Angiotensin II enhances epithelial-to-mesenchymal transition through             the interaction between activated hepatic stellate cells and the stromal cell-derived             factor-1/CXCR4 axis in intrahepatic cholangiocarcinoma.
We previously reported that hepatic stellate cells (HSCs) activated by angiotensin II (AngII) facilitate stromal fibrosis and tumor progression in intrahepatic cholangiocarcinoma (ICC). AngII has been known as a growth factor which can promote epithelial-to-mesenchymal transition (EMT) in renal epithelial cells, alveolar epithelial cells and peritoneal mesothelial cells. However, in the past, the relationship between AngII and stromal cell-derived factor-1 (SDF-1) in the microenvironment around cancer and the role of AngII on EMT of cancer cells has not been reported in detail. SDF-1 and its specific receptor, CXCR4, are now receiving attention as a mechanism of cell progression and metastasis. In this study, we examined whether activated HSCs promote tumor fibrogenesis, tumor progression and distant metastasis by mediating EMT via the AngII/AngII type 1 receptor (AT-1) and the SDF-1/CXCR4 axis. Two human ICC cell lines and a human HSC line, LI-90, express CXCR4. Significantly higher concentration of SDF-1α was released into the supernatant of LI-90 cells to which AngII had been added. SDF-1α increased the proliferative activity of HSCs and enhanced the activation of HSCs as a growth factor. Furthermore, addition of SDF-1α and AngII enhanced the increase of the migratory capability and vimentin expression, reduced E-cadherin expression, and translocated the expression of β-catenin into the nucleus and cytoplasm in ICC cells. Co-culture with HSCs also enhanced the migratory capability of ICC cells. These findings suggest that SDF-1α, released from activated HSCs and AngII, play important roles in cancer progression, tumor fibrogenesis, and migration in autocrine and paracrine fashion by mediating EMT. Our mechanistic findings may provide pivotal insights into the molecular mechanism of the AngII and SDF-1α-initiated signaling pathway that regulates fibrogenesis in cancerous stroma, tumor progression and meta-stasis of tumor cells expressing AT-1 and CXCR4.
Department of Oncology, Kanazawa University, Kanazawa, Ishikawa, Japan. okamotok@staff.kanazawa-u.ac.jp
Koichi
K
Okamoto
Hidehiro
H
Tajima
Shinichi
S
Nakanuma
Seisho
S
Sakai
Isamu
I
Makino
Jun
J
Kinoshita
Hironori
H
Hayashi
Keishi
K
Nakamura
Katsunobu
K
Oyama
Hisatoshi
H
Nakagawara
Hideto
H
Fujita
Hiroyuki
H
Takamura
Itasu
I
Ninomiya
Hirohisa
H
Kitagawa
Sachio
S
Fushida
Takashi
T
Fujimura
Shinichi
S
Harada
Tomohiko
T
Wakayama
Shoichi
S
Iseki
Tetsuo
T
Ohta
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000804:Angiotensin II / Q000378:metabolism / Q000502:physiology*; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism*; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018920:Coculture Techniques; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D016014:Linear Models; D008875:Middle Aged; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000378:metabolism*
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D000804:Angiotensin II