Hepatic stellate cells may relate to progression of intrahepatic cholangiocarcinoma.
BACKGROUND
Although cumulative evidence supports the fact that stromal myofibroblasts promote tumor progression, the influence of myofibroblasts on intrahepatic cholangiocarcinoma (ICC) is unclear. We hypothesized that hepatic stellate (HS) cells can differentiate into myofibroblasts in ICC stroma and that they promote cancer progression. This study aims to: (1) assess the influence of myofibroblasts on the prognosis of ICC, (2) identify HS cells in ICC stroma, and (3) investigate the interaction between HS cells (LI90 and LX-2) and ICC cells (HuCCT-1 and MEC) in vitro.


METHODS
The association between alpha-smooth muscle actin (alpha-SMA) expression and the prognoses of 46 ICC patients after hepatic resection was evaluated by immunohistochemical analysis. The HS cells in myofibroblasts of ICC were identified (double immunostaining) using antibodies for alpha-SMA, glial fibrillary acidic protein (GFAP), and desmin. The influence of HS cells on the invasion and growth of ICC cells was examined in vitro using a coculture system.


RESULTS
Patients with high alpha-SMA expression exhibited the worse outcomes. Multivariate analyses revealed that high alpha-SMA expression (P = 0.0045) and positivity for lymph-node metastasis were independent prognostic factors. Because desmin- or GFAP-positive cells coexpressing alpha-SMA were observed in the ICC samples, they were considered to be derived from the HS cells. On coculturing with HS cells, a remarkable increase was observed in the invasion and growth of the two ICC cell lines.


CONCLUSIONS
Stromal myofibroblasts may relate to the poor prognoses in ICC patients. HS cells appear to be involved in the progression of ICC.
Okabe
Hirohisa
H
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Beppu
Toru
T
Hayashi
Hiromitsu
H
Horino
Kei
K
Masuda
Toshiro
T
Komori
Hiroyuki
H
Ishikawa
Shinji
S
Watanabe
Masayuki
M
Takamori
Hiroshi
H
Iyama
Ken-ichi
K
Baba
Hideo
H
D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D003893:Desmin / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008103:Liver Cirrhosis / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D017154:Stromal Cells / Q000378:metabolism; D015996:Survival Rate
C541116:ACTA2 protein, human; D000199:Actins; D014408:Biomarkers, Tumor; D003893:Desmin; D005904:Glial Fibrillary Acidic Protein