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Toxicologic Pathology
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Immunohistochemical Localization of Transforming Growth Factor Alpha in Chemically Induced Rat Hepatocellular Carcinomas with Reference to Differentiation and Proliferation

Kiyoshi Kobayashi

Pharmacokinetics & Toxicology Laboratory, Yokohama Research Center, Mitsubishi-Tokyo Pharmaceuticals Inc, Kamoshida-cho, Aoba-ku, Yokohama 227-8502 Japan

Manami Kusakabe

Pharmacokinetics & Toxicology Laboratory, Yokohama Research Center, Mitsubishi-Tokyo Pharmaceuticals Inc, Kamoshida-cho, Aoba-ku, Yokohama 227-8502 Japan

Miyoko Okada

Pharmacokinetics & Toxicology Laboratory, Yokohama Research Center, Mitsubishi-Tokyo Pharmaceuticals Inc, Kamoshida-cho, Aoba-ku, Yokohama 227-8502 Japan

Tetsuya Sakairi

Pharmacokinetics & Toxicology Laboratory, Yokohama Research Center, Mitsubishi-Tokyo Pharmaceuticals Inc, Kamoshida-cho, Aoba-ku, Yokohama 227-8502 Japan

Kazuhiro Goto

Pharmacokinetics & Toxicology Laboratory, Yokohama Research Center, Mitsubishi-Tokyo Pharmaceuticals Inc, Kamoshida-cho, Aoba-ku, Yokohama 227-8502 Japan

Takayuki Tsuchiya

Pharmacokinetics & Toxicology Laboratory, Yokohama Research Center, Mitsubishi-Tokyo Pharmaceuticals Inc, Kamoshida-cho, Aoba-ku, Yokohama 227-8502 Japan

Jiro Sugimoto

Pharmacokinetics & Toxicology Laboratory, Yokohama Research Center, Mitsubishi-Tokyo Pharmaceuticals Inc, Kamoshida-cho, Aoba-ku, Yokohama 227-8502 Japan

Fumiko Sano

Pharmacokinetics & Toxicology Laboratory, Yokohama Research Center, Mitsubishi-Tokyo Pharmaceuticals Inc, Kamoshida-cho, Aoba-ku, Yokohama 227-8502 Japan

Mamoru Mutai

Pharmacokinetics & Toxicology Laboratory, Yokohama Research Center, Mitsubishi-Tokyo Pharmaceuticals Inc, Kamoshida-cho, Aoba-ku, Yokohama 227-8502 Japan

Hepatocellular carcinomas (HCCs) were induced in male Fischer 344 rats with dietary 3'-methyl-4-(dimethylamino)-azobenzene treatment and were classified into solid, glandular (well- or poorly differentiated), and trabecular types. Investigation of cell proliferation kinetics and immunohistochemical localization of transforming growth factor alpha (TGF-alpha) demonstrated all solid (n = 24) and poorly differentiated glandular type (n = 6) HCCs to have TGF-alpha-positive nuclei. Nuclear staining of TGF-alpha was also observed in 13 of 28 (46%) trabecular-type HCCs, whereas 12 (43%) exhibited cytoplasmic staining, and 3 (11%) were negative. As for well-differentiated glandular HCCs, 7 of 20 (35%) were positively stained in their nucleus, another 7 (35%) demonstrated antibody binding in the cytoplasm, and 6 (30%) were negative. The order for growth rate evaluated by bromodeoxyuridine (BrdU) labeling was solid (38.22%), poorly differentiated glandular (26.82%), trabecular (7.98%), and well-differentiated glandular (2.57%) types. For trabecular HCCs with nuclear, cytoplasmic, or negative TGF reactions, values were 13.39% (n = 13), 3.61% (n = 12), and 2.01% (n = 3), respectively. Likewise, BrdU-labeling indices for the counterpart groups of well-differentiated glandular type HCCs were 4.53, 1.91, and 1.29%, respectively. The results indicate that TGF-alpha expression might be linked to histopathological differentiation and cell proliferation in rat HCCs.

Key Words: Cell proliferation • differentiation • hepatocarcinogenesis • immunohistory • rat • transforming growth factor-alpha

References

  • Brown PI, Lam R., Laksmanan J., Fisher DA (1989). Transforming growth factor alpha in developing rats. Am J Physiol 259: E256-E260.[Web of Science]
  • Derynck R. (1988). Transforming growth factor-{alpha}. Cell 54: 593-595.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Derynck R., Goeddel D., Ullrich A., Gutterman JU, William RD (1987). Synthesis of messenger RNAs for transforming growth factors a and β and the epidermal growth factor receptor by human tumors. Cancer Res 47: 707-712.[Abstract/Free Full Text]
  • Diwan BA, Ward JM, Rice JM ( 1989). Promotion of malignant 'embryonal' liver tumors by phenobarbital: Increased incidence and shorter latency of hepatoblastomas in (DBA12 x C57BL16) F1 mice initiated with N-nitrosodiethylamine. Carcinogenesis 10: 1345-1348.[Abstract/Free Full Text]
  • Diwan BA, Ward JM, Rice JM ( 1992). Origin and pathology of hepatoblastoma in mice. In: The Role of Cell Types in Hepatocarcinogenesis, Sirica AE (ed). CRC Press, Boca Raton, FL, pp 71-78.
  • Ebner R., Derynck R. (1991). Epidermal growth factor and transforming growth factor {alpha}: differential intracellular routing and processing of ligand-receptor complex. Cell Regul 2: 599-612.[Web of Science][Medline] [Order article via Infotrieve]
  • Frith CH, Ward JM ( 1980). A morphologic classification of proliferative and neoplastic hepatic lesions in mice. J Environ Pathol Perspect 3: 329-351.
  • Hsia CC, Axiotis CA, Di-Bisceglie AM, Tabor E. (1992). Transforming growth factor-alpha in human hepatocellular carcinoma and coexpression with hepatitis B surface antigen in adjacent liver. Cancer 70: 1049-1056.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Imai T., Tashiro T., Hayakawa K., Nakanowatari J., Fukuta T., Hosokawa S., Tsukamoto T., Inada K., Tatematsu M. (1998). Stable expression of glutathione S-transferase P-form mRNA and TGF-{alpha} immunohistochemical expression are useful markers for identification of persistent nodules from an early stage in rat hepatocarcinogenesis. J Toxicol Pathol 11: 249-250.[CrossRef]
  • Imamura T., Oka S., Tanahashi T., Okita Y. (1994). Cell-cycle dependent nuclear localization of exogenously added fibroblast growth factor-1 in BALB/c 3T3 and human vascular endothelial cells. Exp Cell Res 215: 363-372.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Jhappan C., Stahle C., Harkins RN, Fausto N., Smith GH, Merlino GT (1990). TGF{alpha} expression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell 61: 1137-1146.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Kaufmann WK, Zhang Y., Kaufmann DG (1992). Association between expression of transforming growth factor-alpha and progression of hepatocellular foci to neoplasms. Carcinogenesis 13: 1481-1483.[Abstract/Free Full Text]
  • Kira S., Nakanishi T., Suemori S., Kitamoto M., Watanabe, Y., Kajiyama G. (1997). Expression of transforming growth factor alpha and epidermal growth factor receptor in human hepatocellular carcinoma. Liver 17: 177-182.[Web of Science][Medline] [Order article via Infotrieve]
  • Korc M., Chandrasekar B., Yamanaka Y., Friess H., Buchier M., Beger HG (1992). Overexpression of epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increase in the levels of epidermal growth factor and transforming growth factor alpha. J Clin Invest 90: 1352-1360.[Web of Science][Medline] [Order article via Infotrieve]
  • Lee GH, Merlino G., Fausto N. (1992). Development of liver tumors in transforming growth factor {alpha} transgenic mice. Cancer Res 52: 5162-5170.[Abstract/Free Full Text]
  • Liu C., Tsao MS, Grisham JW (1988). Transforming growth factors produced by normal and neoplastically transformed rat liver epithelial cells in culture. Cancer Res 48: 850-855.[Abstract/Free Full Text]
  • Luetteke NC, Michalopoulos GK, Teixido J., Gilmore R., Massagute J., Lee DC (1988). Characterization of high molecular weight transforming growth factor {alpha} produced by rat hepatocellular carcinoma cells. Biochemistry 27: 6487-6494.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Marti U., Burwen SJ, Jones AL (1989). Biological effects of epidermal growth factor, with emphasis on the gastrointestinal tract and liver: An update. Hepatology 9: 126-138.[Web of Science][Medline] [Order article via Infotrieve]
  • Mead JE, Fausto N. (1989). Transforming growth factor {alpha} may be a physiological regulator of liver regeneration by means of an autocrine mechanism. Proc Natl Acad Sci USA 86: 1558-1562.[Abstract/Free Full Text]
  • Morimitsu Y., Hsia CC, Kojiro M., Tabor E. (1995). Nodules of less-differentiated tumors within or adjacent to hepatocellular carcinomas: Relative expression of transforming growth factor-{alpha} and its receptor in the different areas of tumor. Hum Pathol 26: 1126-1132.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Perez-Tomas R., Mayol X., Cullere X., Diaz Ruizz C, Domingo J. (1992). Transforming growth factor-{alpha} expression in rat experimental hepatocarcinogenesis. Histol Histopathol 7: 457-462.[Web of Science][Medline] [Order article via Infotrieve]
  • Salomon DS, Kim N., Saeki T., Ciardiello F. (1990). Transforming growth factor {alpha}. Cancer Cells 2: 389-397.[Web of Science][Medline] [Order article via Infotrieve]
  • Savion N., Vlodavsky I., Gospodarowicz D. (1981). Nuclear accumulation of epidermal growth factor in cultured bovine corneal endothelium and granulosa cells. J Biol Chem 256: 1149-1154.[Abstract/Free Full Text]
  • Steinmetz KL, Klauning JE (1996). Transforming growth factor {alpha} in carcinogen-induced F344 rat hepatic foci. Toxicol Appl Pharmacol 140: 131-145.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Tanno S., Ogawa K. (1994). Abundant TGF{alpha} precursor and EGF receptor expression as a possible mechanism for preferential growth of carcinogen-induced preneoplastic and neoplastic hepatocytes in rats. Carcinogenesis 15: 1689-1694.[Abstract/Free Full Text]
  • Thomas DM, Nasim MM, Gllick WJ, Alison MR (1992). Immunoreactivity of transforming growth factor alpha in the normal adult gastrointestinal tract. Gut 33: 628-631.[Abstract/Free Full Text]
  • Tsao MS, Zhang XY (1992). The effects of continuous exposure to epidermal growth factor on the spontaneous transformation of cultured rat liver epithelial cells. Am J Pathol 140: 85-94.[Abstract]
  • Yankner B., Shooter EM (1979). Nerve growth factor in the nucleus: Interaction with receptors on the nuclear membrane. Proc Natl Acad Sci USA 76: 1269-1273.[Abstract/Free Full Text]

Toxicologic Pathology, Vol. 28, No. 5, 664-667 (2000)
DOI: 10.1177/019262330002800505
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