Angiotensin II induces tumor progression and fibrosis in intrahepatic cholangiocarcinoma through an interaction with hepatic stellate cells

作者：Okamoto Koichi^*; Tajima Hidehiro; Ohta Tetsuo; Nakanuma Shinichi; Hayashi Hironori; Nakagawara Hisatoshi; Onishi Ichiro; Takamura Hiroyuki; Ninomiya Itasu; Kitagawa Hirohisa; Fushida Sachio; Tani Takashi; Fujimura Takashi; Kayahara Masato; Harada Shinichi; Wakayama Tomohiko; Iseki Shoichi

来源：International Journal of Oncology, 2010, 37(5): 1251-1259.

DOI：10.3892/ijo_00000776

• intrahepatic cholangiocarcinoma
• angiotensin II
• angiotensin II type 1 receptor
• hepatic stellate cell
• fibrosis

Intrahepatic cholangiocarcinoma (ICC) is characterized as a highly fatal tumor with poor prognosis because of its strong progression, early invasion, widespread metastasis and rich cancerous stroma. Although it is widely accepted that fibroblasts facilitate stromal fibrosis and tumor progression, the mechanisms of the interaction between cancer cells and activated fibroblasts have not been fully elucidated thus far. In this study, we demonstrate the presence of angiotensin II (AngII) in ICC tissues and explore the interaction between hepatic stellate cells (HSCs) and ICC cells as one of the sources of stromal fibrosis and tumor progression through the interaction of the AngII/AngII type I receptor (AT-1) axis. The concentrations of AngII in ICC tissues were significantly higher than those of HCC and normal liver. Two human ICC cell lines (HuCCT-1, CCKS-1) and a human HSC cell line (LI-90) expressed AT-1 mRNA and protein. The proliferative activity of ICC cells and HSCs to which AngII was added dose-dependently increased and AT-1 antagonist inhibited the proliferative effects. HSCs to which AngII was added showed a higher expression of a-smooth muscle actin (alpha-SMA, a marker of activated HSCs and myofibroblasts), glial fibrillary acidic protein (GFAP, a specific marker of HSCs) and collagen type I than control cells. AT-1 antagonist also inhibited the activation and transformation of HSCs stimulated by MO. These findings suggested that locally formed AngII in ICC tissues plays a role in the proliferation and activation of ICC cells and HSCs expressing AT-1 as a growth factor in autocrine and paracrine fashions. Our mechanistic findings provide the first insight into an autocrine and paracrine AngII-initiated signaling pathway that regulates ICC proliferation and fibrosis.

• 出版日期2010-11