MGH researchers discover how obesity increases inflammation, desmoplasia in PDAC patients -
Massachusetts General Hospital (MGH) investigators discovered the mechanism by which obesity increases inflammation and desmoplasia - an accumulation of connective tissue - in the most common type of pancreatic cancer. In their report, published online in The discovery of cancer , the researchers describe how interactions between fat cells, immune cells and connective tissue cells in obese people stimulate a micro-environment that promotes the progression of the tumor, while blocking the response to chemotherapy. They also identify a treatment strategy that can inhibit the process.
"We evaluated the effects of obesity on many aspects of tumor growth, progression and treatment response in several animal models of pancreatic ductal adenocarcinoma and confirmed our findings in samples from patients cancer, "says Dai Fukumura, MD, PhD, of the Steele Laboratory biology of the tumor in the MGH department of radiation oncology, co-lead author of the study." Along with the research that obese mouse tumors or patients had high levels of adipocytes or fat cells and desmoplasia, two tumors fuel growth and interfere with treatment response, we also identified the underlying cause. "
Pancreatic adenocarcinoma ductal (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, more obesity than double the already high risk death. Previous research by the MGH team and others have shown that PDAC is characterized by high desmoplasia - a tissue overproduction of extracellular matrix by pancreatic stellate cells - which promotes both survival and cell migration cancer and blocks the penetration of chemotherapeutic drugs in tumors. Obesity itself is known to contribute to desmoplasia, with the expansion of adipose tissue leading to inflammation and fibrosis and fat accumulation in normal pancreas, which also causes inflammation.
The experience of the team found that high desmoplasia in obese mouse models of PDAC was caused by the activation of stellate cells of the pancreas in type 1 antiogensin II receptor (AT1) Track signaling. This activation was favored by the production of interleukin-1 beta (IL-1ß) both by fat cells and immune cells called neutrophils in and around tumors. AT1 inhibit signaling with losartan, which is used clinically to treat hypertension, reduced desmoplasia and tumor growth associated with obesity and increased response to chemotherapy in the obese mouse model, but not in animals of normal weight. Analysis of human PDAC patients tumors revealed deposits of desmoplasia and fat increased only in samples from obese patients, and data from more than 300 patients showed that excess weight was associated with a reduced the response of patients to chemotherapy.
João Incio, MD, PhD, of the Steele Laboratory, lead author of the study, said: "Understanding how obesity affects pancreatic cancer can help us to identify biomarkers - such as body weight and increased fibrosis levels of the tumor - that can identify patients who AT1 blockers or IL-1 antibodies would be more beneficial. Since FDA approved versions of the two agents are readily available, this strategy could be easily translated into the clinic. In addition, the body weight of incorporation in the design of preclinical studies may better reflect the lack of response to conventional chemotherapeutic drugs. "
authorCo-principal Rakesh K. Jain, PhD, director of the Steele Laboratory, added:" With the majority of patients with pancreatic cancer overweight or obese at diagnosis, uncovering potential therapeutic targets in the mechanisms linking obesity with poor cancer prognosis is the first step towards the development of remedies that could disrupt that association and to significantly improve patient outcomes. Targeting inflammation and fibrosis holds the promise of improving clinical outcomes for this large group of cancer patients. "
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