Abstract
BACKGROUND: The role that exogenous transforming growth factor-alpha (TGF-alpha) may exert on cell proliferation in vivo is poorly understood. AIM: To investigate the effect of rat TGF-alpha on epithelial cell proliferation in all suckling rat digestive tissues and to compare it with that of rat epidermal growth factor (EGF). ANIMAL AND METHODS: TGF-alpha and EGF were given three times daily either subcutaneously (10 or 20 micrograms/kg) or intraperitoneally (100 micrograms/kg) to rats from the ninth postnatal day. Cell proliferation was assessed through 5-bromo- 2-deoxyuridine incorporation and estimation of labelling indices. RESULTS: For both growth factors, the highest dose given for only two days significantly increased stomach and intestinal weights compared with controls (p < 0.05 to p < 0.001). The proliferative responded depended on the dose given, colonic mucosa being the most sensitive whereas oxyntic mucosa remained unresponsive. TGF-alpha was as potent as EGF in stimulating epithelial cell proliferation in antral, duodenal, and colonic mucosae. However, EGF was more active on oesophageal and jejunal cell proliferation whereas TGF-alpha was more active on pancreatic exocrine cell proliferation and the differences between the two growth factor treated groups were significant. CONCLUSIONS: These results prove for the first time the stimulating effect in vivo of exogenous rat TGF-alpha on epithelial cell proliferation in rat digestive tissues during the developmental period and support a functional role for TGF-alpha at that time.
Full text
PDF






Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Alvares E. P. The effect of fasting on cell proliferation in the gastric mucosa of the 14-day-old suckling rat. Braz J Med Biol Res. 1992;25(6):641–649. [PubMed] [Google Scholar]
- Arsenault P., Ménard D. Stimulatory effects of epidermal growth factor on deoxyribonucleic acid synthesis in the gastrointestinal tract of the suckling mouse. Comp Biochem Physiol B. 1987;86(1):123–127. doi: 10.1016/0305-0491(87)90186-6. [DOI] [PubMed] [Google Scholar]
- Bamba T., Tsujikawa T., Hosoda S. Effect of epidermal growth factor by different routes of administration on the small intestinal mucosa of rats fed elemental diet. Gastroenterol Jpn. 1993 Aug;28(4):511–517. doi: 10.1007/BF02776949. [DOI] [PubMed] [Google Scholar]
- 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]
- Chen M. C., Lee A. T., Karnes W. E., Avedian D., Martin M., Sorvillo J. M., Soll A. H. Paracrine control of gastric epithelial cell growth in culture by transforming growth factor-alpha. Am J Physiol. 1993 Feb;264(2 Pt 1):G390–G396. doi: 10.1152/ajpgi.1993.264.2.G390. [DOI] [PubMed] [Google Scholar]
- Chen M. C., Lee A. T., Soll A. H. Mitogenic response of canine fundic epithelial cells in short-term culture to transforming growth factor alpha and insulinlike growth factor I. J Clin Invest. 1991 May;87(5):1716–1723. doi: 10.1172/JCI115189. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Davies N., Kapur P., Gillespie J., Guillou P. J., Poston G. J. Transforming growth factor alpha is trophic to pancreatic cancer in vivo. Gut. 1993 Aug;34(8):1097–1098. doi: 10.1136/gut.34.8.1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Decker S. J. Epidermal growth factor and transforming growth factor-alpha induce differential processing of the epidermal growth factor receptor. Biochem Biophys Res Commun. 1990 Jan 30;166(2):615–621. doi: 10.1016/0006-291x(90)90853-f. [DOI] [PubMed] [Google Scholar]
- Dembinski A. B., Johnson L. R. Effect of epidermal growth factor on the development of rat gastric mucosa. Endocrinology. 1985 Jan;116(1):90–94. doi: 10.1210/endo-116-1-90. [DOI] [PubMed] [Google Scholar]
- Dempsey P. J., Goldenring J. R., Soroka C. J., Modlin I. M., McClure R. W., Lind C. D., Ahlquist D. A., Pittelkow M. R., Lee D. C., Sandgren E. P. Possible role of transforming growth factor alpha in the pathogenesis of Ménétrier's disease: supportive evidence form humans and transgenic mice. Gastroenterology. 1992 Dec;103(6):1950–1963. doi: 10.1016/0016-5085(92)91455-d. [DOI] [PubMed] [Google Scholar]
- Ebner R., Derynck R. Epidermal growth factor and transforming growth factor-alpha: differential intracellular routing and processing of ligand-receptor complexes. Cell Regul. 1991 Aug;2(8):599–612. doi: 10.1091/mbc.2.8.599. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gan B. S., Hollenberg M. D., MacCannell K. L., Lederis K., Winkler M. E., Derynck R. Distinct vascular actions of epidermal growth factor-urogastrone and transforming growth factor-alpha. J Pharmacol Exp Ther. 1987 Jul;242(1):331–337. [PubMed] [Google Scholar]
- Goldenring J. R., Tsunoda Y., Stoch S. A., Coffey R. J., Modlin I. M. Transforming growth factor-alpha (TGF alpha) inhibition of parietal cell secretion: structural requirements for activity. Regul Pept. 1993 Jan 22;43(1-2):37–47. doi: 10.1016/0167-0115(93)90405-w. [DOI] [PubMed] [Google Scholar]
- Guglietta A., Lesch C. A., Romano M., McClure R. W., Coffey R. J. Effect of transforming growth factor-alpha on gastric acid secretion in rats and monkeys. Dig Dis Sci. 1994 Jan;39(1):177–182. doi: 10.1007/BF02090079. [DOI] [PubMed] [Google Scholar]
- Hormi K., Lehy T. Developmental expression of transforming growth factor-alpha and epidermal growth factor receptor proteins in the human pancreas and digestive tract. Cell Tissue Res. 1994 Dec;278(3):439–450. doi: 10.1007/BF00331362. [DOI] [PubMed] [Google Scholar]
- Hormi K., Onolfo J. P., Gres L., Lebraud V., Lehy T. Developmental expression of transforming growth factor-alpha in the upper digestive tract and pancreas of the rat. Regul Pept. 1995 Jan 5;55(1):67–77. doi: 10.1016/0167-0115(94)00093-d. [DOI] [PubMed] [Google Scholar]
- Ishimura K., Yoshinaga-Hirabayashi T., Fujita H., Ishii-Ohba H., Inano H., Tamaoki B. Light and electron microscopic immunocytochemistry on the localization of 3 beta-hydroxysteroid dehydrogenase/isomerase in the bovine adrenal cortical cells. Histochemistry. 1988;89(1):35–39. doi: 10.1007/BF00496581. [DOI] [PubMed] [Google Scholar]
- Karnes W. E., Jr, Walsh J. H., Wu S. V., Kim R. S., Martin M. G., Wong H. C., Mendelsohn J., Park J. G., Cuttitta F. Autonomous proliferation of colon cancer cells that coexpress transforming growth factor alpha and its receptor. Variable effects of receptor-blocking antibody. Gastroenterology. 1992 Feb;102(2):474–485. doi: 10.1016/0016-5085(92)90093-e. [DOI] [PubMed] [Google Scholar]
- Konturek S. J., Brzozowski T., Majka J., Dembinski A., Slomiany A., Slomiany B. L. Transforming growth factor alpha and epidermal growth factor in protection and healing of gastric mucosal injury. Scand J Gastroenterol. 1992 Aug;27(8):649–655. doi: 10.3109/00365529209000134. [DOI] [PubMed] [Google Scholar]
- Markowitz S. D., Molkentin K., Gerbic C., Jackson J., Stellato T., Willson J. K. Growth stimulation by coexpression of transforming growth factor-alpha and epidermal growth factor-receptor in normal and adenomatous human colon epithelium. J Clin Invest. 1990 Jul;86(1):356–362. doi: 10.1172/JCI114709. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Myrdal S. E., Twardzik D. R., Auersperg N. Cell-mediated co-action of transforming growth factors: incubation of type beta with normal rat kidney cells produces a soluble activity that prolongs the ruffling response to type alpha. J Cell Biol. 1986 Apr;102(4):1230–1234. doi: 10.1083/jcb.102.4.1230. [DOI] [PMC free article] [PubMed] [Google Scholar]
- O'Loughlin E. V., Chung M., Hollenberg M., Hayden J., Zahavi I., Gall D. G. Effect of epidermal growth factor on ontogeny of the gastrointestinal tract. Am J Physiol. 1985 Dec;249(6 Pt 1):G674–G678. doi: 10.1152/ajpgi.1985.249.6.G674. [DOI] [PubMed] [Google Scholar]
- Polk W. H., Jr, Dempsey P. J., Russell W. E., Brown P. I., Beauchamp R. D., Barnard J. A., Coffey R. J., Jr Increased production of transforming growth factor alpha following acute gastric injury. Gastroenterology. 1992 May;102(5):1467–1474. doi: 10.1016/0016-5085(92)91703-7. [DOI] [PubMed] [Google Scholar]
- Pollack P. F., Goda T., Colony P. C., Edmond J., Thornburg W., Korc M., Koldovský O. Effects of enterally fed epidermal growth factor on the small and large intestine of the suckling rat. Regul Pept. 1987 Mar;17(3):121–132. doi: 10.1016/0167-0115(87)90021-8. [DOI] [PubMed] [Google Scholar]
- Potten C. S., Owen G., Hewitt D., Chadwick C. A., Hendry H., Lord B. I., Woolford L. B. Stimulation and inhibition of proliferation in the small intestinal crypts of the mouse after in vivo administration of growth factors. Gut. 1995 Jun;36(6):864–873. doi: 10.1136/gut.36.6.864. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Puccio F., Lehy T. Bombesin ingestion stimulates epithelial digestive cell proliferation in suckling rats. Am J Physiol. 1989 Feb;256(2 Pt 1):G328–G334. doi: 10.1152/ajpgi.1989.256.2.G328. [DOI] [PubMed] [Google Scholar]
- Puccio F., Lehy T. Oral administration of epidermal growth factor in suckling rats stimulates cell DNA synthesis in fundic and antral gastric mucosae as well as in intestinal mucosa and pancreas. Regul Pept. 1988 Jan;20(1):53–64. doi: 10.1016/0167-0115(88)90057-2. [DOI] [PubMed] [Google Scholar]
- Pérez-Tomás R., Culleré X., Díaz C. Immunohistochemical localization of transforming growth factor alpha in the developing rat colon. Gastroenterology. 1993 Mar;104(3):789–795. doi: 10.1016/0016-5085(93)91014-9. [DOI] [PubMed] [Google Scholar]
- 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]
- Romano M., Polk W. H., Awad J. A., Arteaga C. L., Nanney L. B., Wargovich M. J., Kraus E. R., Boland C. R., Coffey R. J. Transforming growth factor alpha protection against drug-induced injury to the rat gastric mucosa in vivo. J Clin Invest. 1992 Dec;90(6):2409–2421. doi: 10.1172/JCI116132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rutten M. J., Dempsey P. J., Solomon T. E., Coffey R. J., Jr TGF-alpha is a potent mitogen for primary cultures of guinea pig gastric mucous epithelial cells. Am J Physiol. 1993 Aug;265(2 Pt 1):G361–G369. doi: 10.1152/ajpgi.1993.265.2.G361. [DOI] [PubMed] [Google Scholar]
- 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]
- Schaudies R. P., Savage C. R., Jr Isolation of rat epidermal growth factor (r-EGF): chemical, biological and immunological comparisons with mouse and human EGF. Comp Biochem Physiol B. 1986;84(4):497–505. doi: 10.1016/0305-0491(86)90113-6. [DOI] [PubMed] [Google Scholar]
- Scheving L. A., Tsai T. H., Scheving L. E., Hoke W. S. Effect of epidermal growth factor (EGF) on [3H]TdR incorporation into DNA in ad lib fed and fasted CD2F1 mice. Peptides. 1987 Mar-Apr;8(2):347–353. doi: 10.1016/0196-9781(87)90110-0. [DOI] [PubMed] [Google Scholar]
- Schreiber A. B., Winkler M. E., Derynck R. Transforming growth factor-alpha: a more potent angiogenic mediator than epidermal growth factor. Science. 1986 Jun 6;232(4755):1250–1253. doi: 10.1126/science.2422759. [DOI] [PubMed] [Google Scholar]
- Sharp R., Babyatsky M. W., Takagi H., Tågerud S., Wang T. C., Bockman D. E., Brand S. J., Merlino G. Transforming growth factor alpha disrupts the normal program of cellular differentiation in the gastric mucosa of transgenic mice. Development. 1995 Jan;121(1):149–161. doi: 10.1242/dev.121.1.149. [DOI] [PubMed] [Google Scholar]
- Stern P. H., Krieger N. S., Nissenson R. A., Williams R. D., Winkler M. E., Derynck R., Strewler G. J. Human transforming growth factor-alpha stimulates bone resorption in vitro. J Clin Invest. 1985 Nov;76(5):2016–2019. doi: 10.1172/JCI112202. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Toyoda S., Lee P. C., Lebenthal E. Interaction of epidermal growth factor with specific binding sites of enterocytes isolated from rat small intestine during development. Biochim Biophys Acta. 1986 Apr 29;886(2):295–301. doi: 10.1016/0167-4889(86)90148-5. [DOI] [PubMed] [Google Scholar]
- Winkler M. E., O'Connor L., Winget M., Fendly B. Epidermal growth factor and transforming growth factor alpha bind differently to the epidermal growth factor receptor. Biochemistry. 1989 Jul 25;28(15):6373–6378. doi: 10.1021/bi00441a033. [DOI] [PubMed] [Google Scholar]
- Yoshida K., Kyo E., Tsuda T., Tsujino T., Ito M., Niimoto M., Tahara E. EGF and TGF-alpha, the ligands of hyperproduced EGFR in human esophageal carcinoma cells, act as autocrine growth factors. Int J Cancer. 1990 Jan 15;45(1):131–135. doi: 10.1002/ijc.2910450124. [DOI] [PubMed] [Google Scholar]
- Ziober B. L., Willson J. K., Hymphrey L. E., Childress-Fields K., Brattain M. G. Autocrine transforming growth factor-alpha is associated with progression of transformed properties in human colon cancer cells. J Biol Chem. 1993 Jan 5;268(1):691–698. [PubMed] [Google Scholar]