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

Abstract

BackgroundPancreatic 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 AT2 receptor-deficient (AT2-KO) mice.MethodsThe role of AT2 receptor-signaling in stromal cells on the growth of murine pancreatic carcinoma cells (PAN02) was studied using various in vitro and in vivo assays. In vivo 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 p < 0.05.ResultsOur 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. In vitro co-culture studies revealed that the growth of PAN02 cells was significantly decreased when grown with AT2 receptor 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.ConclusionsThese results suggest that Ang II regulates the growth of pancreatic carcinoma cells through modulating functions of host stromal cells; Moreover, Ang II AT2 receptor signaling is a negative regulator in the growth of pancreatic carcinoma cells. These findings indicate that the AT2 receptor in stromal fibroblasts is a potentially important target for chemotherapy for pancreatic cancer.

Involvement of angiotensin II type 2 receptor (AT2R) signaling in human pancreatic ductal adenocarcinoma (PDAC): a novel AT2R agonist effectively attenuates growth of PDAC grafts in mice

“…Recent studies suggest that AT2R over-expression alone also exerts biological functions such as apoptosis 29,30 by receptor dimerization without ligand binding. 46 The present study also exhibited such results in cell cultures (Figs.…”

“…These results are consistent with previous reports that stimulation of AT2R induces apoptosis in various types of cells. 11,12,29,30 Accordingly, specific agonist-induced AT2R stimulation is a potential treatment scheme for AT2R expressing PDAC. Since AT2R expression in PDAC cells has been confirmed in the human PDAC specimens by this study and other studies, 41 the AT2R agonist therapy may be applicable to human patients.…”

“…28 On the contrary, over-expression of AT2R is shown to induce apoptosis in various cancer cells but not normal epithelial cells. 29,30 Our recent study demonstrated that the growth of PAN02 mouse PDAC grafts was significantly faster in AT2R knockout syngeneic mice. 30 This implies that the endogenously expressed AT2R plays a role in the attenuation of pancreatic cancer growth.…”

“…29,30 Our recent study demonstrated that the growth of PAN02 mouse PDAC grafts was significantly faster in AT2R knockout syngeneic mice. 30 This implies that the endogenously expressed AT2R plays a role in the attenuation of pancreatic cancer growth. These findings led to the hypotheses that the stimulation of AT2R in cancer cells induces death in cancer cells, thereby controlling tumor growth.…”

Wharton's Jelly Stem Cells as Agents for Cancer Therapy

“…In this culture system, the two cell types were divided by a porous membrane with 0.4 µm pores and were devoid of direct contact. The comparison of gene expression profiles between untreated and co-cultured rat UCMSC identified five up-regulated genes (follistatin (FST), sulfatase1 (SULF-1), glucose phosphate isomerase (GPI), HtrA serine peptidase (HTRA1), and adipocyte differentiation-related protein (ADRP)) and two down-regulated genes (transforming growth factor, beta-induced, 68kDa (TGFBI) and podoplanin (PDPN)) [51].…”