Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Sep;90(3):1161–1167. doi: 10.1172/JCI115936

Hypertrophic gastropathy resembling Ménétrier's disease in transgenic mice overexpressing transforming growth factor alpha in the stomach.

H Takagi 1, C Jhappan 1, R Sharp 1, G Merlino 1
PMCID: PMC329980  PMID: 1522224

Abstract

Transforming growth factor alpha (TGF alpha) is thought to participate in the normal and pathologic processes of numerous tissues, including the gastric mucosa. To explore its role in vivo, transgenic mice were generated overexpressing TGF alpha in the stomach. TGF alpha induced dramatic structural and functional lesions of the glandular stomach that were similar to Ménétrier's disease in humans. Transgenic mice developed severe adenomatous hyperplasia that resulted in a striking nodular thickening or hypertrophy of the gastric mucosa. Secretions obtained from affected stomachs contained no detectable gastric acid, suggesting that parietal cell function had been greatly impaired. These findings demonstrate that overproduction of TGF alpha can stimulate cellular proliferation, suppress acid secretion, and perturb organogenesis of the stomach of transgenic mice. Moreover, TGF alpha may contribute to the pathogenesis of related human hypertrophic gastropathies, such as Ménétrier's disease.

Full text

PDF
1161

Images in this article

Selected References

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

  1. Beauchamp R. D., Barnard J. A., McCutchen C. M., Cherner J. A., Coffey R. J., Jr Localization of transforming growth factor alpha and its receptor in gastric mucosal cells. Implications for a regulatory role in acid secretion and mucosal renewal. J Clin Invest. 1989 Sep;84(3):1017–1023. doi: 10.1172/JCI114223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Davis J. M., Gray G. F., Thorbjarnarson B. A clinicopathologic study of sex cases. Ann Surg. 1977 Apr;185(4):456–461. doi: 10.1097/00000658-197704000-00015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Dembiński A., Gregory H., Konturek S. J., Polański M. Trophic action of epidermal growth factor on the pancreas and gastroduodenal mucosa in rats. J Physiol. 1982 Apr;325:35–42. doi: 10.1113/jphysiol.1982.sp014133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Derynck R., Roberts A. B., Winkler M. E., Chen E. Y., Goeddel D. V. Human transforming growth factor-alpha: precursor structure and expression in E. coli. Cell. 1984 Aug;38(1):287–297. doi: 10.1016/0092-8674(84)90550-6. [DOI] [PubMed] [Google Scholar]
  6. Gentry L. E., Twardzik D. R., Lim G. J., Ranchalis J. E., Lee D. C. Expression and characterization of transforming growth factor alpha precursor protein in transfected mammalian cells. Mol Cell Biol. 1987 May;7(5):1585–1591. doi: 10.1128/mcb.7.5.1585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Marquardt H., Hunkapiller M. W., Hood L. E., Todaro G. J. Rat transforming growth factor type 1: structure and relation to epidermal growth factor. Science. 1984 Mar 9;223(4640):1079–1082. doi: 10.1126/science.6320373. [DOI] [PubMed] [Google Scholar]
  9. Massagué J. Epidermal growth factor-like transforming growth factor. II. Interaction with epidermal growth factor receptors in human placenta membranes and A431 cells. J Biol Chem. 1983 Nov 25;258(22):13614–13620. [PubMed] [Google Scholar]
  10. Matsui Y., Halter S. A., Holt J. T., Hogan B. L., Coffey R. J. Development of mammary hyperplasia and neoplasia in MMTV-TGF alpha transgenic mice. Cell. 1990 Jun 15;61(6):1147–1155. doi: 10.1016/0092-8674(90)90077-r. [DOI] [PubMed] [Google Scholar]
  11. McGeady M. L., Kerby S., Shankar V., Ciardiello F., Salomon D., Seidman M. Infection with a TGF-alpha retroviral vector transforms normal mouse mammary epithelial cells but not normal rat fibroblasts. Oncogene. 1989 Nov;4(11):1375–1382. [PubMed] [Google Scholar]
  12. Merlino G. T. Epidermal growth factor receptor regulation and function. Semin Cancer Biol. 1990 Aug;1(4):277–284. [PubMed] [Google Scholar]
  13. Merlino G. T., Stahle C., Jhappan C., Linton R., Mahon K. A., Willingham M. C. Inactivation of a sperm motility gene by insertion of an epidermal growth factor receptor transgene whose product is overexpressed and compartmentalized during spermatogenesis. Genes Dev. 1991 Aug;5(8):1395–1406. doi: 10.1101/gad.5.8.1395. [DOI] [PubMed] [Google Scholar]
  14. Merlino G. T. Transgenic animals in biomedical research. FASEB J. 1991 Nov;5(14):2996–3001. doi: 10.1096/fasebj.5.14.1752364. [DOI] [PubMed] [Google Scholar]
  15. Rhodes J. A., Tam J. P., Finke U., Saunders M., Bernanke J., Silen W., Murphy R. A. Transforming growth factor alpha inhibits secretion of gastric acid. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3844–3846. doi: 10.1073/pnas.83.11.3844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. Salomon D. S., Kim N., Saeki T., Ciardiello F. Transforming growth factor-alpha: an oncodevelopmental growth factor. Cancer Cells. 1990 Dec;2(12):389–397. [PubMed] [Google Scholar]
  18. Sandgren E. P., Luetteke N. C., Palmiter R. D., Brinster R. L., Lee D. C. Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell. 1990 Jun 15;61(6):1121–1135. doi: 10.1016/0092-8674(90)90075-p. [DOI] [PubMed] [Google Scholar]
  19. Scharschmidt B. F. The natural history of hypertrophic gastrophy (Menetrier's disease). Report of a case with 16 year follow-up and review of 120 cases from the literature. Am J Med. 1977 Oct;63(4):644–652. doi: 10.1016/0002-9343(77)90210-8. [DOI] [PubMed] [Google Scholar]
  20. Todaro G. J., Rose T. M., Spooner C. E., Shoyab M., Plowman G. D. Cellular and viral ligands that interact with the EGF receptor. Semin Cancer Biol. 1990 Aug;1(4):257–263. [PubMed] [Google Scholar]
  21. Vassar R., Fuchs E. Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation. Genes Dev. 1991 May;5(5):714–727. doi: 10.1101/gad.5.5.714. [DOI] [PubMed] [Google Scholar]
  22. Watanabe S., Lazar E., Sporn M. B. Transformation of normal rat kidney (NRK) cells by an infectious retrovirus carrying a synthetic rat type alpha transforming growth factor gene. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1258–1262. doi: 10.1073/pnas.84.5.1258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Yoshida K., Kyo E., Tsujino T., Sano T., Niimoto M., Tahara E. Expression of epidermal growth factor, transforming growth factor-alpha and their receptor genes in human gastric carcinomas; implication for autocrine growth. Jpn J Cancer Res. 1990 Jan;81(1):43–51. doi: 10.1111/j.1349-7006.1990.tb02505.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES