Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Eur J Pharmacol. 2021 Oct 15;909:174415. doi: 10.1016/j.ejphar.2021.174415. Epub 2021 Aug 8.
Angiotensin II (Ang II) reportedly facilitates primary tumor growth and distal hematogenous metastasis formation in various murine intravenous metastasis models. However, it is unclear whether Ang II accelerates the initial processes of metastasis formation that begins in primary tumors surrounded by tumor microenvironment. We examined the effects of Ang II on primary tumors and lung metastasis lesions using a murine spontaneous metastasis model, in which triple negative breast cancer 4T1 cells constitutively expressing luciferase (4T1-Luc cells) were injected into the mammary fat pad of BALB/c mice. Subcutaneous injection of Ang II significantly accelerated primary tumor growth and lung metastasis formation. Ang II increased the protein expression levels of c-Myc, cyclin D1, fibronectin, vimentin, αSMA and Snail, and the treatment with the Ang II type 1 receptor blocker valsartan significantly suppressed the Ang II-induced increases of fibronectin and vimentin. Valsartan also significantly reduced lung metastatic lesions. However, Ang II did not have significant effects on 4T1-Luc cells including the proliferation, migration, invasion, or the expressions of proteins related to cell proliferation and epithelial-to-mesenchymal transition. In contrast, when 4T1-Luc cells were co-cultured with dermal fibroblasts, Ang II significantly accelerated cell migration and increased the expressions of fibronectin, vimentin, αSMA and Snail in 4T1-Luc cells. And moreover, Ang II significantly increased the mRNA expression of IL-6 in fibroblasts co-cultured with 4T1-Luc cells. These results suggested that Ang II accelerates surrounding fibroblasts by soluble factors such as IL-6 to promote epithelial-to-mesenchymal transition, which result in the initiation of cancer metastasis.
血管紧张素 II（Ang II）据报道可促进各种小鼠静脉转移模型中的原发性肿瘤生长和远处血源性转移形成。然而，尚不清楚 Ang II 是否会加速开始于肿瘤微环境周围原发性肿瘤的转移形成的初始过程。我们使用小鼠自发转移模型检查了 Ang II 对原发性肿瘤和肺转移灶的影响，其中三阴性乳腺癌 4T1 细胞持续表达荧光素酶（4T1-Luc 细胞）被注射到 BALB/c 小鼠的乳腺脂肪垫中。Ang II 的皮下注射显著加速了原发性肿瘤的生长和肺转移的形成。Ang II 增加了 c-Myc、细胞周期蛋白 D1、纤维连接蛋白、波形蛋白、αSMA 和 Snail 的蛋白表达水平，并且用 Ang II 型 1 受体阻滞剂缬沙坦治疗可显著抑制 Ang II 诱导的纤维连接蛋白和波形蛋白的增加。缬沙坦也显著减少了肺转移灶。然而，Ang II 对 4T1-Luc 细胞没有显著影响，包括增殖、迁移、侵袭，或与细胞增殖和上皮间质转化相关的蛋白表达。相比之下，当 4T1-Luc 细胞与真皮成纤维细胞共培养时，Ang II 显著加速了细胞迁移，并增加了 4T1-Luc 细胞中纤维连接蛋白、波形蛋白、αSMA 和 Snail 的表达。此外，Ang II 显著增加了与 4T1-Luc 细胞共培养的成纤维细胞中 IL-6 的 mRNA 表达。这些结果表明，Ang II 通过可溶性因子（如 IL-6）加速周围成纤维细胞，促进上皮间质转化，从而启动癌症转移。
