Hepatic stellate cells accelerate the malignant behavior of cholangiocarcinoma cells.
Although tumor-stromal interaction has been discussed, the role of hepatic stellate (HS) cells against cancer, especially cholangiocarcinoma (CC), has not been clarified. The aim of this study is to investigate the effect of HS cells on CC cell progression in vitro and in vivo.



The effects of CC conditioned medium (CC-CM) on activation and proliferation of HS cells (LI90 and LX-2), the influences of HS cell CM (HS-CM) on proliferation and invasion of CC cells (HuCCT-1 and RBE), and the effects of their interaction on HUVEC tube formation were assessed using each CM. The effect of HS cells on tumor growth was examined in vivo by subcutaneous co-injection. Cytokine array was performed to assess the secreted proteins induced by their coculture.



CC-CM activated HS cells and increased their proliferation. HS-CM dose-dependently increased CC cell proliferation and invasion. Chemotherapy of CC cells was less effective when treated with HS-CM. HS-CM activated the mitogen-activated protein kinase and Akt pathways in tumor cells. The indirect interaction of CC and HS cells promotes tube formation of human umbilical venous endothelial cells. Subcutaneous co-injection of tumor cells with HS cells in nude mouse resulted in increased tumor size. Several proteins were found in the culture medium induced by their coculture, thought to be key proteins which regulated tumor-stromal interaction.



This study indicates that HS cells play an important role in accelerating cholangiocarcinoma progression and may be a therapeutic target in cholangiocarcinoma.
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Hirohisa
H
Okabe
Toru
T
Beppu
Hiromitsu
H
Hayashi
Takatoshi
T
Ishiko
Toshiro
T
Masuda
Ryu
R
Otao
Hasita
H
Horlad
Hirohumi
H
Jono
Mitsuharu
M
Ueda
Satoru
S
Shinriki
Yukio
Y
Ando
Hideo
H
Baba
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D016207:Cytokines; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases