Extracellular matrix composition and integrin expression in early hepatocarcinogenesis in human cirrhotic liver

Extracellular matrix (ECM) plays a major role in cell differentiation, proliferation, and gene expression, both in physiological and in pathological conditions. Immunohistochemistry has been used to investigate modifications of ECM and related receptors, the integrins, in 26 small nodular lesions developed in human cirrhotic livers, on the basis that these lesions could represent sequential steps of hepatocarcinogenesis: the lesions were 16 macroregenerative nodules (MRNs), either of ordinary (n = 5) or atypical (n = 11) type, and ten small (< 15 mm) hepatocellular carcinomas (HCCs). Data were compared with those obtained in the surrounding cirrhotic tissue, in large HCCs, and in normal liver. The results indicate similarities between ordinary MRNs and cirrhosis, on the one hand, and between atypical MRNs and small HCCs, on the other. Strong and homogeneous deposition of collagen type IV and laminin in sinusoids and overexpression of alpha 6 integrin by sinusoidal cells and hepatocytes were especially noticeable in dysplastic areas characteristic of atypical MRNs, as in small HCCs. In addition, the staining of alpha 2 and alpha 6 integrins in MRNs revealed the presence of widespread atypical ductular proliferation expanding from periportal and perinodular areas, containing epithelial cells with transitional (hepato-biliary) phenotype. These findings suggest a transition from atypical MRNs to small HCCs and a possible role for liver epithelial precursor cells ('stem cells') in the development and evolution of MRNs.