Inhibition of angiotensin II receptor 1 limits tumor-associated angiogenesis and attenuates growth of murine melanoma.
OBJECTIVE
We evaluated the involvement of angiotensin II (AngII)-dependent pathways in melanoma growth, through the pharmacological blockage of AT1 receptor by the anti-hypertensive drug losartan (LOS).


RESULTS
We showed immunolabeling for both AngII and the AT1 receptor within the human melanoma microenvironment. Like human melanomas, we showed that murine melanomas also express the AT1 receptor. Growth of murine melanoma, both locally and at distant sites, was limited in mice treated with LOS. The reduction in tumor growth was accompanied by a twofold decrease in tumor-associated microvessel density and by a decrease in CD31 mRNA levels. While no differences were found in the VEGF expression levels in tumors from treated animals, reduction in the expression of the VEGFR1 (Flt-1) at the mRNA and protein levels was observed. We also showed downregulation of mRNA levels of both Flt-4 and its ligand, VEGF-C.


CONCLUSIONS
Together, these results show that blockage of AT1 receptor signaling may be a promising anti-tumor strategy, interfering with angiogenesis by decreasing the expression of angiogenic factor receptors.
Otake
Andréia Hanada
AH
Laboratório de Oncologia Experimental (LIM-24), Departamento de Radiologia e Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av Dr Arnaldo, 455 room 4112/4122, São Paulo, Brazil.
Mattar
Ana Lucia
AL
Freitas
Helano Carioca
HC
Machado
Camila Maria Longo
CM
Nonogaki
Suely
S
Fujihara
Clarice Kazue
CK
Zatz
Roberto
R
Chammas
Roger
R
D042501:Angiogenic Proteins / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
D042501:Angiogenic Proteins; D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan