Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1990 Jul;86(1):356–362. doi: 10.1172/JCI114709

Growth stimulation by coexpression of transforming growth factor-alpha and epidermal growth factor-receptor in normal and adenomatous human colon epithelium.

S D Markowitz 1, K Molkentin 1, C Gerbic 1, J Jackson 1, T Stellato 1, J K Willson 1
PMCID: PMC296730  PMID: 2365825

Abstract

Autocrine stimulation of the epidermal growth factor receptor (EGF-R), by coexpression of transforming growth factor-alpha (TGF-alpha), causes malignant transformation of some fibroblast cell lines. TGF-alpha and EGF-R are both known to be expressed in colon carcinoma tissue and have been shown coexpressed in colon carcinoma cell lines. TGF-alpha autocrine activation of EGF-R has been suggested as a potential mechanism contributing to abnormal growth control in colon cancer. We now report coexpression of TGF-alpha and EGF-R transcripts in morphologically normal colonic epithelium from five individuals, in colonic adenomas from three individuals, and in a nontumorigenic colon adenoma cell line, VACO-330. Functional studies demonstrate VACO-330 growth is stimulated by exogenous TGF-alpha and is completely abolished by a blocking anti-EGF-R antibody. Autocrine stimulation of EGF-R by TGF-alpha is therefore required for growth of the adenoma cell line. Autocrine stimulation of EGF-R by TGF-alpha does not cause malignant transformation of the colonic epithelial cell. In normal and adenomatous human colon TGF-alpha, via either an autocrine or paracrine mechanism, is likely an important physiologic stimulant of epithelial proliferation.

Full text

PDF
356

Images in this article

357Image
on p.357
359Image
on p.359
360Image
on p.360

Selected References

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

  1. Anzano M. A., Rieman D., Prichett W., Bowen-Pope D. F., Greig R. Growth factor production by human colon carcinoma cell lines. Cancer Res. 1989 Jun 1;49(11):2898–2904. [PubMed] [Google Scholar]
  2. Arteaga C. L., Coronado E., Osborne C. K. Blockade of the epidermal growth factor receptor inhibits transforming growth factor alpha-induced but not estrogen-induced growth of hormone-dependent human breast cancer. Mol Endocrinol. 1988 Nov;2(11):1064–1069. doi: 10.1210/mend-2-11-1064. [DOI] [PubMed] [Google Scholar]
  3. Baker S. J., Fearon E. R., Nigro J. M., Hamilton S. R., Preisinger A. C., Jessup J. M., vanTuinen P., Ledbetter D. H., Barker D. F., Nakamura Y. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989 Apr 14;244(4901):217–221. doi: 10.1126/science.2649981. [DOI] [PubMed] [Google Scholar]
  4. Bates S. E., Valverius E. M., Ennis B. W., Bronzert D. A., Sheridan J. P., Stampfer M. R., Mendelsohn J., Lippman M. E., Dickson R. B. Expression of the transforming growth factor-alpha/epidermal growth factor receptor pathway in normal human breast epithelial cells. Endocrinology. 1990 Jan;126(1):596–607. doi: 10.1210/endo-126-1-596. [DOI] [PubMed] [Google Scholar]
  5. Bell G. I., Fong N. M., Stempien M. M., Wormsted M. A., Caput D., Ku L. L., Urdea M. S., Rall L. B., Sanchez-Pescador R. Human epidermal growth factor precursor: cDNA sequence, expression in vitro and gene organization. Nucleic Acids Res. 1986 Nov 11;14(21):8427–8446. doi: 10.1093/nar/14.21.8427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bos J. L., Fearon E. R., Hamilton S. R., Verlaan-de Vries M., van Boom J. H., van der Eb A. J., Vogelstein B. Prevalence of ras gene mutations in human colorectal cancers. 1987 May 28-Jun 3Nature. 327(6120):293–297. doi: 10.1038/327293a0. [DOI] [PubMed] [Google Scholar]
  7. Bradley S. J., Garfinkle G., Walker E., Salem R., Chen L. B., Steele G., Jr Increased expression of the epidermal growth factor receptor on human colon carcinoma cells. Arch Surg. 1986 Nov;121(11):1242–1247. doi: 10.1001/archsurg.121.11.1242. [DOI] [PubMed] [Google Scholar]
  8. Carpenter G. Receptors for epidermal growth factor and other polypeptide mitogens. Annu Rev Biochem. 1987;56:881–914. doi: 10.1146/annurev.bi.56.070187.004313. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Coffey R. J., Jr, Goustin A. S., Soderquist A. M., Shipley G. D., Wolfshohl J., Carpenter G., Moses H. L. Transforming growth factor alpha and beta expression in human colon cancer lines: implications for an autocrine model. Cancer Res. 1987 Sep 1;47(17):4590–4594. [PubMed] [Google Scholar]
  11. Coffey R. J., Jr, Shipley G. D., Moses H. L. Production of transforming growth factors by human colon cancer lines. Cancer Res. 1986 Mar;46(3):1164–1169. [PubMed] [Google Scholar]
  12. Derynck R., Goeddel D. V., Ullrich A., Gutterman J. U., Williams R. D., Bringman T. S., Berger W. H. Synthesis of messenger RNAs for transforming growth factors alpha and beta and the epidermal growth factor receptor by human tumors. Cancer Res. 1987 Feb 1;47(3):707–712. [PubMed] [Google Scholar]
  13. Derynck R. Transforming growth factor alpha. Cell. 1988 Aug 26;54(5):593–595. doi: 10.1016/s0092-8674(88)80001-1. [DOI] [PubMed] [Google Scholar]
  14. Di Marco E., Pierce J. H., Fleming T. P., Kraus M. H., Molloy C. J., Aaronson S. A., Di Fiore P. P. Autocrine interaction between TGF alpha and the EGF-receptor: quantitative requirements for induction of the malignant phenotype. Oncogene. 1989 Jul;4(7):831–838. [PubMed] [Google Scholar]
  15. Dugaiczyk A., Haron J. A., Stone E. M., Dennison O. E., Rothblum K. N., Schwartz R. J. Cloning and sequencing of a deoxyribonucleic acid copy of glyceraldehyde-3-phosphate dehydrogenase messenger ribonucleic acid isolated from chicken muscle. Biochemistry. 1983 Mar 29;22(7):1605–1613. doi: 10.1021/bi00276a013. [DOI] [PubMed] [Google Scholar]
  16. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  17. Finch P. W., Rubin J. S., Miki T., Ron D., Aaronson S. A. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science. 1989 Aug 18;245(4919):752–755. doi: 10.1126/science.2475908. [DOI] [PubMed] [Google Scholar]
  18. Friedman E. A., Higgins P. J., Lipkin M., Shinya H., Gelb A. M. Tissue culture of human epithelial cells from benign colonic tumors. In Vitro. 1981 Jul;17(7):632–644. doi: 10.1007/BF02618462. [DOI] [PubMed] [Google Scholar]
  19. Gill G. N., Kawamoto T., Cochet C., Le A., Sato J. D., Masui H., McLeod C., Mendelsohn J. Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem. 1984 Jun 25;259(12):7755–7760. [PubMed] [Google Scholar]
  20. Goodlad R. A., Wilson T. J., Lenton W., Gregory H., McCullagh K. G., Wright N. A. Intravenous but not intragastric urogastrone-EGF is trophic to the intestine of parenterally fed rats. Gut. 1987 May;28(5):573–582. doi: 10.1136/gut.28.5.573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kawamoto T., Sato J. D., Le A., Polikoff J., Sato G. H., Mendelsohn J. Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci U S A. 1983 Mar;80(5):1337–1341. doi: 10.1073/pnas.80.5.1337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Madtes D. K., Raines E. W., Sakariassen K. S., Assoian R. K., Sporn M. B., Bell G. I., Ross R. Induction of transforming growth factor-alpha in activated human alveolar macrophages. Cell. 1988 Apr 22;53(2):285–293. doi: 10.1016/0092-8674(88)90390-x. [DOI] [PubMed] [Google Scholar]
  23. Malden L. T., Novak U., Burgess A. W. Expression of transforming growth factor alpha messenger RNA in the normal and neoplastic gastro-intestinal tract. Int J Cancer. 1989 Mar 15;43(3):380–384. doi: 10.1002/ijc.2910430305. [DOI] [PubMed] [Google Scholar]
  24. Markowitz S., Haut M., Stellato T., Gerbic C., Molkentin K. Expression of the ErbA-beta class of thyroid hormone receptors is selectively lost in human colon carcinoma. J Clin Invest. 1989 Nov;84(5):1683–1687. doi: 10.1172/JCI114349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Markowitz S., Krystal G., Lebacq-Verheyden A. M., Way J., Sausville E. A., Battey J. Transcriptional activation and DNase I hypersensitive sites are associated with selective expression of the gastrin-releasing peptide gene. J Clin Invest. 1988 Sep;82(3):808–815. doi: 10.1172/JCI113683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rosenthal A., Lindquist P. B., Bringman T. S., Goeddel D. V., Derynck R. Expression in rat fibroblasts of a human transforming growth factor-alpha cDNA results in transformation. Cell. 1986 Jul 18;46(2):301–309. doi: 10.1016/0092-8674(86)90747-6. [DOI] [PubMed] [Google Scholar]
  27. Sato J. D., Kawamoto T., Le A. D., Mendelsohn J., Polikoff J., Sato G. H. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med. 1983 Dec;1(5):511–529. [PubMed] [Google Scholar]
  28. Sporn M. B., Todaro G. J. Autocrine secretion and malignant transformation of cells. N Engl J Med. 1980 Oct 9;303(15):878–880. doi: 10.1056/NEJM198010093031511. [DOI] [PubMed] [Google Scholar]
  29. Stern D. F., Hare D. L., Cecchini M. A., Weinberg R. A. Construction of a novel oncogene based on synthetic sequences encoding epidermal growth factor. Science. 1987 Jan 16;235(4786):321–324. doi: 10.1126/science.3492043. [DOI] [PubMed] [Google Scholar]
  30. Ullrich A., Coussens L., Hayflick J. S., Dull T. J., Gray A., Tam A. W., Lee J., Yarden Y., Libermann T. A., Schlessinger J. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. 1984 May 31-Jun 6Nature. 309(5967):418–425. doi: 10.1038/309418a0. [DOI] [PubMed] [Google Scholar]
  31. Watkins L. F., Brattain M. G., Levine A. E. Modulation of a high molecular weight form of transforming growth factor-alpha in human colon carcinoma cell lines. Cancer Lett. 1988 May;40(1):59–70. doi: 10.1016/0304-3835(88)90262-5. [DOI] [PubMed] [Google Scholar]
  32. Wigley C. B., Paraskeva C., Coventry R. Elevated production of growth factor by human premalignant colon adenomas and a derived epithelial cell line. Br J Cancer. 1986 Nov;54(5):799–805. doi: 10.1038/bjc.1986.243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Willson J. K., Bittner G. N., Oberley T. D., Meisner L. F., Weese J. L. Cell culture of human colon adenomas and carcinomas. Cancer Res. 1987 May 15;47(10):2704–2713. [PubMed] [Google Scholar]
  34. Wright N. A., Pike C., Elia G. Induction of a novel epidermal growth factor-secreting cell lineage by mucosal ulceration in human gastrointestinal stem cells. Nature. 1990 Jan 4;343(6253):82–85. doi: 10.1038/343082a0. [DOI] [PubMed] [Google Scholar]
  35. de Larco J. E., Todaro G. J. Growth factors from murine sarcoma virus-transformed cells. Proc Natl Acad Sci U S A. 1978 Aug;75(8):4001–4005. doi: 10.1073/pnas.75.8.4001. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES