title: The growth pattern of transplanted normal and nodular hepatocytes.
abstract: Overt neoplasia is often the end result of a long biological process beginning with the appearance of focal lesions of altered tissue morphology. While the putative clonal nature of focal lesions has often been emphasized, increasing attention is being devoted to the possible role of an altered growth pattern in the evolution of carcinogenesis. Here we compare the growth patterns of normal and nodular hepatocytes in a transplantation system that allows their selective clonal proliferation in vivo. Rats were pre-treated with retrorsine, which blocks the growth of resident hepatocytes, and were then transplanted with hepatocytes isolated from either normal liver or hepatocyte nodules. Both cell types were able to proliferate extensively in the recipient liver, as expected. However, their growth pattern was remarkably different. Clusters of normal hepatocytes integrated in the host liver, displaying a normal histology; however, transplanted nodular hepatocytes formed new hepatocyte nodules, with altered morphology and sharp demarcation from surrounding host liver. Both the expression and distribution of proteins involved in cell polarity, cell communication, and cell adhesion, including connexin 32, E-cadherin, and matrix metalloproteinase-2, were altered in clusters of nodular hepatocytes. Furthermore, we were able to show that down-regulation of connexin 32 and E-cadherin in nodular hepatocyte clusters was independent of growth rate. These results support the concept that a dominant pathway towards neoplastic disease in several organs involves defect(s) in tissue pattern formation.
authors.affiliation: Department of Biomedical Sciences and Biotechnology, Section of Experimental Pathology, University of Cagliari, Via Porcell, 4, 09125, Cagliari, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Doratiotto
authors.forename: Petra
authors.initials: P
authors.lastname: Krause
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Serra
authors.forename: Fabio
authors.initials: F
authors.lastname: Marongiu
authors.forename: Marcella
authors.initials: M
authors.lastname: Sini
authors.forename: Sarah
authors.initials: S
authors.lastname: Koenig
authors.forename: Ezio
authors.initials: E
authors.lastname: Laconi
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division; D017690:Cell Transplantation; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology; D051381:Rats; D000097002:Gap Junction beta-1 Protein
chemical_list: D015820:Cadherins; D017630:Connexins; D020778:Matrix Metalloproteinase 2; D011763:Pyrrolizidine Alkaloids; D000097002:Gap Junction beta-1 Protein; C003300:retrorsine