Pancreatic cancer linked to obesity may be fueled by stress granules

WASHINGTON: Because it causes an ongoing inflammatory condition, obesity is known to increase the chance of developing at least 13 different forms of cancer. One scientist has questioned whether there is more to the story than simply inflammation for years.

According to recent research from the lab of Dr Elda Grabocka, obesity may play a new role in the development of pancreatic cancer, which has an 11% five-year survival rate for most patients. In a study that was published in Cancer Discovery, the researchers discovered that stress granules are much more common in patients with pancreatic cancer related to obesity than they are in non-obese patients.

More importantly, they discovered that blocking the formation of these granules stopped cancer growth in animals. The study suggests a fresh approach to creating cancer treatments.

"Stress granule research is exploding right now, but there's still a lot we don't know regarding what they're made of and how they work," says Dr Grabocka, who is a researcher with the Sidney Kimmel Cancer Center - Jefferson Health and an assistant professor at Thomas Jefferson University. "This work is the first to show that an overload of stress granules enables tumour growth in the pancreas. Our experiments in mice also showed a complete reversal of cancer growth in the lab."

A unique type of cellular compartment is the stress granule. In response to stress and to prevent self-destruction brought on by stress, the cell produces these non-membrane organelles. The animal and plant kingdoms both have this cellular reaction and defence mechanism. To safeguard their cells, even tomato plants release stress granules.

These organelles' composition and precise mechanism of protection for the cell are yet unknown to researchers. But it's obvious that malignancies have appropriated this defence mechanism for their own purposes. In order to prevent the cancer cells from starting a natural self-destruction sequence, many malignancies manufacture significantly more stress granules than normal cells do.

In light of this, Dr Grabocka's group developed a mouse model of cancer that prevented the development of stress granules in animals with pancreatic cancer. In mice, pancreatic cancer growth was reduced by 50% when the genes controlling the production of stress granules were knocked down.

Obesity affects two-thirds of all individuals in the US and 50% of people worldwide, according to Dr Grabocka. "Now, we had two methods to address the question regarding obesity." Additionally, it raises the risk for other malignancies and doubles the mortality rate for pancreatic cancer. Obesity is linked to pancreatic cancer in about 33% of cases, a percentage that is only anticipated to rise over the next few decades.

Researchers examined pancreatic cancer in two types of obese mouse models: one that was genetically inclined to overeat and the other that was fed a high-fat diet. Both animals' tumours contained five to eight times more stress granules than those of non-obese mice. This gave us the idea that the formation of malignancies in obese mice might be dependent on stress granules. A cancer is killed when the source of its survival is removed.

Dr Grabocka reports that the effects of blocking stress granule development in these obese mice with pancreatic cancer were extremely unexpected. In obese mice with intact stress granules in the tumours, "we either saw no cancer growth or between 1/14 and 1/20 the amount of growth we'd see."

The biggest distinction was their overall rate of survival. In these pancreatic cancer models, mice often pass away after 50-60 days. After 300 days, 40% of obese mice with blocked tumour stress granules were cancer-free, showing no evidence of the disease elsewhere in their bodies. According to Dr Grabocka, "This amount of response is exceptionally rare."

These studies demonstrated that stress granules were not only present in cancer cells but were also responsible for cancer's initial growth. According to Dr Grabocka, this is the first concrete proof that stress granules contribute to the development of cancer.

Importantly, Dr Grabocka's lab also discovered pharmacological targets that could prevent stress granule production in pancreatic cancer caused by obesity. Testing currently available small-molecule inhibitors to see if they can be applied to humans is the next step.

Dr Grabocka claims that cellular stress conditions like obesity increase the number of stress granules present in cells and may be the cause of pancreatic and other cancers. "We believe that targeting the development of stress granules could make for a strong candidate for novel cancer therapy because of the significant effect we observe. Our research lays the door for a human clinical study.