Angiotensin II promotes pulmonary metastasis of melanoma through the activation of adhesion molecules in vascular endothelial cells

Shin Ishikane, Hiroshi Hosoda, Takashi Nojiri, Takeshi Tokudome, Tetsuya Mizutani, Koichi Miura, Yoshiharu Akitake, Toru Kimura, Yoshitaka Imamichi, Shinya Kawabe, Yumiko Toyohira, Nobuyuki Yanagihara, Fumi Takahashi-Yanaga, Mikiya Miyazato, Kaoru Miyamoto, Kenji Kangawa

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


Hypertension is considered as one of the cancer progressive factors, and often found comorbidity in cancer patients. Renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, and angiotensin II (Ang II) is well known pressor peptide associated with RAS. Ang II has been reported to accelerate progression and metastasis of cancer cells. However, its precise mechanisms have not been fully understood. In this study, we sought to elucidate the mechanisms by which Ang II exacerbates hematogenous metastasis in mouse melanoma cells, focusing the adhesion pathway in vascular endothelial cells. For this purpose, B16/F10 mouse melanoma cells, which do not express the Ang II type 1 receptor (AT1R), were intravenously injected into C57BL/6 mice. Two weeks after cell injection, the number of lung metastatic colonies was significantly higher in the Ang II-treated group (1 μg/kg/min) than in the vehicle-treated group. The AT1R blocker valsartan (40 mg/kg/day), but not the calcium channel blocker amlodipine (5 or 10 mg/kg/day), significantly suppressed the effect of Ang II. In endothelium-specific Agtr1a knockout mice, Ang II-mediated acceleration of lung metastases of melanoma cells was significantly diminished. Ang II treatment significantly increased E-selectin mRNA expression in vascular endothelial cells collected from lung tissues, and thus promoted adherence of melanoma cells to the vascular endothelium. Ang II-accelerated lung metastases of melanoma cells were also suppressed by treatment with anti-E-selectin antibody (20 mg/kg). Taken together, Ang II-treatment exacerbates hematogenous cancer metastasis by promoting E-selectin-mediated adhesion of cancer cells to vascular endothelial cells.

Original languageEnglish
Pages (from-to)136-147
Number of pages12
JournalBiochemical Pharmacology
Publication statusPublished - Aug 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology


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