Inhibition of angiotensin II receptor 1 limits tumor-associated angiogenesis and attenuates growth of murine melanoma |
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Authors: | Andréia Hanada Otake Ana Lucia Mattar Helano Carioca Freitas Camila Maria Longo Machado Suely Nonogaki Clarice Kazue Fujihara Roberto Zatz Roger Chammas |
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Affiliation: | 1. Laboratório de Oncologia Experimental (LIM-24), Departamento de Radiologia e Instituto do Cancer do Estado de S?o Paulo, Faculdade de Medicina da Universidade de S?o Paulo, Av. Dr. Arnaldo, 455 room 4112/4122, S?o Paulo, SP, 01246-903, Brazil 2. Laboratório de Fisiopatologia Renal (LIM-16), Departamento de Clínica Médica da Faculdade de Medicina da Universidade de S?o Paulo, S?o Paulo, Brazil 3. Instituto Adolfo Lutz, S?o Paulo, Brazil
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Abstract: | Purpose 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. |
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