Abstract
Hepatocyte growth factor (HGF), a stimulator of angiogenesis and cell migration, regulates the growth of a wide variety of cells by binding to its high-affinity receptor met and is involved in the growth and aggressiveness of several tumors. In this study we investigated the expression of HGF and met in normal endocrine cells and related neoplasms of the gut and pancreas to verify their possible role in tumor pathogenesis, growth, and aggressiveness. Normal tissues and 60 different endocrine tumors were immunostained using specific antibodies directed against HGF, met, and various hormones. HGF immunoreactivity (IR) was found in antroduodenal G cells, rectal enterochromaffin (EC) cells, and pancreatic A and B cells, whereas met IR was detected in antral EC and G cells, and in pancreatic B cells; 46 of 60 tumors examined were positive for HGF, and they were mainly represented by ECL-, EC-, and L-cell neoplasms. met IR was identified in 50/60 tumors of various phenotypes. HGF and met coexpression was found in 42/60 cases, most of which were represented by EC-cell tumors. HGF/met coexpression was significantly more frequent in ileolonic EC-cell tumors, which in the majority of cases were malignant, than in appendiceal EC-cell tumors, which were all benign. Our results demonstrated, for the first time, that HGF and met are specifically distributed in normal gut and pancreatic endocrine cells and, in addition, suggest that HGF and met may be implicated as autocrine/paracrine factors regulating the growth of gastroenteropancreatic endocrine tumors, mainly of ileocolonic EC-cell carcinoids.
Similar content being viewed by others
References
Pusztai L, Lewis CE, Lorenzen J, McGee JO. Growth factors: regulation of normal and neoplastic growth. J Pathol 169:191–201, 1993.
Cross M, Dexter TM. Growth factors in development, transformation, and tumorigenesis. Cell 64:271–280, 1991.
Sherbet GV, Lakshmi MS. Angiogenesis in cancer. In: Sherbet GV, Lakshmi MS (eds): The genetics of cancer: gene associated with cancer invasion, metastasis and cell proliferation. San Diego, CA: Academic Press, 1997;86–99.
Michalopoulos GK, Zarnegar R. Hepatocyte growth factor. Hepatology 15:149–155, 1992.
Wolf HK, Zarnegar R, Michalopoulos GK. Localization of hepatocyte growth factor in human and rat tissues: an immunohistochemical study. Hepatology 14:488–494, 1991.
Nakamura T, Nowaka K, Ichiara A. Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem Biophys Res Commun 122:1450–1459, 1984.
Nakamura T. Structure and function of hepatocyte growth factor. Progr Growth Factor Res 3:67–85, 1991.
Naka D, Ishii T, Yoshiyama Y, et al. Activation of hepatocyte growth factor by proteolytic conversion of a single chain to a heterodimer. J Cell Biol 267:20,114–20,119, 1991.
Naldini L, Tamagnone L, Vigna E, et al. Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor. EMBO J 11:4825–4833, 1992.
Weidner KM, Behrens J, Vandekerckhove J, Birchmeier W. Scatter factor: molecular characteristics and effect on invasiveness of epithelial cells. J Cell Biol 111:2097–2108, 1991.
Montesano R, Matsumoto K, Nakamura T, Orci L. Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor. Cell 29:901–908, 1991.
Tsarfaty I, Resau JH, Rulong S, Keydar I, Faletto DL, Vande Woude GF. The met protooncogene receptor and lumen formation. Science 257:1258–1261, 1992.
Bussolino F, Di Renzo MF, Ziche M, et al. Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 119:629–641, 1992.
Dean M, Park M, Le Beau MM, et al. The human met oncogene is related to the tyrosine kinase oncogenes. Nature 318:385–388, 1985.
Naldini L, Vigna E, Narsimhan RP, et al. Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the protooncogene c-met. Oncogene 6:501–504, 1991.
Giordano S, Ponzetto C, Di Renzo MF, Cooper CS, Comoglio PM. Tyrosine kinase receptor indistinguishable from the c-met protein. Nature 339:155–156, 1989.
Bottaro DP, Rubin JS, Faletto DL, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251:802–804, 1991.
Di Renzo MF, Narsimhan RP, Olivero M, et al. Expression of the Met/HGF receptor in normal and neoplastic human tissue. Oncogene 6:1997–2003, 1991.
Kermorgant S, Walker F, Hormi K, Dessirier V, Lewin MJM, Lehi T. Developmental expression and functionality of hepatocyte growth factor and c-met in human fetal digestive tissues. Gastroenterology 112:1635–1647, 1997.
Tuck AB, Park M, Sterns EE, Boag A, Elliott BE. Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma. Am J Pathol 148:225–232, 1996.
Natali PG, Nicotra MR, Di Renzo MF, et al. Expression of the c-Met/HGF receptor in human melanocytic neoplasms: demonstration of the relationship to malignant melanoma tumour progression. Br J Cancer 68:746–750, 1993.
Furukawa T, Duguid WP, Kobari M, Matsuno S, Tsao MS. Hepatocyte growth factor and met receptor expression in human pancreatic carcinogenesis. Am J Pathol 147:889–895, 1995.
Ebert M, Yokoyama M, Friess H, Büchler MW, Koec M. Coexpression of the c-met proto-oncogene and hepatocyte growth factor in human pancreatic cancer. Cancer Res 54:5775–5778, 1994.
Humphrey PA, Zhu X, Zarnegar R, et al. Hepatocyte growth factor and its receptor (c-Met) in prostatic carcinoma. Am J Pathol 147:386–396, 1995.
Kuniyasu H, Yasui W, Kitadai Y, Yokozaki H, Ito H, Tahara E. Frequent amplification of the c-met gene in scirrhous type stomach cancer. Biochem Biophys Res Commun 189:227–232, 1992.
Rao UNM, Sonmez-Alpan E, Michalopoulos GK. Hepatocyte growth factor and c-met in benign and malignant peripheral nerve sheath tumors. Hum Pathol 28:1066–1070, 1997.
Di Renzo MF, Olivero M, Ferro S, et al. Overexpression of the c-met/hgf receptor gene in human thyroid carcinomas. Oncogene 7:2549–2553, 1992.
Nilsson O, Wängberg B, Kölby L, Schultz GS, Ahlman H. Expression of transforming growth factor alpha and its receptor in human neuroendocrine tumors. Int J Cancer 60:645–651, 1995.
Krishnamurthy S, Dayal Y. Immunohistochemical expression of transforming growth factor alpha and epidermal growth factor receptor in gastrointestinal carcinoids. Am J Surg Pathol 21:327–333, 1997.
La Rosa S, Uccella S, Capella C, Chiaravalli AM, Sessa F. Localization of acidic fibroblast growth factor, fibroblast growth factor-4, transforming growth factor-α and epidermal growth factor receptor in human endocrine cells of the gut and related tumors. An immunohistochemical study. Appl Immunohistochem 6:199–208, 1998.
Nilsson O, Wängberg B, Theodorsson E, Skottner A, Ahlman H. Presence of IGF-I in human midgut carcinoid tumours—an autocrine regulator of carcinoid tumour growth? Int J Cancer 51:195–203, 1992.
Chaudhry A, Funa K, Öberg K. Expression of growth factor peptides and their receptors in neuroendocrine tumors of the digestive system. Acta Oncologica 32:107–114, 1993.
Chaudhry A, Papanicolaou V, Öberg K, Heldin CH, Funa K. Expression of platelet-derived growth factor and its receptors in neuroendocrine tumors of the digestive system. Cancer Res 52:1006–1012, 1992.
Nilsson O, Wängberg B, McRae A, Dahlstrom A, Ahlman H. Growth factors and carcinoid tumours. Acta Oncologica 32:115–124, 1993.
Terris B, Scoazec JY, Rubbia L, et al. Expression of vascular endothelial growth factor in digestive neuroendocrine tumours. Histopathology 32:133–138, 1998.
La Rosa S, Uccella S, Billo P, Facco C, Sessa F, Capella C. Immunohistochemical localization of α- and βA-subunits of inhibin/activin in human normal endocrine cells and related tumors of the digestive system. Virchows Arch 434:29–36, 1999.
La Rosa S, Chiaravalli AM, Capella C, Uccella S, Sessa F. Immunohistochemical localization of acidic fibroblast growth factor in normal human enterochromaffin cells and related gastrointestinal tumours. Virchows Arch 430:117–124, 1997.
Bordi C, Falchetti A, Buffa R, et al. Production of basic fibroblast growth factor by gastric carcinoid tumors and their putative cells of origin. Hum Pathol 25:175–180, 1994.
Bordi C, Caruana P, D’Adda T, Azzoni C. Smooth muscle cell abnormalities associated with gastric ECL cell carcinoids. Endocr Pathol 6:103–113, 1995.
Wulbrand U, Wied M, Zofel P, Goke B, Arnold R, Fehmann HC. Growth factor receptor expression in human gastroenteropancreatic tumours. Eur J Clin Invest 28:1038–1049, 1998.
Papotti M, Olivero M, Volante M, et al. Expression of hepatocyte growth factor (HGF) and its receptor (met) in medullary carcinoma of the thyroid. Endocr Pathol 11:19–30, 2000.
Kinoshita Y, Kishi K, Asahara M, et al. Production and activation of hepatocyte growth factor during the healing of rat gastric ulcers. Digestion 58:225–231, 1997.
Schmassmann A, Stettler C, Poulsom R, et al. Roles of hepatocyte growth factor and its receptor met during gastric ulcer healing in rats. Gastroenterology 113:1858–1872, 1997.
Kolatsi-Joannou M, Moore R, Winyard PJD, Woolf AS. Expression of hepatocyte growth factor/scatter factor and its receptor, Met, suggests roles in human embryonic organogenesis. Pediatr Res 41:657–665, 1997.
Lan HY, Mu W, Nikolic-Paterson DJ, Atkins RC. A novel, simple, reliable, and sensitive method for multiple immunoenzyme staining: use of microwave oven heating to block antibody cross reactivity and retrieve antigens. J Histochem Cytochem 43:97–102, 1995.
Beattie GM, Cirulli V, Lopez AD, Hayek A. Ex vivo expansion of human pancreatic endocrine cells. J Clin Endocrinol Metab 82:1852–1856, 1997.
Rong S, Jeffers M, Resau JH, Tsarfaty I, Oskersson M, Vande Woude GF. Met expression and sarcoma tumorigenicity. Cancer Res 53:5355–5360, 1993.
Cortner J, Vande Woude GF, Rong S. The met-HGF/SF autocrine signalling mechanism is involved in sarcomagenesis. In: Goldberg ID, Rosen EN (eds): Epithelial mesenchimal interaction in cancer. Basel, Switzerland: Birkhauser Verlag, 1995; 89–121.
Bellusci S, Moens G, Gaudino G, et al. Creation of a hepatocyte growth factor/scatter factor autocrine loop in carcinoma cells induces invasive properties associated with increased tumorigenicity. Oncogene 9:1091–1099, 1994.
Rong S, Oskarsson M, Faletto D, et al. Tumorigenesis induced by coexpression of human hepatocyte growth factor and human met protooncogene leads to high levels of expression of the ligand and receptor. Cell Growth Differ 4:563–569, 1993.
Rong S, Segal S, Anver M, Resau JH, Vande Woude GF. Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor/scatter factor autocrine stimulation. Proc Natl Acad Sci USA 91:4731–4735, 1994.
Rindi G, Luinetti O, Cornaggia M, Capella C, Solcia E. Three subtypes of gastric argyrophil carcinoids and gastric neuroendocrine carcinomas: a clinicopathologic study. Gastroenterology 104:994–1006, 1993.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
La Rosa, S., Uccella, S., Capella, C. et al. Localization of hepatocyte growth factor and its receptor met in endocrine cells and related tumors of the gut and pancreas: An immunohistochemical study. Endocr Pathol 11, 315–329 (2000). https://doi.org/10.1385/EP:11:4:315
Issue Date:
DOI: https://doi.org/10.1385/EP:11:4:315