Molecular and metabolic changes in human liver clear cell foci resemble the alterations occurring in rat hepatocarcinogenesis.
OBJECTIVE
Activation of the AKT/mTOR and Ras/MAPK pathways and the lipogenic phenotype occurs in both a rat model of insulin-induced hepatocarcinogenesis and in human hepatocellular carcinoma (HCC). In the rat model, activation of these pathways is evident within the earliest morphologic detectable alterations, i.e., clear cell foci (CCF) of altered hepatocytes. CCF have also been described in the human liver, but molecular and metabolic alterations within these foci remain to be determined.


METHODS
A collection of human liver specimens was examined using electron microscopy, histology, enzyme- and immunohistochemistry, and molecular analysis. Human data were compared to rat preneoplastic CCF and HCC induced by N-nitrosomorpholine administration.


RESULTS
CCF occurred in ∼33% of extrafocal tissues of human non-cirrhotic livers. Electron microscopy showed massive glycogen storage within CCF, largely due to the reduced activity of the glycogenolytic enzyme glucose-6-phosphatase. Hepatocytes in CCF overexpressed the insulin receptor and glucose transporter proteins. AKT/mTOR and Ras/MAPK pathways as well as enzymes of glycolysis, de novo lipogenesis, beta-oxidation, and cholesterol synthesis were upregulated, both in human CCF, and in CCF and HCC of N-nitrosomorpholine-treated rats. The Ki-67 proliferation index was 2-fold higher in human CCF than in extrafocal tissue.


CONCLUSIONS
The high degree of similarity between human CCF and pre-neoplastic lesions from experimental models of hepatocarcinogenesis in terms of morphologic, molecular and metabolic features suggests a low-grade dysplastic nature of these lesions in human non-cirrhotic livers.
Institut für Pathologie, Universitätsmedizin Greifswald, Germany. silvia.ribback@uni-greifswald.de
Silvia
S
Ribback
Diego F
DF
Calvisi
Antonio
A
Cigliano
Verena
V
Sailer
Michele
M
Peters
Jenny
J
Rausch
Claus-Dieter
CD
Heidecke
Matthias
M
Birth
Frank
F
Dombrowski
D000818:Animals; D049109:Cell Proliferation; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D009602:Nitrosamines / Q000633:toxicity; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
D005227:Fatty Acids; D009602:Nitrosamines; C002741:N-nitrosomorpholine; D058570:TOR Serine-Threonine Kinases