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Developmental expression of transforming growth factor-α and epidermal growth factor receptor proteins in the human pancreas and digestive tract

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Abstract

This study was designed to localize transforming growth factor alpha (TGF-α) and epidermal growth factor receptor (EGFR) expression in the developing human gastrointestinal tract and pancreas. Immunohistochemical techniques using specific antibodies against human TGF-α and EGFR were performed on digestive tissues of fetuses from 9 to 10 to 24 weeks of gestation, children and adults. In fetuses, TGF-α and EGFR proteins were expressed in all epithelial tissues studied with a good correlation and from an age as early as 9 to 10 weeks of gestation, except for TGF-α in the esophagus. The strongest TGF-α immunostaining was noted in the stomach and the proximal colon. Unexpectedly, immunoreactive gut endocrine cells were observed with the two antibodies used. Relatively numerous in fetuses, they decreased in number with age and were rare in adults particularly along the colon. Enteroglucagon-secreting cells were shown to express TGF-α while some gastrin, somatostatin and pancreatic glucagon cells were immunostained with EGFR antibodies. The presence of TGF-α and of its recetor in digestive tract epithelium and pancreatic tissues early in fetal life suggests a functional role for TGF-α during the developmental process of the digestive system. We demonstrate that TGF-α is also produced by endocrine cells and might have an additional mode of action other than paracrine, at least during fetal life.

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References

  • Barnard JA, Polk WH, Moses HL, Coffey RJ (1991) Production of transforming growth factor-α by normal rat small intestine. Am J Physiol 261:C994-C1000

    Google Scholar 

  • Beauchamp RD, Barnard JA, McCutchen CM, Cherner JA, Coffey RJ (1989) Localization of transforming growth factor α and its receptor in gastric mucosal cells: implication for regulatory role in acid secretion and mucosal renewal. J Clin Invest 84:1017–1023

    Google Scholar 

  • Bennett C, Paterson IM, Corbishley CM, Luqmani YA (1989) Expression of growth factor and epidermal growth factor receptor encoded transcripts in human gastric tissues. Cancer Res 49:2104–2111

    Google Scholar 

  • Brown PI, Lam R, Lakshmanan J, Fisher DA (1990) Transforming growth factor alpha in developing rats. Endocrinol Metab 22:E256-E260

    Google Scholar 

  • Burton PBJ, Quirke P, Sorensen CM, Nehlsen-Cannarella SL, Bailley LL, Knight DE (1993) Growth factor expression during rat development: a comparison of TGF-β3, TGF-α, bFGF, PDGF and PDGF-R. Int Exp Pathol 74:87–96

    Google Scholar 

  • Cartlidge SA, Elder JB (1989) Transforming growth factor alpha and epidermal growth factor levels in normal human gastrointestinal mucosa. Br J Cancer 60:657–660

    Google Scholar 

  • Damjanov I, Mildner B, Knowles BB (1986) Immunohistochemical localization of the epidermal growth factor receptor in normal human tissues. Lab Invest 55:588–592

    Google Scholar 

  • Derynck R, Roberts AB, Eaton DH, Winkler ME, Goeddel DV (1985) Human transforming growth factor-α: precursor sequence, gene structure, and heterologous expression. Cancer Cells 3:79–86

    Google Scholar 

  • Dollander A, Fenart R (1975) Developpement définitif des formes extérieures et croissance du corps de l'embryon puis du foetus. In: Elements d'embryologie. I. Embryologie générale comparée et humaine. Flammarion, Paris, pp 294–300

    Google Scholar 

  • Grand RY, Watkins JB, Torti FM (1976) Development of the human gastrointestinal tract. Gastroenterology 70:790–810

    Google Scholar 

  • Gullick WJ, Downward J, Parker PJ, Whittle N, Kris R, Schlessinger J, Ullrich A, Waterfield MD (1985) The structure and function of the EGFr studied by using antisynthetic peptide antibodies. Proc R Soc London [Biol] 226:127–134

    Google Scholar 

  • Huang S, Trujillo JM, Chakrabarty S (1992) Proliferation of human colon cancer cells: role of epidermal growth factor and transforming growth factor α. Int J Cancer 52:978–986

    Google Scholar 

  • Jankowski J, Murphy S, Coghill G, Grant A, Wormsley KG, Sanders DSA, Kerr M, Hopwood D (1992) Epidermal growth factor receptors in the oesophagus. Gut 33:439–443

    Google Scholar 

  • Karnes WEJ, Walsh JH, Wu SV, Kim RS, Martin MG, Wong HC, Mendelsohn J, Park JG, Cuttitta F (1992) Autonomous proliferation of colon cancer cells that coexpress transforming growth factor alpha and its receptor. Gastroenterology 102:474–485

    Google Scholar 

  • Kobrin MS, Samsoondar J, Kudlow JE (1986) α-Transforming growth factor secreted by untransformed bovine anterior pituitary cells in culture. II. Identification using a sequence-specific monoclonal antibody. J Biol Chem 261:14414–14419

    Google Scholar 

  • Lebenthal E (1989) Human gastrointestinal development. Raven Press, New York

    Google Scholar 

  • Lee DC, Rochford R, Todaro GJ, Villarreal LP (1985) Developmental expression of rat transforming growth factor-α mRNA. Mol Cell Biol 5:3644–3646

    Google Scholar 

  • Lehy T, Voillemot N, Dubrasquet M, Dufougeray F (1975) Gastrin cell hyperplasia in rats with chronic antral stimulation. Gastroenterology 68:71–82

    Google Scholar 

  • Lehy T, Peranzi G, Cristina ML (1981) Correlative immunocytochemical and electron microscopic studies: Identification of enteroglucagon, somatostatin and pancreatic polypeptide-like-containing cells in the human colon. Histochemistry 71:67–80

    Google Scholar 

  • Lehy T, Puccio F, Chariot J, Labeille D (1986) Stimulating effect of bombesin on the growth of gastrointestinal tract and pancreas in suckling rats. Gastroenterology 90:1942–1949

    Google Scholar 

  • Malden LT, Novak U, Burgess AW (1989) Expression of transforming growth factor alpha messenger RNA in the normal and neoplastic gastrointestinal tract. Int J Cancer 43:380–384

    Google Scholar 

  • Markowitz SD, Molkentin K, Gerbic C, Jackson J, Stellato T, Wilson JKV (1990) Growth stimulation by coexpression of transforming growth factor-α and epidermal growth factor-receptor in normal and adenomatous human colon epithelium. J Clin Invest 86:356–362

    Google Scholar 

  • Marquardt H, Hunkapiller MW, Hood LE, Todaro GJ (1984) Rat transforming growth factor type 1: structure and relation to epidermal growth factor. Science 223:1079–1082

    Google Scholar 

  • Ménard D, Pothier P (1991) Radioautographic localization of epidermal growth factor receptors in human fetal gut. Gastroenterology 101:640–649

    Google Scholar 

  • Miettinen PJ (1993) Transforming growth factor-α and epidermal growth factor expression in human fetal gastrointestinal tract. Pediatr Res 33:481–486

    Google Scholar 

  • Miettinen PJ, Heikinheimo K (1992) Transforming growth factor-alpha (TGF-alpha) and insulin gene expression in human fetal pancreas. Development 114:833–840

    Google Scholar 

  • Miettinen PJ, Perheentupa J, Otonkosdki T, Lahteenmaki A, Panula P (1989) EGF- and TGF-α-like peptides in human fetal gut. Pediatr Res 26:25–30

    Google Scholar 

  • Müller W, Borchard F (1992) Expression of transforming growth factor-alpha in gastric carcinoma and normal gastric mucosa cells. Cancer 69:2871–2875

    Google Scholar 

  • Oliver AM (1988) Epidermal growth factor receptor expression in human foetal tissues is age-dependent. Br J Cancer 58:461–463

    Google Scholar 

  • Orsini B, Calabro A, Milani S, Grappone C, Herbst H, Surrenti C (1993) Localization of epidermal growth factor/transforming growth factor-α receptor in the human gastric mucosa. An immunohistochemical and in situ hybridization study. Virchows Arch [A] 423:57–63

    Google Scholar 

  • Pérez-Tomas R, Culleré X, Diaz C (1993) Immunohistochemical localization of transforming growth factor-α in the developing rat colon. Gastroenterology 104:789–795

    Google Scholar 

  • Pothier P, Ménard D (1988) Presence and characteristics of epidermal growth factor receptors in human fetal small intestine and colon. FEBS Lett 228:113–117

    Google Scholar 

  • Puccio F, Lehy T (1988) Oral administration of epidermal growth factor in suckling rats stimulates cell DNA synthesis in fundic and antral mucosae as well as in intestinal mucosa and pancreas. Regul Pept 20:53–64

    Google Scholar 

  • Puccio F, Lehy T (1989) Bombesin ingestion stimulates epithelial digestive cell proliferation in suckling rats. Am J Physiol 256:G328-G334

    Google Scholar 

  • Sakai K, Mori S, Kawamoto T, Taniguchi S, Kabori O, Morioka Y, Kuroki S, Kano K (1986) Expression of epidermal growth factor receptors on normal human gastric epithelia and gastric carcinomas. J Natl Cancer Inst 77:1047–1052

    Google Scholar 

  • Scheving LA, Shiurba RA, Nguyens TD, Gray GM (1989) Epidermal growth factor receptor of the intestinal enterocyte. Localization to basolateral but not brush border membrane. J Biol Chem 264:1735–1741

    Google Scholar 

  • Smith JJ, Derynck R, Korc M (1987) Production of transforming growth factor alpha in human pancreatic cancer cells: evidence for a superagonist autocrine cycle. Proc Natl Acad Sci USA 84:7567–7570

    Google Scholar 

  • Sorvillo JM, McCormack ES, Yanes L, Valenzuela D, Reynolds FHJ (1990) Preparation and characterization of monoclonal antibodies specific for human transforming growth factor-α. Oncogene 5:377–386

    Google Scholar 

  • Sottili M, Sternini C, Brecha NC, Lezoche E, Walsh JH (1992) Transforming growth factor α receptor binding sites in the canine gastrointestinal tract. Gastroenterology 103:1427–1436

    Google Scholar 

  • Thomas DM, Nasim MM, Gullick WJ, Alison MR (1992) Immunoreactivity of transforming growth factor alpha in the normal adult gastrointestinal tract. Gut 33:628–631

    Google Scholar 

  • Thompson JF (1988) Specific receptors for epidermal growth factor in rat intestinal microvillus membranes. Am J Physiol 254:G429-G435

    Google Scholar 

  • Wilcox JN, Derynck R (1988) Developmental expression of transforming growth factor alpha and beta in mouse fetus. Mol Cell Biol 8:3415–3422

    Google Scholar 

  • Wright NA, Poulsom R, Stamp G, Van Noorden S, Sarraf C, Elia G, Ahnen D, Jeffery R, Longcroft J, Pike C, Rio MC, Chambon P (1993) Trefoil peptide gene expression in gastrointestinal epithelial cells in inflammatory bowel disease. Gastroenterology 104:12–20

    Google Scholar 

  • Yasui W, Sumiyoshi H, Hata J, Kameda T, Ochiai A, Ito H, Tahara E (1988) Expression of epidermal growth factor receptor in human gastric and colonic carcinomas. Cancer Res 48:137–141

    Google Scholar 

  • Yasui W, Ji ZO, Kuniyasu H, Ayhan A, Yokozaki H, Ito H, Tahara E (1992) Expression of transforming growth factor alpha in human tissues: immunohistochemical study and Northern blot analysis. Virchows Arch [A] 421:513–519

    Google Scholar 

  • Yoshida K, Kyo E, Tsuda T, Tsujino T, Ito M, Niimoto M, Tahara E (1990) EGF and TGF-α, the ligands of hyperproduced EGFR in human esophageal carcinoma cells, act as autocrine growth factors. Int J Cancer 45:131–135

    Google Scholar 

  • Zimmerman RP, Gates TS, Boehmer CG, Mantyh PW (1988) Epidermal growth factor receptors in the human colon. Eur J Pharmacol 150:201–202

    Google Scholar 

  • Ziober BL, Willson JKV, Hymphrey LE, Childress-Fields K, Brattain MG (1993) Autocrine transforming growth factor-α is associated with progression of transformed properties in human colon cancer cells. J Biol Chem 268:691–698

    Google Scholar 

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Hormi, K., Lehy, T. Developmental expression of transforming growth factor-α and epidermal growth factor receptor proteins in the human pancreas and digestive tract. Cell Tissue Res 278, 439–450 (1994). https://doi.org/10.1007/BF00331362

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  • DOI: https://doi.org/10.1007/BF00331362

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