title: alpha(2)-Macroglobulin: a novel cytochemical marker characterizing preneoplastic and neoplastic rat liver lesions negative for hitherto established cytochemical markers.
abstract: We tried to identify a novel marker characteristic for rat hepatocellular preneoplastic and neoplastic lesions, undetectable by well established cytochemical markers. Glutathione S-transferase placental (GST-P)-negative hepatocellular altered foci (HAF), hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC) were generated by two initiation-promotion models with N-nitrosodiethylamine (NDEN) and peroxisome proliferators, Wy-14,643 and clofibrate. Total RNAs isolated from laser-microdissected GST-P-negative HAF (amphophilic cell foci) and adjacent normal tissues were applied to microarray analysis. As a result, five up-regulated genes were identified, and further detailed examinations of the gene demonstrating most fluctuation, ie, that for alpha(2)-macroglobulin (alpha(2)M) were performed. In reverse transcriptase-polymerase chain reaction, alpha(2)M mRNA was overexpressed not only in amphophilic GST-P-negative HAF but also in amphophilic GST-P-negative HCA and HCC. In situ hybridization showed accumulation of alpha(2)M mRNA to be evenly distributed within GST-P-negative HAF (predominantly amphophilic cell foci). Distinctive immunohistochemical staining for alpha(2)M could be consistently demonstrated in GST-P-negative HAF, HCA, and HCC induced not only by peroxisome proliferators but also N-nitrosodiethylamine alone. Thus our findings suggest that alpha(2)M is an important novel cytochemical marker to identify hepatocellular preneoplastic and neoplastic lesions, particularly amphophilic cell foci, undetectable by established cytochemical markers and is tightly linked to rat hepatocarcinogenesis.
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 1-98, 3-chome, Kasugade-Naka, Konohana-ku, Osaka 554-8558, Japan. sukata@sc.sumitomo-chem.co.jp
authors.forename: Tokuo
authors.initials: T
authors.lastname: Sukata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uwagawa
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ozaki
authors.forename: Kayo
authors.initials: K
authors.lastname: Sumida
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kushida
authors.forename: Koichi
authors.initials: K
authors.lastname: Saito
authors.forename: Keiichirou
authors.initials: K
authors.lastname: Morimura
authors.forename: Kenji
authors.initials: K
authors.lastname: Oeda
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Okuno
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Mikami
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukushima
mesh_terms: D000236:Adenoma / Q000473:pathology; D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor; D002994:Clofibrate / Q000494:pharmacology; D004052:Diethylnitrosamine / Q000494:pharmacology; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007834:Lasers; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015854:Up-Regulation; D000511:alpha-Macroglobulins / Q000502:physiology*
chemical_list: D000477:Alkylating Agents; D000924:Anticholesteremic Agents; D014408:Biomarkers, Tumor; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; D000511:alpha-Macroglobulins; D004052:Diethylnitrosamine; D012313:RNA; C006253:pirinixic acid; D005982:Glutathione Transferase; D002994:Clofibrate