Liver Repopulation and Carcinogenesis: Two Sides of the Same Coin?

Abstract

Liver repopulation by transplanted normal hepatocytes has been described in a number of experimental settings. Extensive repopulation can also occur from the selective proliferation of endogenous normal hepatocytes, both in experimental animals and in the human liver. This review highlights the intriguing association between clinical and experimental conditions related to liver repopulation and an increased risk for development of hepatocellular carcinoma. It is suggested that any microenvironment that is able to sustain the clonal growth of normal transplanted (or endogenous) hepatocytes is also geared to select for the emergence of rare resistant cells with an altered phenotype. Whereas the first pathway leads to liver repopulation with normal histology, the latter results in the growth of focal proliferative lesions and carries an increased risk of neoplastic disease. The implications of this association are discussed, both in terms of pathogenetic significance and possible therapeutic exploitation.

Normal Hepatocyte Transplantation Delays the Emergence of Chemically Induced Preneoplastic Nodules in Rat Liver

“…4B). Furthermore, the mean size of the three largest GST 7-7-positive nodules found ing the growth behavior of altered/nodular hepatocytes, as referred to in the Introduction (18). in each animal of the two groups was reduced by a factor of about 5 in transplanted versus nontransplanted rats…”

“…We have repeatedly shown that preexposure to RS sets the stage for extensive repopulation of the host liver The incidence of preneoplastic lesions was evaluated using immunohistochemical detection of the marker by transplanted normal hepatocytes (18). However, no studies had been published so far on the effect of a com-DPP-IV and GST 7-7 revealed that no overlapping was present between the two markers (i.e., none of the bined treatment with DENA and RS on liver repopulation.…”

“…An important corollary of the hypothesis above is The pathway towards cancer in many organs, including the liver, is often inextricably linked to chronic disthat strategies aimed at normalizing a chronically injured and/or growth-constrained tissue environment might be ease processes that hamper the functional capacity of the tissue, and also its regenerative potential (7,9). For of value in the management of neoplastic disease (18). The present study was designed to test this possibility.…”

“…Thus, it is reasonable ment; donor-derived cells were able to extensively repopulate the host liver and this effect was associated to hypothesize that such a growth-impaired background could provide a favorable competitive landscape for the with a significant decrease in the incidence of chemically induced hepatocyte nodules. selective emergence of rare cells with altered/preneoplastic phenotype (4,8,18,26). Consistent with this interpretation, studies from our laboratory have indicated that MATERIALS AND METHODS hepatocytes isolated from chemically induced liver nodAnimals and Treatments ules can rapidly proliferate and progress to cancer following transplantation into a growth-constrained liver Liver carcinogenesis was induced using a sequential exposure to diethylnitrosamine (DENA) and retrorsine microenvironment, while they are unable to grow to any 672 SERRA ET AL.…”

Animal Models and the Molecular Biology of Hepadnavirus Infection

“…Silencing of the transgene is believed to be associated with clonal repopulation of the liver by hepatocytes that have either lost the transgene or shut down its expression. Clonal hepatocyte repopulation is known in other models of chronic liver disease, including human liver disease, to be a risk factor for HCC (Marongiu et al 2008;Alison et al 2009). Although the L protein overexpression model does not appear directly relevant to chronic hepatitis B, the idea of clonal hepatocyte repopulation may apply.…”