血管紧张素 II 受体 1 抑制剂限制肿瘤相关血管生成并减弱小鼠黑色素瘤的生长。

Inhibition of angiotensin II receptor 1 limits tumor-associated angiogenesis and attenuates growth of murine melanoma.

机构信息

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.

出版信息

Cancer Chemother Pharmacol. 2010 May;66(1):79-87. doi: 10.1007/s00280-009-1136-0. Epub 2009 Sep 22.

DOI:10.1007/s00280-009-1136-0

PMID:19771429

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.

摘要

目的

我们通过抗高血压药物氯沙坦（LOS）对 AT1 受体的药理学阻断来评估血管紧张素 II（AngII）依赖性途径在黑色素瘤生长中的作用。

结果

我们在人类黑色素瘤微环境中显示了 AngII 和 AT1 受体的免疫标记。与人类黑色素瘤一样，我们还表明，鼠黑色素瘤也表达 AT1 受体。用 LOS 治疗的小鼠中，局部和远处部位的鼠黑色素瘤生长受到限制。肿瘤生长的减少伴随着肿瘤相关微血管密度的两倍降低和 CD31 mRNA 水平的降低。虽然在治疗动物的肿瘤中未发现 VEGF 表达水平存在差异，但在 mRNA 和蛋白质水平上观察到 VEGFR1（Flt-1）表达的减少。我们还观察到 Flt-4 及其配体 VEGF-C 的 mRNA 水平下调。