July 6, 2016
Blocking signaling pathways that promote fibrosis in tumor 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 its report published online 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 tumor 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 tumor growth, progression and treatment response in several animal models of pancreatic ductal adenocarcinoma and confirmed our findings in samples from cancer patients,” says Dai Fukumura, MD, PhD, of the Steele Laboratory of Tumor Biology in th MGH Department of Radiation Oncology, the study’s co-senior author. “Along with finding that tumors 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. 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. Obesity, unhealthy diet, and a sedentary lifestyle also cause higher risk of Type 2 Diabetes which is also a major risk factor of getting pancreatic cancer.
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 tumors. 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.
The team’s experiments 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) signaling 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 tumors. Inhibiting AT1 signaling with losartan, which is used clinically to treat hypertension, reduced obesity-associated desmoplasia and tumor growth and increased the response to chemotherapy in the obese mouse model but not in normal weight animals. Analysis of tumors 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.
João Incio, MD, PhD, of the Steele lab, lead author of the study, says, “Understanding the way that obesity affects pancreatic cancer may help us identify biomarkers – such as body weight and increased levels of tumor fibrosis – that could identify patients for whom AT1 blockers or IL-1ß antibodies would be most beneficial. 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.”
Co-senior author Rakesh K. Jain, PhD, director of the Steele Laboratory, adds, “With the majority of pancreaticcancer 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.”
Fukumura is an associate professor of Radiation Oncology, and Jain is the Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School. Jain is among three recipients of the 2013 National Medal of Science, which was awarded in May 2016. This year Incio received the prestigious American Association of Cancer Research Scholar-in-Training award, the European Association for Cancer Research meeting award and a poster of distinction award at the annual MGH Celebration of Science for his work on obesity and cancer in the Steele Laboratories. Additional co-authors of the Cancer Discovery paper include Hao Liu, MD, Priya Suboj, PhD, Yves Boucher, PhD, Shan Chin, MSc, and other members of the Steele Laboratories. The study also involved collaboration with researchers in the MGH Departments of Pathology, Medicine and Surgery.