title: Angiotensin II induces tumor progression and fibrosis in intrahepatic cholangiocarcinoma through an interaction with hepatic stellate cells.
abstract: 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 1 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 α-smooth muscle actin (α-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 AngII. 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.
authors.affiliation: Gastroenterologic Surgery, Department of Oncology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan. kookka5151@gmail.com
authors.forename: Koichi
authors.initials: K
authors.lastname: Okamoto
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Tajima
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohta
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nakanuma
authors.forename: Hironori
authors.initials: H
authors.lastname: Hayashi
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Nakagawara
authors.forename: Ichiro
authors.initials: I
authors.lastname: Onishi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamura
authors.forename: Itasu
authors.initials: I
authors.lastname: Ninomiya
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Sachio
authors.initials: S
authors.lastname: Fushida
authors.forename: Takashi
authors.initials: T
authors.lastname: Tani
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujimura
authors.forename: Masato
authors.initials: M
authors.lastname: Kayahara
authors.forename: Shinichi
authors.initials: S
authors.lastname: Harada
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Wakayama
authors.forename: Shoichi
authors.initials: S
authors.lastname: Iseki
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005355:Fibrosis; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C544065:AGTR1 protein, human; D005904:Glial Fibrillary Acidic Protein; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II