Growth Factors and Growth Factor Receptors in Chronic Pancreatitis, and the Relation to Pancreatic Cancer

  • Helmut Friess
  • Pascal Berberat
  • Markus W. Büchler


Chronic pancreatitis is an inflammatory disease of the pancreas that leads to persistent and progressive morphological and functional alterations of the whole organ and in its terminal state severe exocrine and endocrine insufficiencies are present. (1, 2, 3). Morphologically, chronic inflammation of the pancreas is also associated with pancreatic head enlargement, calcifications of the parenchyma, cysts, necrosis, and pancreatic stones (4, 5, 6). The continuous tissue destruction and subsequent remodeling causes finally the two major clinical symptoms: upper abdominal pain and maldigestion.


Chronic Pancreatitis Acinar Cell Ductal Cell Human Pancreatic Cancer Normal Pancreas 
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  1. 1.
    Sarles H, Bernard JP, Johnson C, and Chir M. Pathogenesis and epidemiology of chronic pancreatitis. Annu Rev Med 1989; 40:453–468.PubMedCrossRefGoogle Scholar
  2. 2.
    DiMagno EP, Layer P, and Clain JE. Chronic pancreatitis. In: Go VLW, DiMagno EP, Gardner JD, Lebenthal E, Reber HA, and Scheele GA, The exocrine pancreas: biology, pathobiology, and diseases. Raven, New York, 1993; pp. 665–706.Google Scholar
  3. 3.
    DiMagno EP. A short, elective history of exocrine pancreatic insufficiency and chronic pancreatitis. Gastroenterology 1993; 104:1255–1262.PubMedGoogle Scholar
  4. 4.
    Friess H, Müller M, Ebert M, and Büchler MW. Chronic pancreatitis with inflammatory enlargement of the pancreatic head. Zentralblatt für Chirurgie 1995; 120:292–297.PubMedGoogle Scholar
  5. 5.
    Bockman DE. Surgical anatomy of the pancreas and adjacent structures. In: Beger HG, Büchler M, and Malfertheiner P (eds), Standards in pancreatic surgery. Springer, Heidelberg-New York, 1993; pp. 1–9.CrossRefGoogle Scholar
  6. 6.
    Oertel JE, Heffess CS, and Oertel YC. Pancreas. In: Sternberg SS (ed), Diagnostic surgical pathology, Raven, New York, 1989; pp. 1057–1093.Google Scholar
  7. 7.
    Di Magno EP, Layer P, and Clain JE. Chronic pancreatitis. In: Go VLW, Di Mango EP, Gardner JD, Lebenthal E, Reber HA, and Scheele GA (eds), The pancreas. Raven, New York, pp. 707–740.Google Scholar
  8. 8.
    Di Magno EP. Conservative management of chronic pancreatitis. In: Beger HG, Büchler M, Malfertheiner P (eds), Standards in pancreatic surgery. Springer, Heidelberg-New York, 1993; pp.325–331.CrossRefGoogle Scholar
  9. 9.
    Bockman DE, Büchler M, Malfertheiner P, and Beger HG. Analysis of nerves in chronic pancreatitis. Gastroenterology 1988; 94:1459–1469.PubMedGoogle Scholar
  10. 10.
    Büchler M, Weihe E, Friess H, Malfertheiner P, Bockman E, Müller S, Nohr D, and Beger HG. Changes in peptidergic innervation in chronic pancreatitis. Pancreas 1992; 7:183–192.PubMedCrossRefGoogle Scholar
  11. 11.
    Weihe E, Nohr D, Müller S, Büchler M, Friess H, and Zentel HJ. The tachykinin neuroimmune connection in inflammatory pain. Ann Y Acad Sci 1991; 632:283–295.PubMedCrossRefGoogle Scholar
  12. 12.
    Sarles H, Dagom JC, Giorgi D, and Bernard JP. Remaining pancreatic stone protein as “lithostatine”. Gastroenterology 1990; 99:900–905.PubMedGoogle Scholar
  13. 13.
    Klöppel G and Maillet B. Pseudocysts in chronic pancreatitis: a morphological analysis of 57 resection specimens and 9 autopsy pancreata. Pancreas 1991; 6:266–274.PubMedCrossRefGoogle Scholar
  14. 14.
    Noronha, M, Bordalo O, Dreiling DA. Alcohol and the pancreas. II. Pancreatic morphology of ad van ced alcoholic pancreatitis. Am J Gastroenterol 1981; 76:120–124.PubMedGoogle Scholar
  15. 15.
    Braganza JM. Pancreatic disease: a casualty of hepatic “detoxification”? Lancet ii 1983; 8357:1000–1003.CrossRefGoogle Scholar
  16. 16.
    DiMagno EP. A short, eclectic history of exocrine pancreatic insufficiency and chronic pancreatitis. Gastroenterology 1993; 104:1255–1262.PubMedGoogle Scholar
  17. 17.
    Di Sebastiano P, Fink Th, Weihe E, Friess H, Innocenti P, Beger HG, and Büchler MW. Immune cell infiltration and growth-associated protein-43 expression correlate with pain in chronic pancreatitis. Gastroenterology 1997; 112:1648–1655.PubMedCrossRefGoogle Scholar
  18. 18.
    Hunger R, Müller Ch, Zgraggen K, Friess H, and Büchler MW. Cytotoxic cells are activated in cellular infiltrates of alcoholic chronic pancreatitis. Gastroenterology 1997; 112:1656–1663.PubMedCrossRefGoogle Scholar
  19. 19.
    Friess H, Cantero H, Graber H, Tang WH, Guo XZ, Kashiwagi M, et al. Enhanced urokinase plasminogen activation in chronic pancreatitis suggests a role in its pathogenesis. Gastroenterology 1997; 113:904–913.PubMedCrossRefGoogle Scholar
  20. 20.
    Bockman DE and Merlino G. Cytological changes in the pancreas of transgenic mice over-expressing transforming growth factor. Gastroenterology 1992; 103:1883–1892.PubMedGoogle Scholar
  21. 21.
    Ullrich A and Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990; 61:203–212.PubMedCrossRefGoogle Scholar
  22. 22.
    Schlessinger J and Ullrich A. Growth factor signaling by receptor tyrosine kinases. Neuron 1992; 9:383–391.PubMedCrossRefGoogle Scholar
  23. 23.
    Yarden Y and Ullrich A. Molecular analysis of signal transduction by growth factors. Biochemistry 1988;27:3113–3119.Google Scholar
  24. 24.
    Coussens L, Yank-Feng TL, Liao YC, Chen E, Gray A, McGrath J, et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 1985; 230:1132–1139.PubMedCrossRefGoogle Scholar
  25. 25.
    Di Fiore PP, Pierce JH, Kraus MH, Segatto O, King CR, and Aaronson SA. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 1987; 237:178–182.Google Scholar
  26. 26.
    Kraus MH, Issing W, Miki T, Popescu NC, and Aaronson SA. Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors. Proc Nat Acad Sci USA 1989; 86:9193–9197.PubMedCrossRefGoogle Scholar
  27. 27.
    Plowman GD, Green JM, McDonald VL, Neubauer MG, Disteche CM, Todaro GJ, and Shoyab M. The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity. Mol Cell Biol 1981; 10:1969–1981.Google Scholar
  28. 28.
    Barton CM, Hall PA, Hughes CM, Gullick WJ, and Lemoine NR. Transforming growth factor alpha and epidermal growth factor in human pancreatic cancer. J Pathol 1991; 163:111–116.PubMedCrossRefGoogle Scholar
  29. 29.
    Ciccodicola A, Dono R, Obici S, Simeone A, Zollo M, and Persico MG. Molecular characterization of a gene of the ‘EGF family’ expressed in undifferentiated human NTERA2 teratocarcinoma cells. EMBO J 1989; 8:1987–1991.PubMedGoogle Scholar
  30. 30.
    Higashiyama S, Abraham JA, Miller J, Fiddes JC, and Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science 1991; 251:936–939.PubMedCrossRefGoogle Scholar
  31. 31.
    Plowman GD, Culouscou JM, Whitney GS, Green JM, Carlton GW, Foy L, Neubauer MG, and Shoyab M. Ligand specific activation of HER4/pl80erbB4, a fourth member of the epidermal growth factor receptor family. Proc Nat Acad Sci USA 1993; 90:1746–1750.PubMedCrossRefGoogle Scholar
  32. 32.
    Prigent SA and Lemoine NR. The type 1 (EGFR-related) family of growth factor receptors and their ligands. Prog Growth Factor Res 1992; 4:1–24.PubMedCrossRefGoogle Scholar
  33. 33.
    Dautry-Varsat A and Lodish HF. How receptors bring proteins and particles into cells. Sci Am 1984; 250:52–58.PubMedCrossRefGoogle Scholar
  34. 34.
    Carpenter G and Cohen S. 125I-labeled human epidermal growth factor: binding, internal-ization, and degradation in human fibroblasts. J Cell Biol 1976; 71:159–163.PubMedCrossRefGoogle Scholar
  35. 35.
    Carpenter G. Epidermal growth factor is a major factor-promoting agent in human milk. Science 1980; 210:198–199.PubMedCrossRefGoogle Scholar
  36. 36.
    Tsutsumi O, Kurachi H, and Oka T. A physiological role of epidermal growth factor in male reproductive function. Science 1986; 233:975–977.PubMedCrossRefGoogle Scholar
  37. 37.
    Korc M, Chandrasekar B, Yamanaka Y, Friess H, Büchler M, and Beger HG. Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. J Clin Invest 1992; 90:1352–1360.PubMedCrossRefGoogle Scholar
  38. 38.
    Yamanaka Y, Friess H, Kobrin MS, Büchler M, Beger HG, and Korc M. Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res 1993; 13:565–570.PubMedGoogle Scholar
  39. 39.
    Korc M, Friess H, Yamanaka Y, Kobrin M, Büchler MW, and Beger HG. Chronic pancreatitis is associated with increased concentrations of epidermal growth factor receptor, transforming growth factor alpha and phospholipase C gamma. Gut 1994; 35:1468–1473.PubMedCrossRefGoogle Scholar
  40. 40.
    Friess H, Yamanaka Y, Büchler MW, Hammer K, Kobrin M, and Beger HG. A subgroup of patients with chronic pancreatitis overexpress the c-erbB-2 protooncogene. Ann Surg 1994; 220:183–192.PubMedCrossRefGoogle Scholar
  41. 41.
    Yamanaka Y, Friess H, Kobrin MS, Büchler M, Kunz J, Beger HG, and Korc M. Overexpression of HER2/neu oncogene in human pancreatic cancer. Hum Pathol 1993; 24:1127–1134.PubMedCrossRefGoogle Scholar
  42. 42.
    Friess H, Yamanaka Y, Kobrin SM, Do DA, Büchler MW, and Korc M. Enhanced erbB-3 expression in human pancreatic cancer correlates with tumor progression. Clin Cancer Res 1995; 1:1413–1420.PubMedGoogle Scholar
  43. 43.
    Ciardiello F, Dono R, Kim N, Persico MG, and Salomon DS. Expression of cripto, a novel gene of the epidermal growth factor gene family, leads to in vitro transformation of a normal mouse mammary epithelial cell line. Cancer Res 1991; 51:1051–1054.PubMedGoogle Scholar
  44. 44.
    Baldassarre G, Bianco C, Tórtora G, Ruggiero A, Moasser M, Dmitrovsky E, Bianco AR, and Ciardiello F. Transfection with a cripto anti-sense plasmid suppresses endogenous CRIPTO expression and inhibits transformation in a human embryonal carcinoma cell line. Int J Cancer 1996; 66:538–543.PubMedCrossRefGoogle Scholar
  45. 45.
    Friess H, Yamanaka Y, Büchler M, Kobrin MS, Tahara E, and Korc M. Cripto, a member of the epidermal growth factor family, is overexpressed in human pancreatic cancer and chronic pancreatitis. Int J Cancer 1994; 56:668–674.PubMedCrossRefGoogle Scholar
  46. 46.
    Burgess WH and Maciag T. The heparin-binding (fibroblast) growth factor family of proteins. Ann Rev Biochem 1989; 58:575–606.PubMedCrossRefGoogle Scholar
  47. 47.
    Damon DH, Lobb RR, D’Amore PA, and Wagner JA. Heparin potentiates the action of acidic fibroblast growth factor by prolonging its biological half-life. J Cell Physiol 1989; 138:221–226.PubMedCrossRefGoogle Scholar
  48. 48.
    Folkman J and Klagsbrun M. Angiogenic factors. Science 1987; 235:442–447.PubMedCrossRefGoogle Scholar
  49. 49.
    Gospoderowicz D, Neufeld G, and Schweigerer L. Molecular and biological characterization of fibroblast growth factor, an angiogenic factor which also controls the proliferation and differentiation of mesoderm and neuroectoderm derived cells. Cell Differ 1986; 19:1–17.CrossRefGoogle Scholar
  50. 50.
    Gospoderowicz D, Ferrara N, Schweigerer L, and Neufeld G. Structural characterization and biological functions of fibroblast growth factor. Endocr Rev 1987; 8:95–114.CrossRefGoogle Scholar
  51. 51.
    Klagsbrun M. The fibroblast growth factor family: structural and biological properties. Prog Growth Factor Res 1989; 1:207–235.PubMedCrossRefGoogle Scholar
  52. 52.
    Givol D and Yardon A. Complexity of FGF receptors: genetic basis for structural diversity and functional specificity. FASEB J 1992; 6:3362–3369.PubMedGoogle Scholar
  53. 53.
    Moscatelli D, Presta M, and Rifkin DB. Purification of a factor from human placenta that stimulates capillary endothelial cell protease production, DNA synthesis and migration. Proc Nat Acad Sci 1986; 83:2091–2095.PubMedCrossRefGoogle Scholar
  54. 54.
    Saksela O, Moscatelli D, and Rifkin DB. The opposing effects of basic fibroblast growth factor and transforming growth factor-β on the regulation of plasminogen activator activity in capillary endothelial cells. J Cell Biol 1987; 105:957–963.PubMedCrossRefGoogle Scholar
  55. 55.
    Courty J, Loret C, Chevallier B, Moenner M, and Barritault D. Biochemical comparative studies between eye and brain derived growth factors. Biochemie 1987; 69:511–516.CrossRefGoogle Scholar
  56. 56.
    Kobrin MS, Yamanaka Y, Friess H, Lopez ME, and Korc M. Aberrant expression of the type I fibroblast growth factor receptor in human pancreatic adenocarcinomas. Cancer Res 1993; 53:4741–4744.PubMedGoogle Scholar
  57. 57.
    Mori H, Maki M, Oishi K, Jaye M, Igarashi K, Yoshida O, and Hatanaku M. Increased expression of genes for basic fibroblast growth factor and transforming growth factor type 2 in human benign prostatic hyperplasia. Prostate 1990; 16:71–80.PubMedCrossRefGoogle Scholar
  58. 58.
    Schulze-Osthoff K, Risau W, Vollmer E, and Sorg C. In situ detection of basic fibroblast growth factor by highly specific antibodies. Am J Pathol 1990; 137:85–92.PubMedGoogle Scholar
  59. 59.
    Friess H, Kobrin MS, and Korc M. Acidic and basic fibroblast growth factors and their receptors are expressed in the human pancreas. Pancreas 1992; 7:737.Google Scholar
  60. 60.
    Yamanaka Y, Friess H, Büchler M, Beger HG, Uchida E, Onda M, Kobrin MS, and Korc M. Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advan ced tumor stage. Cancer Res 1993; 53:5289-5296.Google Scholar
  61. 61.
    Friess H, Yamanaka Y, Büchler M, Beger HG, Do DA, Kobrin MS, and Korc M. Increased expression of acidic and basic fibroblast growth factors in chronic pancreatitis. Am J Pathol 1994;144:117–128.Google Scholar
  62. 62.
    Yingling JM, Wang XF, and Bassing CH. Signaling by the transforming growth factor-beta receptors. Biochim Biophys Acta 1995; 1242:115–136.PubMedGoogle Scholar
  63. 63.
    Massague J. The transforming growth factor-beta family. Rev Cell Biol 1990; 6:597–641.CrossRefGoogle Scholar
  64. 64.
    Hebda PA. Stimulatory effects of transforming growth factor-beta and epidermal growth factor on epidermal cell outgrowth from porcine skin expiant cultures. J Invest Dermatol 1988; 91:440–445.PubMedCrossRefGoogle Scholar
  65. 65.
    Massague J, Cheifetz S, Laiho M, Ralph DA, Weiss FMB, and Zentella A. Transforming growth factor-beta. Cancer Surveys 1992; 12:81–103.PubMedGoogle Scholar
  66. 66.
    Roberts AB, Sporn MG, Assoian RK, Smith JM, and Roche NS. Transforming growth factor type-b: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Nat Acad Sci USA 1986; 83:4167–4171.PubMedCrossRefGoogle Scholar
  67. 67.
    Sporn MB and Roberts AB. Transforming growth factor-beta: recent progress and new challenges. J Cell Biol 1992; 119:1017–1021.PubMedCrossRefGoogle Scholar
  68. 68.
    Roberts AB and Sporn MB. Physiological actions and clinical applications of transforming growth factor-beta. Growth Factors 1993; 8:1–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Roberts AB and Sporn MB. The transforming growth factor-beta. In: Sporn MB and Roberts AB (eds), Peptide growth factors and their receptors, vol. 95 of Handbook of experimental pharmacology. Springer-Verlag, New York, 1990; pp. 419–472.Google Scholar
  70. 70.
    Friess H, Yamanaka Y, Büchler M, Beger HG, Kobrin MS, Baldwin RL, and Korc M. Enhanced expression of the type II transforming growth factor-beta receptor in human pancreatic cancer cells without alteration of type III receptor expression. Cancer Res 1993; 53:2704–2707.PubMedGoogle Scholar
  71. 71.
    Lin HY, Wang X-F, Ng-Eaton E, Weinberg RA, and Lodish HF. Expression cloning of the TGF-β type II receptor, a functional transmembrane serine/threonine kinase. Cell 1992; 68:775–785.PubMedCrossRefGoogle Scholar
  72. 72.
    Lopez-Casillas F, Cheifetz S, Doody J, Andres JL, Lane WS, and Massague J. Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-β receptor system. Cell 1991; 67:785–795.PubMedCrossRefGoogle Scholar
  73. 73.
    Wrana JL, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M, Wang X-F, and Massague J. TGF-β signals through a heteromeric protein kinase receptor complex. Cell 1992; 71:1003–1014.PubMedCrossRefGoogle Scholar
  74. 74.
    Lopez-Casillas F, Wrana JL, and Massague J. Betaglycan presents ligand to the TGF beta signaling receptor. Cell 1993; 73:1435–1444.PubMedCrossRefGoogle Scholar
  75. 75.
    Yamashita H, Ichijo H, Grimsby S, Moren A, ten Dijke P, and Miyazono K. Endoglin forms a heteromeric complex with the signaling receptors for transforming growth factor-beta. J Biol Chem 1994; 269:1995–2001.PubMedGoogle Scholar
  76. 76.
    Slater SD, Williamson RCN, and Foster CS. Expression of transforming growth factor-beta 1 in chronic pancreatitis. Digestion 1995; 56:237–241.PubMedCrossRefGoogle Scholar
  77. 77.
    Van Laethem JL, Deviere J, Resibios A, Rickaert F, Vertongen P, Ohtani H, et al. Localization of transforming growth factor beta 1 and its latent binding protein in human chronic pancreatitis. Gastroenterology 1995; 108:1873–1881.PubMedCrossRefGoogle Scholar
  78. 78.
    Van Laethem JL, Robberecht P, Resibios A, and Deviere J. Transforming growth factor beta promotes development of fibrosis after repeated courses of acute pancreatitis in mice. Gastroenterology 1996; 110:576–582.PubMedCrossRefGoogle Scholar
  79. 79.
    Estival A, Louvel D, Couderc B, Prats H, Hollande E, Vaysse N, and Clemente F. Morphological and biological modifications induced in a rat pancreatic acinar cancer cell line (AR4 2J) by unscheduled expression of basic fibroblast growth factors. Cancer Res 1993; 53:1182–1187.PubMedGoogle Scholar
  80. 80.
    Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 1993; 328:1433–1437.Google Scholar
  81. 81.
    Border WA and Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994; 331:1286–1292.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Helmut Friess
  • Pascal Berberat
  • Markus W. Büchler

There are no affiliations available

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