Angiotensin II type 2 receptor signaling significantly attenuates growth of murine pancreatic carcinoma grafts in syngeneic mice

• Main Authors: Troyer Deryl, Isayama Yuka, Pickel Lara, Ayuzawa Rie, Uppalapati Deepthi, Ohta Naomi, Maurya Dharmendra, Kawabata Atsushi, Egashira Noboru, Doi Chiyo, Takekoshi Susumu, Tamura Masaaki
• Format: Article
• Language: English
• Published: BMC 2010-02-01
• Series: BMC Cancer
• Online Access: http://www.biomedcentral.com/1471-2407/10/67

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer is one of the most aggressive human malignancies, with a very poor prognosis. To evaluate the effect of angiotensin II (Ang II) type 2 receptor (AT₂) expression in the host's body on the growth of pancreatic carcinoma, we have investigated the growth of mouse pancreatic ductal carcinoma grafts in syngeneic wild type and AT₂receptor-deficient (AT₂-KO) mice.</p> <p>Methods</p> <p>The role of AT₂receptor-signaling in stromal cells on the growth of murine pancreatic carcinoma cells (PAN02) was studied using various <it>in vitro </it>and <it>in vivo </it>assays. <it>In vivo </it>cell proliferation, apoptosis, and vasculature in tumors were monitored by Ki-67 immunostaining, TUNEL assay, and von Willebrand factor immunostaining, respectively. In the co-culture study, cell proliferation was measured by MTT cell viability assay. All the data were analyzed using t-test and data were treated as significant when <it>p </it>< 0.05.</p> <p>Results</p> <p>Our results show that the growth of subcutaneously transplanted syngeneic xenografts of PAN02 cells, mouse pancreatic ductal carcinoma cells derived from the C57/BL6 strain, was significantly faster in AT₂-KO mice compared to control wild type mice. Immunohistochemical analysis of tumor tissue revealed significantly more Ki-67 positive cells in xenografts grown in AT₂-KO mice than in wild type mice. The index of apoptosis is slightly higher in wild type mice than in AT₂-KO mice as evaluated by TUNEL assay. Tumor vasculature number was significantly higher in AT₂-KO mice than in wild type mice. <it>In vitro </it>co-culture studies revealed that the growth of PAN02 cells was significantly decreased when grown with AT₂receptor gene transfected wild type and AT₂-KO mouse-derived fibroblasts. Faster tumor growth in AT₂-KO mice may be associated with higher VEGF production in stromal cells.</p> <p>Conclusions</p> <p>These results suggest that Ang II regulates the growth of pancreatic carcinoma cells through modulating functions of host stromal cells; Moreover, Ang II AT₂receptor signaling is a negative regulator in the growth of pancreatic carcinoma cells. These findings indicate that the AT₂receptor in stromal fibroblasts is a potentially important target for chemotherapy for pancreatic cancer.</p>