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Obesity and pancreatic cancer

Obesity blocks treatment of pancreatic cancer

Axial CT image with i.v. contrast. Macrocystic adenocarcinoma of the pancreatic head (Credit: MBq at German Wikipedia)
Blocking signalling pathways that promote fibrosis in tumour microenvironment may be effective in obese patients

Massachusetts General Hospital (MGH) investigators have discovered the mechanism by which obesity increases inflammation and desmoplasia, an accumulation of connective tissue, in the most common form of pancreatic cancer. In their report published in Cancer Discovery the researchers describe how interactions among fat cells, immune cells and connective tissue cells in obese individuals stimulate a microenvironment that promotes tumour progression, while blocking the response to chemotherapy. They also identify a treatment strategy that may inhibit the process.

"We evaluated the effects of obesity on numerous aspects of tumour growth, progression and treatment response in several animal models of pancreatic ductal adenocarcinoma and confirmed our findings in samples from cancer patients," says Dr Dai Fukumura of the Steele Laboratory of Tumor Biology in the MGH Department of Radiation Oncology, the study's co-senior author. "Along with finding that tumours from obese mice or patients exhibited elevated levels of adipocytes or fat cells and of desmoplasia, both of which fuel tumor progression and interfere with treatment response, we also identified the underlying cause."

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death worldwide, and more than half of patients diagnosed with PDAC are overweight or obese. Among patients with PDAC, obesity more than doubles the already high risk of death. Previous research by the MGH team and others has shown that PDAC is characterized by elevated desmoplasia, with an overproduction of extracellular matrix tissue by pancreatic stellate cells, which both promotes the survival and migration of cancer cells and blocks the penetration of chemotherapy drugs into tumours. Obesity itself is known to contribute to desmoplasia, with the expansion of fat tissue leading to inflammation and fibrosis and an accumulation of fat within the normal pancreas, which also causes inflammation.

In the study, Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy’, the team revealed that the elevated desmoplasia in obese mouse models of PDAC was caused by activation of pancreatic stellate cells through the antiogensin II type-1 receptor (AT1) signalling pathway. This activation was promoted by production of interleukin-1 beta (IL-1ß) both by fat cells and by the immune cells called neutrophils within and around tumours. Inhibiting AT1 signalling with losartan, which is used clinically to treat hypertension, reduced obesity-associated desmoplasia and tumour growth and increased the response to chemotherapy in the obese mouse model but not in normal weight animals.

"Understanding the way that obesity affects pancreatic cancer may help us identify biomarkers, such as body weight and increased levels of tumour fibrosis, that could identify patients for whom AT1 blockers or IL-1ß antibodies would be most beneficial,” said Dr João Incio of the Steele lab and lead author of the study. “Since FDA-approved versions of both agents are readily available, this strategy could be readily translated into the clinic. In addition, incorporating body weight into the design of preclinical studies could better account for the lack of response to conventional chemotherapeutical drugs."

Analysis of tumours from human PDAC patients revealed increased desmoplasia and fat deposits only in samples from obese patients, and data from more than 300 patients showed that excess weight was associated with a reduction in patients' response to chemotherapy.

"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,” added co-senior author, Dr Rakesh K Jain, director of the Steele Laboratory. “Targeting inflammation and fibrosis holds the promise to improve the clinical outcome of this major group of cancer patients."

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