Angiotensin II increase the pulmonary metastasis through the vascular endothelial cell adherent pathway in hematogenous metastasis of melanoma cells

[Speaker] Shin Ishikane:1,2
[Co-author] Hiroshi Hosoda:3, Takashi Nojiri:2, Takeshi Tokudome:2, Tetsuya Mizutani:4, Yumiko Toyohira:1, Mikiya Miyazato:2, Kaoru Miyamoto:4, Kenji Kangawa:5, Fumi Takahashi-Yanaga:1
1:Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Japan, 2:Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Japan, 3:Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, Japan, 4:Department of Biochemistry, Faculty of Medical Sciences, University of Fukui, Japan, 5:National Cerebral and Cardiovascular Center Research Institute, Japan

Background: Angiotensin II (Ang II), a pressor peptide of the renin-angiotensin system, has been reported to accelerate progression and metastasis of cancers. However, its precise mechanisms have not been fully understood. In the present study, we investigated the mechanisms by which Ang II-induced exacerbates of hematogenous metastasis using mouse melanoma cells with special attention to the effect of Ang II on the adhesion pathway in vascular endothelial cells.
Methods: B16/F10 mouse melanoma cells, which do not express the Ang II type1a receptor (AT1R), were intravenously injected into C57BL/6 mice or endothelium-specific AT1R knockout (E-AT1R KO) mice. Ang II (1 μg/kg/min) was continuously administrated subcutaneously for 7 days using an implanted osmotic pump 3 days before cell injection. Valsartan (10, 20, 40 mg/kg/day) and amlodipine (5, 10 mg/kg/day) were administered in drinking water 8 days before cell injection. E-selectin neutralizing antibody (20 mg/kg) was injected at 1 day before, 4 hours before, and 1 day after cell injection. Lung vascular endothelial cells were isolated by magnetic-activated cell sorting, and expression of adhesion molecules were analyzed by polymerase chain reaction.
Results: Two weeks after cell injection, the number of lung metastatic colonies in Ang II-treated group was significantly increased compared with those in vehicle-treated group. Although both Ang II type1 receptor blocker valsartan (40 mg/kg/day) and calcium channel blocker amlodipine (5 or 10 mg/kg/day) successfully decreased blood pressure, only valsartan significantly suppressed the lung metastatic colony formation (Figure 1). In E-AT1R KO mice, Ang II-accerelated lung metastases of melanoma cells were significantly reduced compared with wild-type mice. We also found that Ang II treatment significantly increased E-selectin mRNA expression in pulmonary vascular endothelial cells, thereby promoting adherence of melanoma cells to the vascular endothelium. These Ang II-accerelated lung metastases of melanoma cells was suppressed by the treatment with anti-E-selectin antibody.
Conclusions: Ang II-treatment exacerbated hematogenous cancer metastasis by promoting E-selectin-mediated adhesion of cancer cells to vascular endothelial cells. Our results strongly suggest that drugs that can inhibit Ang II signaling could be useful for preventing metastasis in patients with Ang II-related hypertension.

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