Journal of Molecular Medicine

, Volume 74, Issue 1, pp 35–42

Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors

  • H. Friess
  • P. Berberat
  • M. Schilling
  • J. Kunz
  • M. W. Büchler
  • M. Korc


Molecular alterations play a key role in the pathogenesis of gastrointestinal cancers. In the present paper we describe relevant molecular alterations in human pancreatic adenocarcinomas. Overexpression of growth factor receptors (EGF receptor, c-erbB2, c-erbB3, TGFβ receptor I–III), growth factors (EGF, TGFα, TGFβ-1-3, aFGF, bFGF), adhesion molecules (ICAM-1, ELAM-1) and gene mutations (p53, K-ras, DCC, APC) are present in a significant number of these tumors. These changes stimulate tumor growth and enhance the metastatic behavior of pancreatic cancer cells and thereby may contribute to shorter postoperative survival following tumor resection.

Key words

Pancreatic cancer Growth factor receptors Growth factors Adhesion molecules Gene mutations 



Epidermal growth factor


Endothelial leukocyte adhesion molecule


Acidic fibroblast growth factor


Basic fibroblast growth factor


Human EGF-receptor


Intercellular adhesion molecule


Transforming growth factor


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Aaronson, SA (1991) Growth factors and cancer. Science 254:1146–1153Google Scholar
  2. 2.
    Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucheo M (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–554PubMedGoogle Scholar
  3. 3.
    Andrén-Sandberg A (1990) Treatment with an LHRH analogue in patients with advanced pancreatic cancer. Acta Chir Scand 156:549–551Google Scholar
  4. 4.
    Barton CM, Hall PA, Hughes CM, Gullick WJ, Lemoine NR (1991) Transforming growth factor alpha and epidermal growth factor in human pancreatic cancer. J Pathol 163:111–116Google Scholar
  5. 5.
    Barton CM, Staddon SL, Hughes CM, Hall PA, O'Sullivan C, Klöppel G, Theis B, Russel RCG, Neoptolemos J, Williamson RCN, Lane DP, Lemoine NR (1991) Abnormalities of the p53 tumor suppressor gene in human pancreatic cancer. Br J Cancer 64:1076–1082PubMedGoogle Scholar
  6. 6.
    Bellosta P, Talarico D, Rogers D, Basilico C (1993) Cleavage of K-FGF produces a tuncated molecule with increased biological activity and receptor binding affinity. J Cell Biol 121:705–713Google Scholar
  7. 7.
    Bouche G, Gas N, Prats H, Baldin V, Tauber JP, Teissie J, Amalrie F (1987) Basic fibroblast growth factor enters the nucleolus and stimulates the transcription of ribosomal genes in ABAE cells undergoing G0-G1 transition. Proc Natl Acad Sci USA 84:6770–6774Google Scholar
  8. 8.
    Büchler M, Friess H, Schultheiss KH, Gebhardt C, Kübel R, Muhrer KH, Winkelmann M, Wagener T, Klapdor R, Kaul M, Müller G, Schulz G, Beger HG (1991) A randomized controlled trial of adjuvant immuno-therapy (murine monoclonal antibody 494/32) in resectable pancreatic cancer. Cancer 68:1507–1512PubMedGoogle Scholar
  9. 9.
    Büchler M, Ebert M, Beger HG (1993) Grenzen chirurgischen Handelns beim Pankreaskarzinom. Langenbecks Arch Chir Suppl:460–464Google Scholar
  10. 10.
    Bugler B, Amalrie F, Prats H (1991) Alternative initiation of translation determines cytoplasmic or nuclear localization of basic fibroblast growth factor. Mol Cell Biol 11:573–577Google Scholar
  11. 11.
    Burgess WH, Maciag T (1989) The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem 58:575–606Google Scholar
  12. 12.
    Caldas C, Hahn SA, Hurban RH, Redston MS, Yeo CJ, Kern SE (1994) Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res 54:3568–3573Google Scholar
  13. 13.
    Caron de Fromentel C, Soussi T (1992) TP 53 Tumour suppressor gene: a model for investigating human mutagenesis. Genes Chromosom Cancer 4:1–15Google Scholar
  14. 14.
    Casey G, Yamanaka Y, Friess H, Kobrin MS, Lopez ME, Büchler M, Beger HG, Korc M (1993) p53 mutations are common in pancreatic cancer and are absent in chronic pancreatitis. Cancer Lett 69:151–160Google Scholar
  15. 15.
    Chandrasekar B, Korc M (1992) Binding and biological actions of acidic and basic fibroblast growth factors in isolated rat pancreatic acini. Gastroenterology 102:A725 (abstract)Google Scholar
  16. 16.
    Chen P-L, Chen Y, Brookstein R, Lee W-H (1990) Genetic mechanisms of tumor suppression by the human p53 gene. Science 250:1576–1580Google Scholar
  17. 17.
    Ciccodicola A, Dono R, Obici S, Simeone A, Zollo M, Persico MG (1989) Molecular characterization of a gene of the ‘EGF family’ expressed in undifferentiated human NTERA2 teratocarcinoma cells. EMBO J 8:1987–1991Google Scholar
  18. 18.
    Couffinhal T, Duplaa C, Moreau C, Lamaziere J-M D, Bonnet J (1994) Regulation of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human vascular smooth muscle cells. Circ Res 74:225–234Google Scholar
  19. 19.
    Coussens L, Yank-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U (1985) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230:1132–1139PubMedGoogle Scholar
  20. 20.
    Cullinan SA, Moertel CG, Fleming TR, for the North Central Cancer Treatment Group (1985) A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. JAMA 253:2061CrossRefPubMedGoogle Scholar
  21. 21.
    Damon DH, Lobb RR, D'Amore PA, Wagner JA (1989) Heparin potentiates the action of acidic fibroblast growth factor by prolonging its biological half-life. J Cell Physiol 138:221–226Google Scholar
  22. 22.
    Derynck R (1988) Transforming growth factor-alpha. Cell 54:593–595Google Scholar
  23. 23.
    Di Fiore PP, Pierce JH, Kraus MH, Segatto O, King CR, Aaronson, SA (1987) erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 237:178–182Google Scholar
  24. 24.
    Diller L, Kassel J, Nelson CE, Gryka MA, Litwak G, Gebhardt M, et al (1990) p53 functions as a cell cycle control protein in osteosarcoms. Mol Cell Biol 10:5772–5781Google Scholar
  25. 25.
    Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767Google Scholar
  26. 26.
    Folkman J, Klagsbrun M (1987) Angiogenic factors. Science 235:442–447Google Scholar
  27. 27.
    Friess H, Büchler M, Schulz G, Beger HG (1989) Therapie des Pankreaskarzinoms mit dem monoklonalen Antikörper BW 494/32: erste klinische Ergebnisse. Immun Infekt: 17:24–26Google Scholar
  28. 28.
    Friess H, Büchler M, Krüger M, Beger HG (1992) Treatment of duct carcinoma of the pancreas with the LH-RH analogue buserelin. Pancreas 7:516–521PubMedGoogle Scholar
  29. 29.
    Friess H, Kobrin MS, Korc M (1992) Acidic and basic fibroblast growth factors and their receptors are expressed in the human pancreas (abstract). Pancreas 7:737Google Scholar
  30. 30.
    Friess H, Büchler M, Beglinger C, Krüger M, Beger HG (1993) Low-dose octreotide treatment is not effective in patients with advanced pancreatic cancer. Pancreas 8:540–544PubMedGoogle Scholar
  31. 31.
    Friess H, Yamanaka Y, Büchler M, Beger HG, Kobrin MS, Baldwin RL, Korc M (1993) 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 53:2704–2707PubMedGoogle Scholar
  32. 32.
    Friess H, Yamanaka Y, Büchler M, Ebert M, Beger HG, Gold LI, Korc M (1993) Enhanced expression of transforming growth factor-beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 105:1846–1856PubMedGoogle Scholar
  33. 33.
    Friess H, Yamanaha Y, Korc M, Büchler MW (1994) Overexpression of c-erbB-3 in human pancreatic cancer: correlation with tumor aggressiveness (abstract). Digestion 55:299Google Scholar
  34. 34.
    Fu Y-M, Spirito P, Yu Z-X, Biro S, Sasse J, Lei J, Ferrans VJ, Epstein SE, Casscells W (1991) Acidic fibroblast growth factor in the developing rat embryo. J Cell Biol 114:1261–1273Google Scholar
  35. 35.
    Givol D, Yayon A (1992) Complexity of FGF receptors: genetic basis for structural diversity and functional specificity. FASEB J 6:3362–3369Google Scholar
  36. 36.
    Glinsmann-Gibson BJ, Korc M (1991) Regulation of transforming growth factor-a mRNA expression in T3M4 human pancreatic carcinoma cells. Pancreas 6:142–149Google Scholar
  37. 37.
    Gomm JJ, Smith J, Ryall GK, Baillie R, Turnbull L, Coombes RC (1991) Localization of basic fibroblast growth factor and transforming growth factor b1 in the human mammary gland. Cancer Res 51:4685–4692Google Scholar
  38. 38.
    Gospoderowicz D, Neufeld G, Schweigerer L (1986) 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 Diff 19:1–17Google Scholar
  39. 39.
    Gospodarowicz D, Ferrara N, Schweigerer L, Neufeld G (1987) Structural characterization and biological functions of fibroblast growth factor. Endocrine Rev 8:95–114Google Scholar
  40. 40.
    Grünewald K, Lyons J, Fröhlich A, Feichtinger H, Weger RA, Schwab G, Janssen JWG, Bartram CR (1989) High frequency of Ki-ras codon 12 mutations in pancreatic adenocarcinomas. Int J Cancer 43:1037–1041Google Scholar
  41. 41.
    Gudjonsson B (1987) Cancer of the pancreas. 50 years of surgery. Cancer 60:2284–2303PubMedGoogle Scholar
  42. 42.
    Haines DS, Landers JE, Engle LJ, George DL (1994) Physical and fucntional interaction between wild-type p53 and mdm2 proteins. Mol Cell Biol 14:1171–1178Google Scholar
  43. 43.
    Hall PA, Huges CM, Staddon SL, Richman PI, Gullick WJ, Lemoine NR (1990) The c-erbB-2 protooncogene in human pancreatic cancer. J Pathol 161:1995–2000Google Scholar
  44. 44.
    Hebda PA (1988) Stimulatory effects of transforming growth factor-beta and epidermal growth factor on epidermal cell outgrowth from porcine skin explant cultures. J Invest Dermatol 91:440–445Google Scholar
  45. 45.
    Hendler FJ, Ozanne BW (1984) Human squamous cell lung cancers express increased epidermal growth factor receptors. J Clin Invest 74:647–651Google Scholar
  46. 46.
    Higashiyama S, Abraham JA, Miller J, Fiddes JC, Klagsbrun M (1991) A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science 251:936–939Google Scholar
  47. 47.
    Hitoshi K, Kokichi S, Noriko F, Akiko K, Haruhiko N, Kazuaki S, et al (1994) Detection of point mutations in the K-ras oncogene at codon 12 in pure pancreatic juice for diagnosis of pancreatic carcinoma. Cancer 73:1589–1594Google Scholar
  48. 48.
    Höhne MW, Halatsch M-E, Kahl GF, Weinel RJ (1992) Frequent loss of expression of the potential tumor suppressor gene DCC in ductal pancreatic adenocarcinoma. Cancer Res 52:2616–2619Google Scholar
  49. 49.
    Hollenstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53PubMedGoogle Scholar
  50. 50.
    Holmes WE, Sliwkowski MX, Akita RW (1992) Identification of heregulin, a specific activator of p185erbB2. Science 256:1205–1210Google Scholar
  51. 51.
    Horii A, Nakatsuru S, Miyoshi Y, Ichii S, Nagase H, Ando H, Yanagisawa A, Tsuchiya E, Kato Y, Nakamura Y (1992) Frequent somatic mutations of the APC gene in human pancreatic cancer. Cancer Res 52:6696–6698Google Scholar
  52. 52.
    Hudziak RM, Schlessinger J, Ullrich A (1987) Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells. Proc Natl Acad Sci USA 84:7159–7163Google Scholar
  53. 53.
    Iggo R, Gatter K, Bartek J, Lane DP, Harris AL (1990) Increased expression of mutant forms of p53 oncogene in primary lung cancer. Lancet 335:675–677Google Scholar
  54. 54.
    Kalthoff H, Schmiegel W, Roeder C, Kasche D, Schmidt A, Lauer G, et al (1993) p53 and K-ras alterations in pancreatic epithelial cell lesions. Oncogene 8:289–298PubMedGoogle Scholar
  55. 55.
    Kazuhiro I, Ishkura H, Kaji M, Sugiura H, Ishizu A, Takahashi C, et al (1993) Importance of E-selectin (ELAM-1) and Sialyl Lewis in the adhesion of pancreatic carcinoma cells to activated endothelium. Int J Cancer 54:972–977Google Scholar
  56. 56.
    Klagsbrun M (1989) The fibroblast growth factor family: structural and biological properties. Progr Growth Factor Res 1:207–235Google Scholar
  57. 57.
    Kobrin MS, Yamanaka Y, Friess H, Lopez ME, Korc M (1993) Aberrant expression of the type I fibroblast growth factor receptor in human pancreatic adenocarcinomas. Cancer Res 53:4741–4744Google Scholar
  58. 58.
    Korc M, Finman JE (1989) Attenuated processing of epidermal growth factor in the face of marked degradation of transforming growth factor alpha. J Biol Chem 264:14990–14999Google Scholar
  59. 59.
    Korc M, Magun B (1985) Recycling of epidermal growth factor in a human pancreatic carcinoma cell line. Proc Natl Acad Sci USA 82:6172–6175Google Scholar
  60. 60.
    Korc M, Meltzer P, Trent J (1986) Enhanced expression of epidermal growth factor receptor correlates with alterations of chromosome 7 in human pancreatic cancer. Proc Natl Acad Sci USA 83:5141–5144Google Scholar
  61. 61.
    Korc M, Chandrasekar B, Yamanaka Y, Friess H, Büchler M, Beger HG (1992) Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increase in the levels of epidermal growth factor and transforming growth factor alpha. J Clin Invest 90:1352–1360Google Scholar
  62. 62.
    Kraus MH, Issing W, Miki T, Popescu NC, Aaronson SA (1989) 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 Natl Acad Sci USA 86:9193–9197Google Scholar
  63. 63.
    Lane DP, Bechimol S (1990) p53: oncogene or anti-oncogene? Gene Dev 4:1–8Google Scholar
  64. 64.
    Laurent-Puig P, Lubin R, Semhoun-Ducloux S, Pelletier G, Fourre C, Ducreux M, et al (1995) Antibodies against p53 protein in serum of patients with benign or malignant pancreatic and biliary diseases. Gut 36:455–458Google Scholar
  65. 65.
    Lemoine NR (1990) ras oncogenes in human cancers. In: Sluyser M (ed) Molecular biology of cancer genes. Horwood, Chichester, pp 82–118Google Scholar
  66. 66.
    Lemoine NR, Hall PA (1990) Growth factors and oncogenes in pancreatic cancer. Baillieres Clin Gastroenterol 4:815–832Google Scholar
  67. 67.
    Lemoine NR, Lobresco M, Leung H, Barton C, Hughes CM, Prigent SA, Gullick WJ, Klöppel G (1992) The erbB-3 gene in human pancreatic cancer. J Pathol 168:269–273Google Scholar
  68. 68.
    Lemoine NR, Jain S, Hughes CM, Staddon SL, Maillet B, Hall PA, Kloppel G (1992) Ki-ras oncogene activation in preinvasive pancreatic cancer. Gastroenterology 102:230–236Google Scholar
  69. 69.
    Levine A (1992) The p53 tumour suppressor gene and product. Cancer Surv 12:59–79Google Scholar
  70. 70.
    Levine AJ, Momand J, Finaly CA (1991) The p53 tumour suppressor gene. Nature 351:453–456Google Scholar
  71. 71.
    Levine AJ, Perry ME, Chang A, Silver A, Dittmer D, Wu M, Welsh D (1994) The 1993 Walter Hubert Lecture: the role of the p53 tumour-suppressor gene in tumorigenesis. Br J Cancer 69:409–416Google Scholar
  72. 72.
    Li S, Shipley GD (1991) Expression of multiple species of basic fibroblast growth factor mRNA and protein in normal and tumor-derived mammary epithelial cells in culture. Cell Growth Diff 2:195–202Google Scholar
  73. 73.
    Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A, Schlessinger J (1985) Amplification, enhanced expression, and possible rearrangement of the EGF receptor gene in primary human brain tumors of glial origin. Nature 313:144–147PubMedGoogle Scholar
  74. 74.
    Lin HY, Wang X-F, Ng-Eaton E, Weinberg RA, Lodish HP (1992) Expression cloning of the TGF-ß type II receptor, a functional transmembrane serine/threonine kinase. Cell 68:775–785Google Scholar
  75. 75.
    Lopez-Casillas F, Cheifetz S, Doody J, Andres JL, Lane WS, Massague J (1991) Structure and expression of the membrane proteoglycan betaglycan, a component of the TGF-B receptor system. Cell 67:785–795Google Scholar
  76. 76.
    Madri JA, Pratt BM, Tucker AM (1988) Phenotypic modulation of endothelial cells by transforming growth factor-b depends upon the composition and organization of the extracellular matrix. J Cell Biol 106:1375–1384Google Scholar
  77. 77.
    Marchionni MA, Goodearl ADJ, Chen MS (1993) Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 362:312–318Google Scholar
  78. 78.
    Mariyama M, Kishi K, Nakamura K, Oata H, Nishimura S (1989) Frequency and types of point mutation at the 12th codon of the c-Ki-ras gene found in pancreatic cancers in Japanese patients. Jpn J Cancer Res 80:622–266Google Scholar
  79. 79.
    Massague J (1990) The transforming growth factor-beta family. Annu Rev Cell Biol 6:597–641PubMedGoogle Scholar
  80. 80.
    Massague J, Cheifetz S, Laiho M, Ralph DA, Weiss FMB, Zentella A (1992) Transforming growth factor beta. Cancer Surv 12:81–103Google Scholar
  81. 81.
    Moertel CG, Childs DS, Reitemeier RJ, Colby MY, Holbrook M (1969) Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet II:865–900Google Scholar
  82. 82.
    Moertel, CG, Frytak, S, Hahn, R G. (1981) Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: the Gastrointestinal Tumor Study Group. Cancer 48:1705Google Scholar
  83. 83.
    National Cancer Institute (1991) Annual cancer statistics review 1973–1988. NIH publication no 91–2789, Department of Health and Human Services, BethesdaGoogle Scholar
  84. 84.
    Neal DE, Marsh C, Bennett MK, Abel PD, Hall RR, Sainsbury JR, Harris AL (1985) Epidermal-growth-factor receptors in human bladder cancer: comparison of invasive and superficial tumours. Lancet 1:366–368Google Scholar
  85. 85.
    Neoptolemos JP (ed) (1990) Cancer of the pancreas. Baillieres Clin Gastroenterol, London, 4:4Google Scholar
  86. 86.
    Nigro JM, Baker SF, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P et al. (1989) Mutatines in the p53 gene occur in diverse human tumour types. Nature 342:705–708Google Scholar
  87. 87.
    Peles E, Ben-Levy R, Tzahar E, Liu N, Wen D, Yarden Y (1993) Cell-type specific interaction of Neu differentiation factor (NDF/heregulin) with Neu/Her-2 suggests complex ligand receptor relationships. EMBO J 12:961–971Google Scholar
  88. 88.
    Pellegata NS, Sessa F, Renault B, Bonato M, Leone BE, Solcia E, Ranzani GN (1994) K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. Cancer Research 54: 1556–1560Google Scholar
  89. 89.
    Plowman GD, Green JM, McDonald VL, Neubauer MG, Disteche CM, Todaro GJ, Shoyab M (1981) The ampiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity. Mol Cell Biol 10:1969–1981Google Scholar
  90. 90.
    Plowman GD, Culouscou JM, Whitney GS, Green JM, Carlton GW, Foy L, Neubauer MG, Shoyab M (1993) Ligand specific activation of HER4/pl80erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci USA 90:1746–1750Google Scholar
  91. 91.
    Prigent SA, Lemoine NR (1992) The type 1 (EGFR-related) family of growth factor receptors and their ligands. Progress in Growth Factor Research 4:1–24Google Scholar
  92. 92.
    Roberts AB, Sportn MG, Assoian RK, Smith JM, Roche NS (1986) Transforming growth factor type-b: rapid induction of fibrosis and angiogenesis vivo and stimulation of collagen formation vitro. Proc Natl Acad Sci USA 83:4167–4171Google Scholar
  93. 93.
    Ruggeri B, Zhang SY, Caamano J, Dirado M, Flynn SD, Kleinszanto AJP (1992) Human pancreatic carcinomas and cell lines reveal frequent and multiple alterations in the p53 and Rb-1 tumour suppressor genes. Oncogene 7:1503–1511Google Scholar
  94. 94.
    Sainsbury JR, Farndon JR, Sherbet GV, Harris AL (1985) Epidermal-growth-factor receptors and oestrogen receptors in human breast cancer. Lancet 1:364–366Google Scholar
  95. 95.
    Sawada T, Ho JJL, Chung Y-S, Sowa M, Kim Ys (1994) Eselectin binding by pancreatic tumor cells is inhibited by cancer sera. Int J Cancer 57:901–907Google Scholar
  96. 96.
    Scarpa A, Capelli P, Mukai K, Zamboni G, Oda T, Iacono C, et al (1993) Pancreatic adenocarcinomas frequently show p53 gene mutations. Am J Pathol 142:1534–1543Google Scholar
  97. 97.
    Schaeffer B, Zunlo J, Longnecker DS (1990) Activation of c-K-ras is not detectable in adenomas or adenocarcinomas arising in the rat pancreas. Mol Carcinogen 3:165–170Google Scholar
  98. 98.
    Schlessinger J, Ullrich A (1992) Growth factor signaling by receptor tyrosine kinases. Neuron 9:383–391Google Scholar
  99. 99.
    Schwaeble W, Kerlin M, Meyer zum Büschenfelde M, Dippold W (1993) De novo expression of intercellular adhesion molecule-1 in pancreas cancer. Int J Cancer 53:328–333Google Scholar
  100. 100.
    Shimoyama Y, Gotoh M, Ino Y, Sakamoto M, Kato K, Hirohashi S (1991) Characterization of high-molecular-mass forms of basic fibroblast growth factor produced by hepatocellular carcinoma cells: possible involvement of basic fibroblast growth factor in hepatocarcinogenesis. Jpn J Cancer Res 82:1263–1270Google Scholar
  101. 101.
    Silverberg, E, Lubera, J A (1989) Cancer statistics. Cancer J Clin 3:3–39Google Scholar
  102. 102.
    Simon B, Weinel R, Höhne M, Watz J, Schmidt J, Kortner G, Arnold R (1994) Frequent alterations of the tumor suppressor genes p53 and DCC in human pancreatic carcinoma. Gastroenterology 106:1645–1651Google Scholar
  103. 103.
    Smit VTHBM, Boot AJM, Smits AMM, Fleuren GJ, Cornelisse CJ, Bos JL (1988) KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acid Res 16:7773–7782Google Scholar
  104. 104.
    Smith JJ, Derynck R, Korc M (1987) Production of transforming growth factor in human pancreatic cancer cells: evidence for a superagonist autocrine cycle. Proc Natl Acad Sci USA 84:7567–7570Google Scholar
  105. 105.
    Sporn MB, Roberts AB (1992) Transforming growth factor-b: recent progress and new challenges. J Cell Biol 119:1017–1021CrossRefPubMedGoogle Scholar
  106. 106.
    Springer TA, Dustin ML, Kishimoto TK, Marlin SD (1987) The lymphocyte-function-associated LFA-1, CD2 and LFA-3 molecules: cell-adhesion receptores of the immune system. Am Rev Immun 5:223–252Google Scholar
  107. 107.
    Steiner MS, Barrack ER (1992) Transforming growth factor-b1, overproduction in prostate cancer: effects on growth vivo and vitro. Mol Endocrinol 6:15–25Google Scholar
  108. 108.
    Tada M, Omata M, Kawai S, Saisho H, Ohto M, Saiki RK, Sninsky JJ (1993) Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res 53:2472–2474Google Scholar
  109. 109.
    Takahasi K, Suzuki K, Ono T (1990) Loss of growth inhibitory activity of TGF-ß toward normal human mammary epithelial cells grown within collagen gel matrix. Biochem Biophys Res Commun 173:1239–1247Google Scholar
  110. 110.
    Ullrich A, Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61:203–212PubMedGoogle Scholar
  111. 111.
    Vogelstein B, Kinzler KW (1992) p53 function and dysfunction. Cell 70:523–526Google Scholar
  112. 112.
    Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9:138–141Google Scholar
  113. 113.
    Warshaw AL, Fernandes-Del Castillo, C (1992) Pancreatic carcinoma. N Engl J Med 326:455–465PubMedGoogle Scholar
  114. 114.
    Watanabe H, Sawabu N, Ohta H, Satomura Y, Yamakawa O, Motoo Y, et al (1993) Identification of K-ras oncogene mutaions in the pure pancreatic juice of patients with ductal pancreatic cancers. Jpn J Cancer Res 84:961–965Google Scholar
  115. 115.
    Wrana JL, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M, Wang X-F, Massague J (1992) TGF-ß signals through a heteromeric protein kinase receptor complex. Cell 71:1003–1014Google Scholar
  116. 116.
    Yamanaka Y, Friess H, Büchler M, Beger HG, Gold LI, Korc M (1993) Synthesis and expression of transforming growth factor-beta 1, beta 2 and beta 3 in the endocrine and exocrine pancreas. Diabetes 42:746–756Google Scholar
  117. 117.
    Yamanaka Y, Friess H, Büchler M, Beger HG, Uchida E, Onda M, Kobrin MS Korc M (1993) Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage. Cancer Res 53:5289–5296Google Scholar
  118. 118.
    Yamanaka Y, Friess H, Kobrin MS, Büchler M, Beger HG, Korc M (1993) Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res 13:565–570PubMedGoogle Scholar
  119. 119.
    Yamanaka Y, Friess H, Kobrin MS, Büchler M, Kunz J, Beger HG, Korc M (1993) Overexpression of HER2/neu oncogene in human pancreatic cancer. Hum Pathol 24:1127–1134Google Scholar
  120. 120.
    Yokoyama M, Yamanaka Y, Friess H, Büchler M, Korc M (1994) p53 expression in human pancreatic cancer correlates with enhanced biological aggressiveness. Anticancer Res 14:2477–284Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • H. Friess
    • 1
  • P. Berberat
    • 1
  • M. Schilling
    • 1
  • J. Kunz
    • 1
  • M. W. Büchler
    • 1
  • M. Korc
    • 2
  1. 1.Department of Visceral and Transplantation SurgeryUniversity of BerneBerneSwitzerland
  2. 2.Departments of Medicine and Biological Chemistry, Division of Endocrinology and MetabolismUniversity of CaliforniaIrvineUSA

Personalised recommendations