Angiotensin II type 2 receptor (AT2R) stimulation is thought to induce vasodilation and apoptosis. Nevertheless, its role remains controversial. In hypertension and aging, AT2R might promote vasoconstriction and cell growth. In cancer cells, AT2R is highly expressed but its role remains poorly understood. Thus, we investigated the role of AT2R in tumor growth, hypothesizing that AT2R affects cell proliferation and/or tumor vascularization.

Tumor induction by 3-methylcholanthrene was significantly delayed in AT2R knockout mice, suggesting a role for AT2R in tumor initiation.

Tumor growth after subcutaneous injection of LL/2 cancer cells in C57/BL6 mice treated with PD123,319, an AT2R antagonist, was decreased when PD123,319 was given at an early stage, suggesting that AT2R is also involved in tumor promotion. In vitro proliferation of LL/2 cells was reduced by PD123,319 with a significant decrease in Ki67 expression and ERK1/2 phosphorylation. In addition, tumor vascular density, measured by CD31 labeling and angiogenesis using the aortic ring assay on Matrigel®, were reduced by PD123,319 and in AT2R-null mice. Therefore, we uncovered a novel mechanism by which AT2R promotes tumor development favoring both malignant cancer cell proliferation and tumor angiogenesis. Thus, blocking AT2R could be a new approach in tumor therapy.