancreatic cancer is expected to become the second-deadliest cancer in the United States by 2030, driven in part by rising obesity rates.

In a new study, researchers have demonstrated that hormones released from the pancreas itself can advance pancreatic cancer — and that weight loss can stop this process in its early stages.

These discoveries raise the hope of finding new ways to prevent both the growth and the spread of pancreatic cancer.

The research was led by Yale Cancer Center (YCC) scientists.

The team 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.

Next, the team studied whether weight loss could slow the development of cancer in the mice who had developed pre-cancerous lesions. The results were dramatic.

They found that if we made the mice lose weight prior to advanced cancer development, they could essentially block the progression to advanced cancer almost as if they were never obese.

If they 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.

The team 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 the 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.

One author of the study is Mandar Muzumdar, M.D., an assistant professor of genetics at Yale School of Medicine, a member of the Yale Cancer Biology Institute.

The study is published in the journal Cell.

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