High metalloproteinase inhibitor content of human cirrhosis and its possible conference of metastasis resistance.

Human cirrhotic livers exhibited a strong resistance to metastasis and demonstrated high levels of both soluble and 3 M NaCl extractable metalloproteinase inhibitor(s) directed against tumor type I and type IV collagenases. This inhibitory activity was detected in human cirrhosis from diverse causes, including alpha-1-antitrypsin deficiency, alcoholic liver disease, postviral hepatitis, and biliary cirrhosis, but was nearly undetectable in normal liver. The inhibitory activity was able to be purified by carboxymethyl cellulose chromatography and gel filtration, had a molecular weight of approximately 40,000, and was relatively heat stable. Such metalloproteinase inhibitory activity was also present in conditioned media of human myofibroblast primary cultures obtained from cirrhotic liver explants but absent in conditioned media of primary normal liver explants. Purified fractions of the metalloproteinase inhibitor activity obtained from both myofibroblast conditioned media and extracts of cirrhotic liver blocked invasion but not attachment of MCF-7 cells on human amnion in vitro. The results further support the role of myofibroblasts in inhibiting tumor invasion and metastasis and provide one possible mechanism by which cirrhotic livers resist metastasis.