Fibrolamellar variant is an uncommon subcategory of
hepatocellular carcinoma with a better prognostic outcome.
Proteinases and
growth factors that are involved in the remodeling of extracellular matrix may influence the behavior of
cancers. To determine whether these factors contribute to the distinct etiologies of
fibrolamellar hepatocellular carcinoma and traditional
hepatocellular carcinoma, we assayed
hepatocyte growth factor, the
hepatocyte growth factor receptor, and two
hepatocyte growth factor activators,
hepatocyte growth factor activator and
urokinase-type plasminogen activator, in
hepatocellular carcinoma,
fibrolamellar hepatocellular carcinoma, cirrhotic liver and normal liver. In addition, we examined the
urokinase-type plasminogen activator receptor, the
type 1 plasminogen activator inhibitor,
plasmin,
fibrinogen, and the type IV
matrix metalloproteinases. Eighteen
hepatocellular carcinomas and 11 fibrolamellar
hepatocellular carcinomas were obtained as
paraffin embedded sections from the University of Pittsburgh Department of Pathology. Frozen tissues from a subset of cases (9
hepatocellular carcinomas, 4 fibrolamellar
hepatocellular carcinomas, 12 cirrhotic livers and 2 normal livers) were also available for analysis.
Antibodies against
urokinase-type plasminogen activator,
urokinase-type plasminogen activator receptor,
hepatocyte growth factor and
hepatocyte growth factor receptor were used to analyze immunoperoxidase stained slides from the
paraffin blocks. Western blot analyses using
antibodies against
hepatocyte growth factor,
hepatocyte growth factor receptor,
phosphotyrosine,
hepatocyte growth factor activator,
urokinase-type plasminogen activator receptor,
urokinase-type plasminogen activator,
plasminogen activator inhibitor-1,
fibrinogen and
plasmin were performed on membrane-enriched fractions from the frozen tissue, as was
collagen zymography for
matrix metalloproteinase-2 and
matrix metalloproteinase-9. The most notable findings are as follows:
hepatocyte growth factor activator was only detected in malignant tissue but not cirrhotic liver or normal liver. Although
hepatocyte growth factor was detected in most samples, it was significantly elevated in 5/9
hepatocellular carcinomas. Furthermore, 8/9 fibrolamellar
hepatocellular carcinomas demonstrated
hepatocyte growth factor receptor levels similar to normal, whereas 8/9
hepatocellular carcinomas and 11/12 cirrhotic livers exhibited either an increase or decrease. In contrast, active
matrix metalloproteinase-2, which was absent in normal liver, was elevated in
fibrolamellar hepatocellular carcinoma as compared to cirrhotic liver and conventional
hepatocellular carcinoma. Surprisingly, 10/12 cirrhotic livers and 2/4 fibrolamellar
hepatocellular carcinomas but only 1/9
hepatocellular carcinomas were enriched for
plasmin. The combined data suggest that the
hepatocyte growth factor and
plasmin systems tend to be operative in
hepatocellular carcinoma and cirrhotic liver, more than
fibrolamellar hepatocellular carcinoma. Furthermore, matrix turnover appears to be a more prominent feature of
fibrolamellar hepatocellular carcinoma. These findings provide insight into the behavioral differences between
hepatocellular carcinoma and the fibrolamellar variant.