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.

Recent progress in histochemistry and cell biology

“…Such animals were then transplanted with hepatocytes isolated from either normal liver or hepatocyte nodules and subsequently screened for proteins involved in cell polarity, cell communication, and cell adhesion. Doratiotto et al (2011) observed that the growth pattern of transplanted nodular hepatocytes was remarkably different, with the lesions sharply demarcated from the surrounding host tissue. Expression and distribution of screened proteins were also altered in the clusters of nodular hepatocytes.…”

Aging and Cancer: The Waning of Community Bonds

“…However, they pose an overall increased risk of neoplastic progression, and this is likely to depend on the specific cellular phenotype that has been selected [ 54 ]. Along these lines, we have provided evidence to suggest that a focal growth pattern, rather than clonal growth per se, represents a critical hallmark of pre-neoplastic lesions, including polyps, nodules/adenomas, and papillomas, while clones that are histologically normal and well-integrated in the host tissue bear little or no relevance to neoplastic disease [ 103 , 104 ]. Within this perspective, cancer is fundamentally interpreted as a disease originating from an alteration in tissue pattern formation [ 105 , 106 , 107 ].…”