Cellular origins of hepatomas and cell lineage pathways involved in liver cancer will be investigated in chemically-induced hepatocarcinoma rat models considered analogous to the hepatocarcinogenesis process in humans.
The specific aims are to determine whether bile ductule cells and/or hepatocytes contribute to the formation of hepatomas since both cell types proliferate after carcinogen exposure and to delineate the interactions and cellular and subcellular properties of proliferated cells expressed during stages in the development of hepatomas. Bile ductule cells (BD) and hepatocytes from livers of rat hepatoma models (Solt-Farber and Lombardi-Shinozuka) will be analysed for the expression of specific subcellular and macromolecular chemical markers associated with maintenance of cell polarity, development of cell communication and interaction with extracellular matrix. Alterations in the distribution of the following markers will be investigated: 1) cell surface proteins that are restricted to specific domains of the plasma membrane, including the asialoglycoprotein receptor (ASGP), adenosine triphosphatase and dipeptidyl dipeptidase IV; 2) desmosome protein, desmoplakin 1; 3) gap junction proteins, connexins 26, 32 and 43; and 4) extracellular matrix proteins, collagen type IV and laminin. BD cells will also be examined for the acquisition of hepatocyte-specific organelles (e.g. ASGP-positive endocytic vesicles, nucleoid-containing peroxisomes, lipoprotein particles) and hepatocyte-specific functions (e.g. receptor-mediated endocytosis, lipoprotein metabolism). Diverse microscopic methods (light, confocal and electron microscopies in combination with enzyme-, immuno-, cDNA hybridization cytochemistry, freeze fracture and autoradiography) will be employed in these studies. An in situ analysis of livers from rat hepatoma models may reveal new subcellular characteristics of carcinogeninduced proliferated hepatic cells not possible by other methodologies thereby allowing the identification of the origin of preneoplastic cells and the delineation of cell lineage pathways in the progression to liver carcinoma.
