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(American Journal of Pathology. 2004;165:1479-1488.)
© 2004 American Society for Investigative Pathology

{alpha}2-Macroglobulin: A Novel Cytochemical Marker Characterizing Preneoplastic and Neoplastic Rat Liver Lesions Negative for Hitherto Established Cytochemical Markers

Tokuo Sukata*{dagger}, Satoshi Uwagawa*{dagger}, Keisuke Ozaki*{dagger}, Kayo Sumida*, Kaoru Kikuchi{ddagger}, Masahiko Kushida*{dagger}, Koichi Saito*, Keiichirou Morimura{dagger}, Kenji Oeda*, Yasuyoshi Okuno*, Nobuyoshi Mikami* and Shoji Fukushima{dagger}

From the Environmental Health Science Laboratory,* Sumitomo Chemical Company, Limited, Osaka; the Department of Pathology,{dagger} Osaka City University Medical School, Osaka; and Sumitomo Pharmaceuticals Company, Limited,{ddagger} Osaka, Japan

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}2M) were performed. In reverse transcriptase-polymerase chain reaction, {alpha}2M 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}2M mRNA to be evenly distributed within GST-P-negative HAF (predominantly amphophilic cell foci). Distinctive immunohistochemical staining for {alpha}2M 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}2M 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.




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