Deficiency or blockade of angiotensin II type 2 receptor delays tumorigenesis by inhibiting malignant cell proliferation and angiogenesis

Abstract

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.

Use of Angiotensin Receptor Blockers and the Risk of Cancer

“…However, type 2 receptor activation would be expected to have antitumor effects, 28 -31 although data are somewhat conflicting. 27,32 Safety studies in animals have also demonstrated the absence of carcinogenicity with high doses of ARBs. [33][34][35][36][37][38][39] Some strengths and limitations of our large nationwide cohort study deserve particular mention.…”

Angiotensin-(1–1) Suppresses Hepatocellular Carcinoma Growth and Angiogenesis via Complex Interactions of Angiotensin II Type 1 Receptor, Angiotensin II Type 2 Receptor and Mas Receptor

“…AT 1 R-mediated proangiogenic effect can be triggered by HIF-1α (57). Deficiency or blockade of AT 2 R-inhibited tumor angiogenesis by impairing VEGF expression in murine fibrosarcoma and Lewis lung carcinoma (58). Whether AT 2 R activation exerts beneficial or detrimental effects on tumor angiogenesis needs further studies.…”

Relationship between drugs affecting the renin-angiotensin system and colorectal cancer: The MCC-Spain study

“…ARBs, in turn, selectively block the angiotensin II type 1 receptors, responsible for vasoconstriction, cell growth, and sympathetic activation and in this way exerts their potential antineoplastic effect, maintaining the beneficial effects of angiotensin II type 2-receptor stimulation (vasodilatory and antiproliferative action mediated via the kinin system) [21,37]. Nevertheless, some studies have suggested a pro-tumoral effect of the ARBs as a result of the stimulation of free angiotensin II type 2-receptor, which results in increased tumor progression [18,43,44].…”