Blockade of angiotensin II type 2 receptor delays early tumorigenesis by inhibiting tumor cell proliferation and angiogenesis

Whereas the angiotensin II type 2 receptor (AT2R) is known to oppose the proliferative and growth properties of the type 1 receptor, its role in pathological conditions may be different. Although it is highly expressed in cancer cells, its role in tumor progression remains poorly understood. We aimed to investigate the involvement of the AT2R in early tumorigenesis hypothesizing that it may affect tumor cell proliferation and/or tumor angiogenesis. Tumors were induced with 3-methylcholanthrene (3-MCA, 20 mg/kg, s.c.) in FVB/N mice lacking the AT2R (AT2R-KO) or through LL/2 cells injection in C57/BL6N mice treated with the AT2R antagonist PD123,319. Cell proliferation was evaluated by Ki-67 immunochemistry. Vascular density was determined using CD31 labelling and angiogenesis was measured using the aortic ring assay. Tumor initiation by 3-MCA was significantly delayed in AT2R-KO compared to wild type mice (56 days vs 28 days).Tumorigenesis following LL/2 cells injection in C57BL/6N mice was significantly reduced then the AT2R antagonist PD123,319 was given at an early stage of tumor development, suggesting a role of AT2R in tumor promotion. Moreover, in vitro proliferation of LL/2 cells was reduced by PD123,319 with a significant decrease in Ki-67 expression, a marker of cell proliferation. Tumor microvascular density and angiogenesis were significantly reduced in wild type mice treated with PD123,319 and in AT2R-null mice, compared to control animals. Thus, we showed that the AT2R has a key role in tumor development, favouring both malignant cell proliferation and tumor angiogenesis.