Despite significant expression level in
cancer cells, the role of the
angiotensin II Type 2 receptor (AT2R) in
cancer progression remains poorly understood. We aimed to investigate the involvement of AT2R in
tumorigenesis, hypothesizing a role in
tumor cell proliferation and/or
tumor angiogenesis. Two animal
tumor models were used:
fibrosarcoma induced by
3-methylcholanthrene (3-MCA) in FVB/N mice invalidated for AT2R (AT2R-KO) and
carcinoma LL/2 cells injected in C57BL/6N mice treated with AT2R antagonist PD123,319.
Tumor growth was monitored, microvascular density (MVD) evaluated by CD31 staining. Proliferation index of LL/2 and
3-MCA tumor cells was evaluated by expression of Ki-67. Angiogenesis was assessed by aorta ring assay and angiogenic mediators' expression by real-time RT-PCR.
Tumor induction by
3-MCA was significantly delayed in AT2R-KO compared to wild-type mice (56 days vs. 28 days).
Tumorigenesis following LL/2 cell injection in mice was also significantly reduced by early administration of the antagonist PD123,319. In vitro, inactivation or invalidation of AT2R inhibited proliferation of LL/2 and
3-MCA tumor cells, respectively.
Tumor MVD was reduced in mice treated early with PD123,319. Ex vivo experiments revealed a significant decrease in angiogenesis after PD123,319 treatment or in AT2R-KO mice. Finally, we identified
vascular endothelial growth factor (
VEGF) as a soluble proangiogenic factor produced by LL/2 cells and we showed that in LL/2 and
3-MCA tumor cells, inhibition or deficiency of AT2R was associated with impaired production of proangiogenic factors included
VEGF. This study uncovered novel mechanisms by which AT2R would promote
tumor development, favoring both malignant cell proliferation and
tumor angiogenesis.