Skip to main content
NCBI home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1984 Feb;114(2):287–300.

Light- and electron-microscopic autoradiographic analysis of proliferating cells during the early stages of chemical hepatocarcinogenesis in the rat induced by feeding N-2-fluorenylacetamide in a choline-deficient diet.

S Sell, J Salman
PMCID: PMC1900337  PMID: 6696045

Abstract

Proliferating cells that appear after feeding the hepatocarcinogen N-2-fluorenylacetamide in a choline-deficient diet were identified by autoradiographic electron and light microscopy. Labeled cells are first seen as nondescript periductular cells 1 day after feeding carcinogen. Proliferation of duct lining cells begins at 2-3 days. For the next three weeks there is proliferation and extension of a mixture of nondescript cells and cells with a duct like appearance from the portal zone into the adjacent liver. By 3-4 weeks the entire liver lobule contains this new cell population. At 3 weeks more differentiated duct like structures are seen at the edge of the advancing new cell population. Newly appearing duct like cells differ from normal duct cells in that they contain AFP and albumin. It is concluded that the new cell population may arise from duct cells or periportal "stem" cells, or both.

Full text

PDF
287

Images in this article

290Figure 1
on p.290
292Figure 3
on p.292
297Figure 7
on p.297
291Figure 2
on p.291
293Figure 4
on p.293
294Figure 5
on p.294
295Figure 6
on p.295
298Figure 8
on p.298

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Becker F. F., Sell S. Early elevation of alpha 1-fetoprotein in N-2-fluorenylacetamide hepatocarcinogenesis. Cancer Res. 1974 Oct;34(10):2489–2494. [PubMed] [Google Scholar]
  2. Dempo K., Chisaka N., Yoshida Y., Kaneko A., Onoé T. Immunofluorescent study on alpha-fetoprotein-producing cells in the early stage of 3'-methyl-4-dimethylaminoazobenzene carcinogenesis. Cancer Res. 1975 May;35(5):1282–1287. [PubMed] [Google Scholar]
  3. FARBER E. ETHIONINE CARCINOGENESIS. Adv Cancer Res. 1963;7:383–474. doi: 10.1016/s0065-230x(08)60986-0. [DOI] [PubMed] [Google Scholar]
  4. FARBER E. Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine, 2-acetylamino-fluorene, and 3'-methyl-4-dimethylaminoazobenzene. Cancer Res. 1956 Feb;16(2):142–148. [PubMed] [Google Scholar]
  5. Farber E., Cameron R. The sequential analysis of cancer development. Adv Cancer Res. 1980;31:125–226. doi: 10.1016/s0065-230x(08)60658-2. [DOI] [PubMed] [Google Scholar]
  6. GILLMAN J., GILBERT C., SPENCE I. Some factors regulating the structural integrity of the intrahepatic bile ducts with special reference to primary carcinoma of the liver and vitamin A. Cancer. 1954 Nov;7(6):1119–1154. doi: 10.1002/1097-0142(195411)7:6<1109::aid-cncr2820070605>3.0.co;2-e. [DOI] [PubMed] [Google Scholar]
  7. GRISHAM J. W., PORTA E. A. ORIGIN AND FATE OF PROLIFERATED HEPATIC DUCTAL CELLS IN THE RAT: ELECTRON MICROSCOPIC AND AUTORADIOGRAPHIC STUDIES. Exp Mol Pathol. 1964 Jun;86:242–261. doi: 10.1016/0014-4800(64)90057-7. [DOI] [PubMed] [Google Scholar]
  8. Hruban Z., Mochizuki Y., Slesers A., Morris H. P. A comparative study of cellular organelles of Morris hepatomas. Cancer Res. 1972 Apr;32(4):853–867. [PubMed] [Google Scholar]
  9. Inaoka Y. Significance of the so-called oval cell proliferation during azo-dye hepatocarcinogenesis. Gan. 1967 Aug;58(4):355–366. [PubMed] [Google Scholar]
  10. Kuhlmann W. D. Alpha-fetoprotein: cellular origin of a biological marker in rat liver under various experimental conditions. Virchows Arch A Pathol Anat Histol. 1981;393(1):9–26. doi: 10.1007/BF00430867. [DOI] [PubMed] [Google Scholar]
  11. LEDUC E. H. Cell modulation in liver pathology. J Histochem Cytochem. 1959 Jul;7(4):253–255. doi: 10.1177/7.4.253. [DOI] [PubMed] [Google Scholar]
  12. Lombardi B., Shinozuka H. Enhancement of 2-acetylaminofluorene liver carcinogenesis in rats fed a choline-devoid diet. Int J Cancer. 1979 Apr 15;23(4):565–570. doi: 10.1002/ijc.2910230419. [DOI] [PubMed] [Google Scholar]
  13. Merkow L. P., Epstein S. M., Farber E., Pardo M., Bartus B. Cellular analysis of liver carcinogenesis. 3. Comparison of the ultrastructure of hyperplastic liver nodules and hepatocellular carcinomas induced in rat liver by 2-fluorenylacetamide. J Natl Cancer Inst. 1969 Jul;43(1):33–63. [PubMed] [Google Scholar]
  14. Merkow L. P., Epstein S. M., Slifkin M., Farber E., Pardo M. The cellular analysis of liver carcinogenesis. V. Ultrastructural alterations within hepatocellular carcinoma induced by ethionine. Lab Invest. 1972 Mar;26(3):300–305. [PubMed] [Google Scholar]
  15. Mochizuki Y., Hruban Z., Morris H. P., Slesers A., Vigil E. L. Microbodies of Morris hepatomas. Cancer Res. 1971 Jun;31(6):763–773. [PubMed] [Google Scholar]
  16. Onda H. Immunohistological studies on alpha1-fetoprotein and alpha1-acid glycoprotein during azo dye hepatocarcinogenesis in rats. Gan. 1976 Apr;67(2):253–262. [PubMed] [Google Scholar]
  17. POPPER H., KENT G., STEIN R. Ductular cell reaction in the liver in hepatic injury. J Mt Sinai Hosp N Y. 1957 Sep-Oct;24(5):551–556. [PubMed] [Google Scholar]
  18. PRICE J. M., HARMAN J. W., MILLER E. C., MILLER J. A. Progressive microscopic alterations in the livers of rats fed the hepatic carcinogens 3'-methyl-4-dimethylaminoazobenzene and 4'-fluoro-4-dimethylaminoazobenzene. Cancer Res. 1952 Mar;12(3):192–200. [PubMed] [Google Scholar]
  19. Pugh T. D., Goldfarb S. Quantitative histochemical and autoradiographic studies of hepatocarcinogenesis in rats fed 2-acetylaminofluorene followed by phenobarbital. Cancer Res. 1978 Dec;38(12):4450–4457. [PubMed] [Google Scholar]
  20. Richards W. L., Tsukada Y., Potter V. R. gamma-Glutamyl transpeptidase and alpha-fetoprotein expression during alpha-naphthylisothiocyanate-induced hepatotoxicity in rats. Cancer Res. 1982 Dec;42(12):5133–5138. [PubMed] [Google Scholar]
  21. SCHAFFNER F., POPPER H. Electron microscopic studies of normal and proliferated bile ductules. Am J Pathol. 1961 Apr;38:393–410. [PMC free article] [PubMed] [Google Scholar]
  22. STEIN R. J., KENT G., POPPER H. Effect of cortisone and growth hormone upon ductular cell proliferation in liver ethionine intoxication. Proc Soc Exp Biol Med. 1958 Oct;99(1):24–28. doi: 10.3181/00379727-99-24233. [DOI] [PubMed] [Google Scholar]
  23. Sell S. Comparison of oval cells induced in rat liver by feeding N-2-fluorenylacetamide in a choline-devoid diet and bile duct cells induced by feeding 4,4'-diaminodiphenylmethane. Cancer Res. 1983 Apr;43(4):1761–1767. [PubMed] [Google Scholar]
  24. Sell S. Distribution of alpha-fetoprotein- and albumin-containing cells in the livers of Fischer rats fed four cycles of N-2-fluorenylacetamide. Cancer Res. 1978 Sep;38(9):3107–3113. [PubMed] [Google Scholar]
  25. Sell S., Gord D. Rat alpha-fetoprotein. 8. Refinement of radioimmunoassay for detection of 1 ng rat alpha 1F. Immunochemistry. 1973 Jul;10(7):439–442. doi: 10.1016/0019-2791(73)90013-x. [DOI] [PubMed] [Google Scholar]
  26. Sell S. Heterogeneity of alpha-fetoprotein(AFP) and albumin containing cells in normal and pathological permissive states for AFP production: AFP containing cells induced in adult rats recapitulate the appearance of AFP containing hepatocytes in fetal rats. Oncodev Biol Med. 1980;1(2):93–105. [PubMed] [Google Scholar]
  27. Sell S., Leffert H. L. An evaluation of cellular lineages in the pathogenesis of experimental hepatocellular carcinoma. Hepatology. 1982 Jan-Feb;2(1):77–86. doi: 10.1002/hep.1840020113. [DOI] [PubMed] [Google Scholar]
  28. Sell S., Leffert H. L., Shinozuka H., Lombardi B., Gochman N. Rapid development of large numbers of alpha-fetoprotein-containing "oval" cells in the liver of rats fed N-2-fluorenylacetamide in a choline-devoid diet. Gan. 1981 Aug;72(4):479–487. [PubMed] [Google Scholar]
  29. Sell S., Nichols M., Becker F. F., Leffert H. L. Hepatocyte proliferation and alpha 1-fetoprotein in pregnant, neonatal, and partially hepatectomized rats. Cancer Res. 1974 Apr;34(4):865–871. [PubMed] [Google Scholar]
  30. Sell S., Osborn K., Leffert H. L. Autoradiography of "oval cells" appearing rapidly in the livers of rats fed N-2-fluorenylacetamide in a choline devoid diet. Carcinogenesis. 1981;2(1):7–14. doi: 10.1093/carcin/2.1.7. [DOI] [PubMed] [Google Scholar]
  31. Sell S., Ruoslahti E. Expression of fibronectin and laminin in the rat liver after partial hepatectomy, during carcinogenesis, and in transplantable hepatocellular carcinomas. J Natl Cancer Inst. 1982 Nov;69(5):1105–1114. [PubMed] [Google Scholar]
  32. Smith H. S., Riggs J. L., Mosesson M. W. Production of fibronectin by human epithelial cells in culture. Cancer Res. 1979 Oct;39(10):4138–4144. [PubMed] [Google Scholar]
  33. Tchipysheva T. A., Guelstein V. I., Bannikov G. A. alpha-fetoprotein-containing cells in the early stages of liver carcinogenesis induced by 3'-methyl-4-dimethyl-aminoazobenzene and 2-acetylaminofluorene. Int J Cancer. 1977 Sep 15;20(3):388–393. doi: 10.1002/ijc.2910200310. [DOI] [PubMed] [Google Scholar]
  34. Teebor G. W., Becker F. F. Regression and persistence of hyperplastic hepatic nodules induced by N-2-Fluorenylacetamide and their relationship to hepatocarcinogenesis. Cancer Res. 1971 Jan;31(1):1–3. [PubMed] [Google Scholar]
  35. Watabe H. Early appearance of embryonic -globulin in rat serum during carcinogenesis with 4-dimethylaminoazobenzene. Cancer Res. 1971 Sep;31(9):1192–1194. [PubMed] [Google Scholar]
  36. Williams G. M., Watanabe K. Quantitative kinetics of development of N-2-fluorenylacetamide-induced, altered (hyperplastic) hepatocellular foci resistant to iron accumulation and of their reversion or persistence following removal of carcinogen. J Natl Cancer Inst. 1978 Jul;61(1):113–121. doi: 10.1093/jnci/61.1.113. [DOI] [PubMed] [Google Scholar]
  37. Williams G. M., Yamamoto R. S. Absence of stainable iron from preneoplastic and neoplastic lesions in rat liver with 8-hydroxyquinoline-induced siderosis. J Natl Cancer Inst. 1972 Sep;49(3):685–692. [PubMed] [Google Scholar]
  38. Wu P. C., Ma L., Gibson J. B., Hirai H., Tsukada Y. Serum alpha-fetoprotein in rats after ligation of the common bile duct: relation to ductular cell (oval cell) proliferation. J Pathol. 1981 Jan;133(1):61–74. doi: 10.1002/path.1711330107. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES