Abstract
Background/Aims: Marked changes in extracellular matrix occur in the stroma of hepatocellular carcinoma,
as compared to normal or cirrhotic liver. The cell types responsible for extracellular
matrix synthesis within hepatocellular carcinoma have not been clearly identified.
Methods:In vivo collagen synthesis was studied by in situ hybridization and immunohistochemistry for types I, IV, V and VI collagen, together
with immunolabeling of alpha-smooth muscle actin, a myofibroblast marker, and CD34,
an endothelial cell marker. In vitro, extracellular matrix deposition by cultured myofibroblasts was studied by reticulin
staining, immunocytochemistry and RNase protection.
Results: All collagens studied were expressed in the stroma of the tumor, with a higher level
of type VI and IV collagens than of type I and V. The majority of the cells expressing
collagen transcripts in human hepatocellular carcinoma stroma were alpha-actin positive
and CD 34 negative. In vitro experiments demonstrated that the hepatocellular carcinoma cell lines HepG2, HuH7
and Hep3B markedly increased extracellular matrix deposition by human liver myofibroblasts.
This increase was mediated by a soluble mediator present in tumor cell conditioned
medium. It was not explained by an increase in mRNA levels of extracellular matrix
components, nor by a decrease in the secretion of matrix-degrading proteinases by
myofibroblasts.
Conclusions: Myofibroblasts are the main source of collagens in the stroma of hepatocellular carcinoma.
Our data also indicate that tumoral hepatocytes increase extracellular matrix deposition
by cultured myofibroblasts, probably by post-transcriptional mechanisms. The generation
of hepatocellular carcinoma stroma by myofibroblasts could thus be under control of
tumoral cells.
Keywords
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Article info
Publication history
Accepted:
July 27,
1998
Received in revised form:
July 13,
1998
Received:
February 19,
1998
Identification
Copyright
© 1999 Published by Elsevier Inc.
