The growth pattern of transplanted normal and nodular hepatocytes

Introduction:

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.

Methods:

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. Liver samples were harvested 4 weeks following transplantation and immunofluorescence stainings were examined with the TEXAS Red-, FITC- and UV filter set on a confocal microscope.

Results:

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. 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, down-regulation of connexin 32 and E-cadherin in nodular hepatocytes clusters was independent of growth rate.

Conclusion:

These results support the concept that a dominant pathway towards neoplastic disease in several organs begins as a defect of tissue pattern formation.

clonal expansion - growth pattern - nodular hepatocytes - tumor