Deficiency or blockade of angiotensin II type 2 receptor delays tumorigenesis by inhibiting malignant cell proliferation and angiogenesis.
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.
Faculté de Médecine, CNRS UMR 6214, INSERM UMR U771, Université d'Angers, Angers, France.
Nicolas
N
Clere
Isabelle
I
Corre
Sébastien
S
Faure
Anne-Laure
AL
Guihot
Emilie
E
Vessières
Marie
M
Chalopin
Alain
A
Morel
Olivier
O
Coqueret
Lutz
L
Hein
Yves
Y
Delneste
François
F
Paris
Daniel
D
Henrion
D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D005260:Female; D005354:Fibrosarcoma / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D007093:Imidazoles / Q000494:pharmacology; D008748:Methylcholanthrene; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D044139:Receptor, Angiotensin, Type 2 / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; C073402:PD 123319; D008748:Methylcholanthrene