Shimizu Yuki, Amano Hideki, Ito Yoshiya, Betto Tomohiro, Yamane Sakiko, Inoue Tomoyoshi, Nishizawa Nobuyuki, Matsui Yoshio, Kamata Mariko, Nakamura Masaki, Kitasato Hidero, Koizumi Wasaburo, Majima Masataka
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan.
Department of Gastroenteology, Kitasato University School of Medicine, Kanagawa, Japan.
Cancer Sci. 2017 Sep;108(9):1757-1768. doi: 10.1111/cas.13306. Epub 2017 Jul 27.
Liver metastases from colorectal cancer (CRC) are a clinically significant problem. The renin-angiotensin system is involved in tumor growth and metastases. This study was designed to evaluate the role of angiotensin II subtype receptor 1a (AT1a) in the formation of liver metastasis in CRC. A model of liver metastasis was developed by intrasplenic injection of mouse colon cancer (CMT-93) into AT1a knockout mice (AT1aKO) and wild-type (C57BL/6) mice (WT). Compared with WT mice, the liver weight and liver metastatic rate were significantly lower in AT1aKO. The mRNA levels of CD31, transforming growth factor- β1 (TGF-β1), and F4/80 were suppressed in AT1aKO compared with WT. Double immunofluorescence analysis showed that the number of accumulated F4/80 cells expressing TGF-β1 in metastatic areas was higher in WT than in AT1aKO. The AT1aKO bone marrow (BM) (AT1aKO-BM)→WT showed suppressed formation of liver metastasis compared with WT-BM→WT. However, the formation of metastasis was further suppressed in WT-BM→AT1aKO compared with AT1aKO-BM→WT. In addition, accumulated F4/80 cells in the liver metastasis were not BM-derived F4/80 cells, but mainly resident hepatic F4/80 cells, and these resident hepatic F4/80 cells were positive for TGF-β1. Angiotensin II enhanced TGF-β1 expression in Kupffer cells. Treatment of WT with clodronate liposomes suppressed liver metastasis by diminishing TGF-β1 F4/80 cells accumulation. The formation of liver metastasis correlated with collagen deposition in the metastatic area, which was dependent on AT1a signaling. These results suggested that resident hepatic macrophages induced liver metastasis formation by induction of TGF-β1 through AT1a signaling.
结直肠癌（CRC）肝转移是一个具有临床意义的问题。肾素-血管紧张素系统参与肿瘤生长和转移。本研究旨在评估血管紧张素II 1a型受体（AT1a）在CRC肝转移形成中的作用。通过将小鼠结肠癌（CMT-93）脾内注射到AT1a基因敲除小鼠（AT1aKO）和野生型（C57BL/6）小鼠（WT）中建立肝转移模型。与WT小鼠相比，AT1aKO小鼠的肝脏重量和肝转移率显著降低。与WT相比，AT1aKO中CD31、转化生长因子-β1（TGF-β1）和F4/80的mRNA水平受到抑制。双重免疫荧光分析显示，WT中转移区域表达TGF-β1的F4/80细胞积累数量高于AT1aKO。与WT骨髓（BM）→WT相比，AT1aKO骨髓（AT1aKO-BM）→WT显示肝转移形成受到抑制。然而，与AT1aKO-BM→WT相比，WT-BM→AT1aKO中转移形成进一步受到抑制。此外，肝转移中积累的F4/80细胞不是BM来源的F4/80细胞，而是主要是驻留肝F4/80细胞，并且这些驻留肝F4/80细胞TGF-β1呈阳性。血管紧张素II增强了枯否细胞中TGF-β1的表达。用氯膦酸盐脂质体处理WT可通过减少TGF-β1 F4/80细胞积累来抑制肝转移。肝转移的形成与转移区域的胶原沉积相关，这依赖于AT1a信号传导。这些结果表明，驻留肝巨噬细胞通过AT1a信号传导诱导TGF-β1从而诱导肝转移形成。
