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 path ological conditions. Immunohistochemistry has been used to investigate modifications of ECM and related receptors, the integrins, in 26 smal l nodular lesions developed in human cirrhotic livers, on the basis th at these lesions could represent sequential steps of hepatocarcinogene sis: the lesions mere 16 macroregenerative nodules (MRNs), either of o rdinary (n=5) or atypical (n=11) type, and ten small (<15 mm) hepatoce llular carcinomas (HCCs), Data mere compared with those obtained in th e surrounding cirrhotic tissue, in large HCCs, and in normal liver, Th e results indicate similarities between ordinary MRNs and cirrhosis, o n the one hand, and between atypical MRNs and small HCCs, on the other , Strong and homogenous deposition of collagen type IV and laminin in sinusoids and overexpression of alpha 6 integrin by sinusoidal cells a nd hepatocytes were especially noticeable in dysplastic areas characte ristic of atypical MRN's, as in small HCCs. In addition, the staining of alpha 2 and alpha 6 integrins in MRNs revealed the presence of wide spread atypical ductular proliferation expanding from periportal and p erinodular areas, containing epithelial cells with transitional (hepat o-biliary) phenotype. These findings suggest a transition from atypica l MRNs to small HCCs and a possible role for liver epithelial precurso r cells ('stem cells') in the development and evolution of MRNs. (C) 1 997 by John Wiley and Sons, Ltd.