Inhibition of angiotensin II receptor 1 limits tumor-associated angiogenesis and attenuates growth of murine melanoma
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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).
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.
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.
KeywordsMelanoma Angiogenesis AT1 receptors Angiotensin II Losartan
This work was supported by Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, Grants 1998/14247-6, 2006/60200-0) and Conselho Nacional de Desenvolvimento Científico and Ministério da Saúde/DECIT(CNPq, Grants CNPq/DECIT 401030/05-9, 152083/06-5). We thank Prof. A. Colquhoun, Instituto de Ciências Biomédicas da Universidade de São Paulo for providing us both anti-VEGFR1 and anti-VEGFR2 antibodies.
Conflict of interest statement
The authors declare no conflict of interest.
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