title: Glutamine synthetase heterogeneous expression as a marker for the cellular lineage of preneoplastic and neoplastic liver populations.
abstract: The distribution of glutamine synthetase (GS) in rat liver and in putative preneoplastic and neoplastic lesions was studied at stages of hepatocarcinogenesis induced by diethylnitrosamine (DEN), 2-acetylaminofluorene (AAF) and aflatoxin B1 (AFB1) using immunohistochemistry. In control rats, GS was localized entirely to rings 1-3 cells deep surrounding the central veins. Exposure to DEN or AAF resulted in a reduction of these GS-positive (GS+) zones by 96 and 61% respectively, due to necrosis of the cells in this compartment, while AFB1 had little effect (less than 14%). At later times GS+ foci, adenomas and carcinomas developed in animals exposed to DEN or AAF, but not AFB1, corresponding to the acute effects. Small GS+ foci also identified by other phenotypic abnormalities (e.g. gamma-glutamyltransferase) were exclusively associated with the regenerating GS+ zone as were a few collections of GS+ hepatocytes, the nature of which was uncertain. Although accounting for a very small fraction (less than 3%) of total foci, these GS+ foci or GS+ hepatocytes apparently gave rise to a substantial fraction of adenomas that were GS+ (DEN: 43% and AAF: 33%) and an even higher percentage of GS+ carcinomas (DEN: 59% and AAF: 39%). No GS+ neoplasms were induced by AFB1. Statistical evaluation of these data strongly suggests that GS+ neoplasms originate through initiation of hepatocytes which possess this particular phenotype. Thus, GS might serve as a specific marker for tracing cell lineage relationships during hepatocarcinogensis. The GS+ phenotype which confers glutamine independence may also provide a growth advantage.
authors.affiliation: Physiologisch-chemisches Institut der Universität, Tübingen, FRG.
authors.forename: R
authors.initials: R
authors.lastname: Gebhardt
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: G M
authors.initials: GM
authors.lastname: Williams
mesh_terms: D015073:2-Acetylaminofluorene / Q000633:toxicity; D000236:Adenoma / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D016604:Aflatoxin B1; D000348:Aflatoxins / Q000633:toxicity; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D004052:Diethylnitrosamine / Q000633:toxicity; D005974:Glutamate-Ammonia Ligase / Q000032:analysis / Q000096:biosynthesis*; D007124:Immunoenzyme Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology*; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D012016:Reference Values
chemical_list: D000348:Aflatoxins; D014408:Biomarkers, Tumor; D004052:Diethylnitrosamine; D015073:2-Acetylaminofluorene; D016604:Aflatoxin B1; D005974:Glutamate-Ammonia Ligase