The angiotensin II type I receptor blocker olmesartan inhibits the growth of pancreatic cancer by targeting stellate cell activities in mice

Abstract

There is accumulating evidence that pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, promote the progression of pancreatic cancer. The interactions between PSCs and pancreatic cancer have attracted substantial attention as a novel therapeutic target for the treatment of pancreatic cancer. We examined here the effects of olmesartan, an angiotensin II type I receptor blocker, on pancreatic cancer-associated fibrosis using a subcutaneous tumor model developed by co-injection of pancreatic cancer cells with PSCs in nude mice. Co-injection of pancreatic cancer cells AsPC-1 with PSCs increased the size of tumors compared with AsPC-1 cells alone. Olmesartan administrated at 10 mg/kg in drinking water inhibited the growth of subcutaneous tumors derived from the co-injection, but not those derived from mono-injection. This effect was accompanied by decreased expression of α-smooth muscle actin (a marker of activated PSCs) and collagen deposition. The inhibitory effect of olmesartan was also observed even if it was administrated after significant development of subcutaneous tumors. In addition, olmesartan decreased cell growth and type I collagen production in PSCs in vitro. These results suggest that olmesartan inhibited the growth of tumors by targeting stellate cell activities, and that olmesartan might be useful as an anti-fibrosis therapy in pancreatic cancer.

Key Words::

• desmoplasia
• myofibroblast
• pancreatic stellate cells
• renin–angiotensin
• stroma

Acknowledgments

The authors are grateful to Ms. Kiiko Ogashiwa for excellent preparation of histological samples. This work was supported in part by Grant-in-Aid from Japan Society for the Promotion of Science (#23591008 to A. Masamune), by the Pancreas Research Foundation of Japan (to A. Masamune and T. Takikawa), by the Kanae Foundation for Life and Socio-Medical Science (to A. Masamune), by the Uehara Memorial Foundation (to A. Masamune), by the Astellas Foundation for Research on Metabolic Disorders (to A. Masamune), and by the Research Committee of Intractable Pancreatic Diseases provided by the Ministry of Health, Labour, and Welfare of Japan.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.