Researchers revealed the mechanism by which obesity increases inflammation and desmoplasia — an accumulation of connective tissue — in the most frequent type of pancreatic cancer, in mouse models and human tissue samples.1
This study evaluated how obesity influences tumor growth, progression, and treatment response in several animal models of pancreatic ductal adenocarcinoma (PDAC). These findings were confirmed in samples from patients with cancer, explained Dai Fukumura, MD, PhD, Steele Laboratory of Tumor Biology in the Massachusetts General Hospital Department of Radiation Oncology and associate professor of Radiation Oncology at Harvard Medical School, Boston, Massachusetts, and co-senior author of the study.
“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 carcinoma is the fourth leading cause of cancer deaths in the world. More than half of patients with PDAC are overweight or obese, which more than doubles their already high risk of death.
Previous research shows that elevated desmoplasia characterizes PDAC. This desmoplasia promotes the survival and movement of cancer cells and inhibits chemotherapy from entering tumors. Obesity alone contributes to desmoplasia due to the expansion of adipose tissue resulting in inflammation and fibrosis and the inflammatory accumulation of fat in the pancreas.
This study indicated that activation of pancreatic stellate cells through the angiotensin II type-1 receptor (AT1) signaling pathway caused elevated desmoplasia in an obese mouse model of PDAC. Production of interleukin-1 beta (IL-1beta) by fat cells and neutrophils promoted this activation within tumors and in the tumor microenvironment.
The antihypertensive losartan inhibits AT1 signaling, thereby reducing obesity-related desmoplasia and tumor growth. Losartan also increased response to chemotherapy in the obese mouse model but not in normal-weight mice.
Subsequent analysis of tumor samples from patients with PDAC showed increased desmoplasia and fat deposits exclusively in samples from obese patients. Analysis of data from more than 300 patients with PDAC revealed excess body weight was correlated with reduced responses to chemotherapy.
1. Incio J, Liu H, Suboj P, et al. Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. Cancer Discov. 2016 May 31. doi: 10.1158/2159-8290.CD-15-1177. [Epub ahead of print]