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Carcinogenesis, Vol. 20, No. 7, 1337-1344, July 1999
© 1999 Oxford University Press

Carcinogenesis

Immunohistochemical localization of inducible nitric oxide synthase and 3-nitrotyrosine in rat liver tumors induced by N-nitrosodiethylamine

Byeongwoo Ahn1,2, Beom Seok Han1, Dae Joong Kim1 and Hiroshi Ohshima2,3

1 Department of Pathology, National Institute of Toxicology Research, Korea Food and Drug Administration, 5 Nokbun-Dong, Eunpyung-Ku, Seoul 122-704, Korea and
2 Unit of Endogenous Cancer Risk Factors, International Agency for Research on Cancer, 150 cours Albert-Thomas, 69372, Lyon Cedex 08, France

Human liver cancers have been associated mainly with chronic inflammations such as viral hepatitis B or C. This suggests that prolonged cell damage by chronic inflammation is critical in cancer development. Overproduction of nitric oxide (NO·) and its derivative (NOx, peroxynitrite) has been implicated as a cause of tissue damage by inflammation, thus contributing to tumor promotion. We have demonstrated the expression of the inducible isoform of nitric oxide synthase (iNOS) and 3-nitrotyrosine, a marker of peroxynitrite formation, by immunohistochemistry in preneoplastic and neoplastic rat liver tissues induced by continuous infusion of N-nitrosodiethylamine with mini-pumps. The preneoplastic lesions were characterized by proliferation of phenotypically altered hepatic foci (PAHF), dysplastic hepatocytes and oval cells. Histologically, the tumors were hepatocellular carcinomas (HCCs) of trabecular, (pseudo)glandular and solid types with or without cholangiocellular involvement. iNOS was located mainly in oval cells, capillary endothelial and muscular cells, epithelia of cholangiomas and glandular HCCs. 3-Nitrotyrosine was observed in the cytoplasms of PAHF and dysplastic hepatocytes in preneoplasias and in the cytoplasms of some living or apoptotic HCC cells, connective tissues, proteinaceous fluids, sinusoidal endothelia of tumorous hepatocytes and cholangiomas in tumors. From these observations, we suggest that: (i) chronic tissue damage by chemical carcinogens may act to induce iNOS and peroxynitrite formation; (ii) oval cells play a key role in development and/or growth of tumor tissues by producing NO· via iNOS, which may also cause tissue damage by peroxynitrite; (iii) iNOS can be considered as a phenotypic marker in cells of oval cell lineage and neovascularized capillaries in tumor tissues.

Abbreviations: 2-AAF, 2-acetylaminofluorene; CCC, cholangiocellular carcinoma; DMSO, dimethyl sulphoxide; HCCs, hepatocellular carcinomas; iNOS, inducible NOS; NDEA, N-nitrosodiethylamine; NOS, nitric oxide synthase; PAHF, phenotypically altered hepatic foci.

3 To whom correspondence should be addressed Email: ohshima{at}iarc.fr


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