Pancreatic cancer: Study yields insight into effect of obesity

A new study reveals how obesity appears to promote a microenvironment that favors tumor progression while blocking the effects of chemotherapy in patients with the most common form of pancreatic cancer.

man pinching fat around waist
The researchers discovered a mechanism through which obesity might promote tumor growth and disrupt chemotherapy in patients with the most common form of pancreatic cancer.

The study, by researchers at Massachusetts General Hospital, Harvard Medical School, Boston, is published in the journal Cancer Discovery.

Pancreatic cancer begins when cells in the pancreas – an organ located behind the stomach – start to grow uncontrollably.

There are different types of pancreatic cancer. The main difference depends on whether the cancer arises in exocrine cells or endocrine cells.

Exocrine cells account for most of the cells in the pancreas. They form glands that make enzymes that are released via ducts into the intestines to help digest food – especially fats. The vast majority of pancreatic cancers arise from these cells.

Endocrine cells make up a much smaller proportion of the cells in the pancreas. They occur in small clusters called islets (the islets of Langerhans) and produce hormones – like insulin and glucagon that help control blood sugar.

Exocrine tumors account for the vast majority of pancreatic cancers, and of these, pancreatic ductal adenocarcinoma (PDAC) is by far the most common and is the one investigated in the study.

The authors note that PDAC is the fourth leading cause of cancer death worldwide, and more than half of patients diagnosed with PDAC are overweight or obese – a condition that more than doubles the already high risk of death.

Obesity increases inflammation and desmoplasia

The team already knew from previous research that an overproduction of extracellular matrix tissue – molecular structures that help hold cells in place – is a feature of PDAC.

Elevated “desmoplasia” – as the condition is known – both promotes the survival and migration of cancer cells, and prevents chemotherapy drugs entering the tumor.

Obesity is also known to promote desmoplasia – the expansion of fat tissue leads to inflammation and fibrosis. The extra fat can also accumulate in the normal pancreas and cause inflammation.

In the new study, the MGH team discovered the mechanism by which obesity increases inflammation and desmoplasia.

Their paper describes how interactions among fat cells, immune cells, and connective tissue cells in obese patients encourages a tumor microenvironment that makes it easier for the tumor cells to grow, while at the same time blocking the response to chemotherapy.

The researchers also report how they identified a treatment that might block the mechanism, as co-senior author Dai Fukumura, associate professor of radiation oncology at Harvard Medical School, explains:

“We evaluated the effects of obesity on numerous aspects of tumor growth, progression and treatment response in several animal models of pancreatic ductal adenocarcinoma and confirmed our findings in samples from cancer patients.”

He and his colleagues found that tumors from obese PDAC mice and tumor tissue from patients showed high levels of fat cells and desmoplasia.

AT1 blockers and IL-1β antibodies could be effective

Experiments revealed that the high level of desmoplasia in obese mice with PDAC was the result of activation of pancreatic cells called stellate cells. The activation occurred via the antiogensin II type-1 receptor (AT1) signaling pathway.

Production of the protein interleukin-1 beta (IL-1β) – both by fat cells and by immune cells called neutrophils within and around the tumors – was the trigger.

In further experiments, the team found they could inhibit the AT1 pathway with a blood pressure drug called losartan. This had the effect of reducing obesity-linked desmoplasia and tumor growth, and it also increased response to chemotherapy in the obese PDAC mice – although it had no effect on normal weight animals.

When they analyzed tumor tissue from human PDAC patients, the team found increased desmoplasia and fat deposits only in samples from obese patients. They note that evidence from over 300 PDAC patients also shows being overweight is linked to reduction in chemotherapy response.

The team believes it may be possible, from these discoveries, to find biomarkers that can identify PDAC patients for whom AT1 blockers or IL-1β antibodies could be effective.

Approved versions of both of these agents are already available, so it should not be difficult to make such treatments ready for clinical use.

“With the majority of pancreatic cancer patients being overweight or obese at diagnosis, uncovering potential therapeutic targets within the mechanisms associating obesity with poor cancer prognoses is the first step towards developing remedies that could disrupt this association and significantly improve patient outcome.

Targeting inflammation and fibrosis holds the promise to improve the clinical outcome of this major group of cancer patients.”

Co-senior author Professor Rakesh K. Jain

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