Diabetes Drug Found to Inhibit Pancreatic Cancer Progression

Researchers at the Massachusetts General Hospital (MGH) believe a diabetes drug could potentially inhibit the progression of pancreatic cancer.

The most common form of pancreatic cancer is pancreatic ductal adenocarcinoma, which accounts for about 40,000 deaths in the United States each year. Approximately half of the people diagnosed with this form of pancreatic cancer are obese or overweight. Eighty percent have type 2 diabetes or are insulin resistant.

A study published in the journal PLOS One found that the type 2 diabetes drug metformin was able to decrease inflammation and scarring observed in more common pancreatic cancers.

Furthermore, diabetic patients administered metformin have shown a reduced risk of developing pancreatic cancer. Additionally, those patients taking metformin who do develop cancer were found to have a reduced risk of death.

However, prior to the current study, the role of metformin against pancreatic cancer was unclear, with reported responses to the drug.

"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 study co-senior author Dai Fukumura, MD, PhD. "We also found these effects only evident in tumors from overweight or obese individuals, who appear to have tumors with increased fibrosis."

The researchers looked at cellular and animal models, as well as patient tumor samples. They found that the levels of hyaluronan, which is a component of the extracellular matrix, were about 30% lower in the tumor samples of overweight and/or obese patients taking metformin compared with patients who didn’t take the drug.

When looking at an obese animal model of pancreatic cancer, researchers found metformin was associated with the reduced expression of hyaluronan and collagen-1, as well as a drop in activated pancreatic stellate cells (PSCs).

In cultured cells, investigators were able to identify the signaling pathway where metformin reduces production of hyaluronan and collagen-1 by PSCs and inhibits the recruitment of tumor-associated macrophages that increase inflammation, according to the study.

Obese mouse models showed reduced levels of tumor-associated macrophages by 60% and reduced expression of genes in the extracellular matrix with metformin treatment.

The tumors of animals treated with metformin showed decreases in the overall level of metastasis and in metastasis-associated change among cellular characteristics, which is called epithelial to mesenchymal transition.

"Nearly 200 clinical trials are currently underway investigating the effect of metformin on tumors in both diabetic and non-diabetic patients," said co-senior author Rakesh K. Jain, PhD.

"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."