Skip to main content
NCBI home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1992 Jan;140(1):85–94.

The effects of continuous exposure to epidermal growth factor on the spontaneous transformation of cultured rat liver epithelial cells.

M S Tsao 1, X Y Zhang 1
PMCID: PMC1886239  PMID: 1731531

Abstract

A long-term continuous exposure to epidermal growth factor (EGF) enhanced the tumorigenicity of spontaneously transformed cells arising in a clonal population of normal cultured rat liver epithelial cells propagated in a selective growth condition. Lengthy EGF exposure also induced the expression of several phenotypes that differed from the phenotypes of rat liver epithelial cells transformed spontaneously in the absence of EGF. Epidermal growth factor treatment caused consistently an enhancement of the constitutive mRNA expression of transforming growth factor-alpha (TGF-alpha), but not of the EGF receptor and transforming growth factor-beta. The overexpression of TGF-alpha persisted in cell lines derived from tumors formed by the EGF-treated transformed cells. These tumors also exhibited high metastatic incidence and ductal cell differentiation. In contrast, untreated spontaneously transformed cells formed non-metastatic tumors with hepatocellular differentiation. These results suggest that long-term, continuous exposure to EGF/TGF-alpha may modulate the phenotypic expressions of neoplastic transformation.

Full text

PDF
85

Images in this article

90Figure 5
on p.90
91Figure 6
on p.91
91Figure 7
on p.91

Selected References

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

  1. Becker F. F. Presidential address. Recent concepts of initiation and promotion in carcinogenesis. Am J Pathol. 1981 Oct;105(1):3–9. [PMC free article] [PubMed] [Google Scholar]
  2. Blasband A. J., Rogers K. T., Chen X. R., Azizkhan J. C., Lee D. C. Characterization of the rat transforming growth factor alpha gene and identification of promoter sequences. Mol Cell Biol. 1990 May;10(5):2111–2121. doi: 10.1128/mcb.10.5.2111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cerutti P. A. Response modification creates promotability in multistage carcinogenesis. Carcinogenesis. 1988 Apr;9(4):519–526. doi: 10.1093/carcin/9.4.519. [DOI] [PubMed] [Google Scholar]
  4. Chester J. F., Gaissert H. A., Ross J. S., Malt R. A. Pancreatic cancer in the Syrian hamster induced by N-nitrosobis(2-oxopropyl)-amine: cocarcinogenic effect of epidermal growth factor. Cancer Res. 1986 Jun;46(6):2954–2957. [PubMed] [Google Scholar]
  5. Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Coffey R. J., Jr, Derynck R., Wilcox J. N., Bringman T. S., Goustin A. S., Moses H. L., Pittelkow M. R. Production and auto-induction of transforming growth factor-alpha in human keratinocytes. 1987 Aug 27-Sep 2Nature. 328(6133):817–820. doi: 10.1038/328817a0. [DOI] [PubMed] [Google Scholar]
  7. Derynck R., Jarrett J. A., Chen E. Y., Goeddel D. V. The murine transforming growth factor-beta precursor. J Biol Chem. 1986 Apr 5;261(10):4377–4379. [PubMed] [Google Scholar]
  8. Dubeau L., Jones P. A., Rideout W. M., 3rd, Laug W. E. Differential regulation of plasminogen activators by epidermal growth factor in normal and neoplastic human urothelium. Cancer Res. 1988 Oct 1;48(19):5552–5556. [PubMed] [Google Scholar]
  9. Earp H. S., Austin K. S., Blaisdell J., Rubin R. A., Nelson K. G., Lee L. W., Grisham J. W. Epidermal growth factor (EGF) stimulates EGF receptor synthesis. J Biol Chem. 1986 Apr 15;261(11):4777–4780. [PubMed] [Google Scholar]
  10. Egan S. E., Wright J. A., Jarolim L., Yanagihara K., Bassin R. H., Greenberg A. H. Transformation by oncogenes encoding protein kinases induces the metastatic phenotype. Science. 1987 Oct 9;238(4824):202–205. doi: 10.1126/science.3659911. [DOI] [PubMed] [Google Scholar]
  11. Ellis R. W., Defeo D., Shih T. Y., Gonda M. A., Young H. A., Tsuchida N., Lowy D. R., Scolnick E. M. The p21 src genes of Harvey and Kirsten sarcoma viruses originate from divergent members of a family of normal vertebrate genes. Nature. 1981 Aug 6;292(5823):506–511. doi: 10.1038/292506a0. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Farber E., Sarma D. S. Hepatocarcinogenesis: a dynamic cellular perspective. Lab Invest. 1987 Jan;56(1):4–22. [PubMed] [Google Scholar]
  14. Farber E. The multistep nature of cancer development. Cancer Res. 1984 Oct;44(10):4217–4223. [PubMed] [Google Scholar]
  15. Goustin A. S., Leof E. B., Shipley G. D., Moses H. L. Growth factors and cancer. Cancer Res. 1986 Mar;46(3):1015–1029. [PubMed] [Google Scholar]
  16. Grisham J. W. Cell types in long-term propagable cultures of rat liver. Ann N Y Acad Sci. 1980;349:128–137. doi: 10.1111/j.1749-6632.1980.tb29521.x. [DOI] [PubMed] [Google Scholar]
  17. Grisham J. W., Tsao M. S., Lee D. C., Earp H. S. Sequential changes in epidermal growth factor receptor/ligand function in cultured rat liver epithelial cells transformed chemically in vitro. Pathobiology. 1990;58(1):3–14. doi: 10.1159/000163560. [DOI] [PubMed] [Google Scholar]
  18. Jakowlew S. B., Kondaiah P., Dillard P. J., Sporn M. B., Roberts A. B. A novel low molecular weight ribonucleic acid (RNA) related to transforming growth factor alpha messenger RNA. Mol Endocrinol. 1988 Nov;2(11):1056–1063. doi: 10.1210/mend-2-11-1056. [DOI] [PubMed] [Google Scholar]
  19. Jhappan C., Stahle C., Harkins R. N., Fausto N., Smith G. H., Merlino G. T. TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell. 1990 Jun 15;61(6):1137–1146. doi: 10.1016/0092-8674(90)90076-q. [DOI] [PubMed] [Google Scholar]
  20. Kingsnorth A. N., Abu-Khalaf M., Ross J. S., Malt R. A. Potentiation of 1,2-dimethylhydrazine-induced anal carcinoma by epidermal growth factor in mice. Surgery. 1985 Jun;97(6):696–700. [PubMed] [Google Scholar]
  21. Laiho M., Keski-Oja J. Growth factors in the regulation of pericellular proteolysis: a review. Cancer Res. 1989 May 15;49(10):2533–2553. [PubMed] [Google Scholar]
  22. Lee D. C., Rose T. M., Webb N. R., Todaro G. J. Cloning and sequence analysis of a cDNA for rat transforming growth factor-alpha. Nature. 1985 Feb 7;313(6002):489–491. doi: 10.1038/313489a0. [DOI] [PubMed] [Google Scholar]
  23. Lee L. W., Tsao M. S., Grisham J. W., Smith G. J. Emergence of neoplastic transformants spontaneously or after exposure to N-methyl-N'-nitro-N-nitrosoguanidine in populations of rat liver epithelial cells cultured under selective and nonselective conditions. Am J Pathol. 1989 Jul;135(1):63–71. [PMC free article] [PubMed] [Google Scholar]
  24. Liotta L. A. Tumor invasion and metastases--role of the extracellular matrix: Rhoads Memorial Award lecture. Cancer Res. 1986 Jan;46(1):1–7. [PubMed] [Google Scholar]
  25. Liu C., Tsao M. S., Grisham J. W. Transforming growth factors produced by normal and neoplastically transformed rat liver epithelial cells in culture. Cancer Res. 1988 Feb 15;48(4):850–855. [PubMed] [Google Scholar]
  26. Merlino G. T., Xu Y. H., Ishii S., Clark A. J., Semba K., Toyoshima K., Yamamoto T., Pastan I. Amplification and enhanced expression of the epidermal growth factor receptor gene in A431 human carcinoma cells. Science. 1984 Apr 27;224(4647):417–419. doi: 10.1126/science.6200934. [DOI] [PubMed] [Google Scholar]
  27. Nagy P., Evarts R. P., McMahon J. B., Thorgeirsson S. S. Role of TGF-beta in normal differentiation and oncogenesis in rat liver. Mol Carcinog. 1989;2(6):345–354. doi: 10.1002/mc.2940020609. [DOI] [PubMed] [Google Scholar]
  28. Niedbala M. J., Sartorelli A. C. Regulation by epidermal growth factor of human squamous cell carcinoma plasminogen activator-mediated proteolysis of extracellular matrix. Cancer Res. 1989 Jun 15;49(12):3302–3309. [PubMed] [Google Scholar]
  29. Reynolds V. H., Boehm F. H., Cohen S. Enhancement of chemical carcinogenesis by an epidermal growth factor. Surg Forum. 1965;16:108–109. [PubMed] [Google Scholar]
  30. Rose S. P., Stahn R., Passovoy D. S., Herschman H. Epidermal growth factor enhancement of skin tumor induction in mice. Experientia. 1976;32(7):913–915. doi: 10.1007/BF02003764. [DOI] [PubMed] [Google Scholar]
  31. Schaeffer W. I. The long-term culture of a diploid rat hepatocyte cell strain. Ann N Y Acad Sci. 1980;349:165–182. doi: 10.1111/j.1749-6632.1980.tb29524.x. [DOI] [PubMed] [Google Scholar]
  32. Stoscheck C. M., King L. E., Jr Role of epidermal growth factor in carcinogenesis. Cancer Res. 1986 Mar;46(3):1030–1037. [PubMed] [Google Scholar]
  33. Tsao M. S., Duong M., Batist G. Glutathione and glutathione S-transferases in clones of cultured rat liver epithelial cells that express varying activity of gamma-glutamyl transpeptidase. Mol Carcinog. 1989;2(3):144–149. doi: 10.1002/mc.2940020307. [DOI] [PubMed] [Google Scholar]
  34. Tsao M. S., Earp H. S., Grisham J. W. Gradation of carcinogen-induced capacity for anchorage-independent growth in cultured rat liver epithelial cells. Cancer Res. 1985 Sep;45(9):4428–4432. [PubMed] [Google Scholar]
  35. Tsao M. S., Grisham J. W. Hepatocarcinomas, cholangiocarcinomas, and hepatoblastomas produced by chemically transformed cultured rat liver epithelial cells. A light- and electron-microscopic analysis. Am J Pathol. 1987 Apr;127(1):168–181. [PMC free article] [PubMed] [Google Scholar]
  36. Tsao M. S., Liu C. Inhibition of growth of early passage normal rat liver epithelial cell lines by epidermal growth factor. Lab Invest. 1988 Jun;58(6):636–642. [PubMed] [Google Scholar]
  37. Tsao M. S., Shepherd J., Batist G. Phenotypic expression in spontaneously transformed cultured rat liver epithelial cells. Cancer Res. 1990 Mar 15;50(6):1941–1947. [PubMed] [Google Scholar]
  38. Tsujino T., Yoshida K., Nakayama H., Ito H., Shimosato T., Tahara E. Alterations of oncogenes in metastatic tumours of human gastric carcinomas. Br J Cancer. 1990 Aug;62(2):226–230. doi: 10.1038/bjc.1990.265. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES