Diabetes Drug Metformin Could Inhibit Progression of Pancreatic Cancer

Researchers at Massachusetts General Hospital believe they have identified the mechanism behind diabetes drug metformin’s ability to stop the progression of pancreatic cancer. The team found that metformin is capable of suppressing inflammation and the fibrotic nature of adenocarcinoma – the most common form of pancreatic cancer. According to the researchers – whose article was published in the journal, PLOS One – their results suggest that the inhibitive benefits of metformin may be most pronounced in overweight and obese patients.

“We found that metformin alleviates desmoplasia – an accumulation of dense connective tissue and tumor-associated immune cells that is a hallmark of pancreatic cancer – by inhibiting the activation of the pancreatic stellate cells that produce the extracellular matrix, and by reprogramming immune cells to reduce inflammation,” said Dr. Dai Fukumura, a researcher in the Steele Laboratory of Tumor Biology in the Massachusetts General Hospital Department of Radiation Oncology, and a senior author on the publication. “We also found these effects were only evident in tumors from overweight or obese individuals, who appear to have tumors with increased fibrosis.”

Pancreatic ductal adenocarcinoma – the focus of the study – is the most common form of the disease, responsible for nearly 40,000 deaths in the US each year. Fifty percent of all patients diagnosed with this form of pancreatic cancer are considered to be overweight or obese; many of these individuals – up to 80 percent – have some form of diabetes.

While previous research identified that diabetic patients taking metformin were at a decreased risk of developing pancreatic cancer – and those that do develop the disease have a decreased risk of death – the current study is the first to show a possible mechanism explaining this phenomenon. Previous studies have failed to identify any biomarkers explaining the pancreatic tumor’s response to metformin.

Fukumura and his colleagues found that tumor samples taken from overweight patients taking metformin to manage diabetes, contained 30 percent less hyaluronan – a compound found in the extracellular matrix – compared to patients not taking the drug. Further, the researchers found that obese animal models used to study pancreatic cancer displayed lower levels of expression of hyaluronan and collagen-1, when treated with metformin.

The animals also had fewer pancreatic stellate cells (PSCs) – the cells responsible for the production of hyaluronan and collagen-1. When the researchers studied the pathway responsible for metformin’s suppression of these compounds in cell culture, they found that the drug also prevents tumor-associated macrophages from being recruited, thereby reducing the inflammatory response.

“Nearly 200 clinical trials are currently underway investigating the effect of metformin on tumors in both diabetic and non-diabetic patients,” said Dr. Rakesh K. Jain, director of the Steele Laboratory, and the study’s co-senior author. “Understanding the mechanism behind metformin’s effects on pancreatic and other cancers may help us identify biomarkers – such as patient body weight and increased tumor fibrosis – that can identify the patients for whom metformin treatment would be most beneficial.”

Sources:

• Study Finds How Diabetes Drug Metformin Inhibits Progression of Pancreatic Cancer
• Incio, J., Suboj, P., Chin, S., Vardam-Kaur, T., Liu, H., Hato, T., Babykutty, S., Chen, I., Deshpande, V., Jain, R., and Fukumura, D. (2015). Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages. PLOS ONE. 10 (12).