Skip to main content
SpringerLink
Log in

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

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

EGF :

Epidermal growth factor

ELAM :

Endothelial leukocyte adhesion molecule

aFGF :

Acidic fibroblast growth factor

bFGF :

Basic fibroblast growth factor

HER :

Human EGF-receptor

ICAM :

Intercellular adhesion molecule

TGF :

Transforming growth factor

References

  1. Aaronson, SA (1991) Growth factors and cancer. Science 254:1146–1153

    Google Scholar 

  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 53:549–554

    CAS  PubMed  Google Scholar 

  3. Andrén-Sandberg A (1990) Treatment with an LHRH analogue in patients with advanced pancreatic cancer. Acta Chir Scand 156:549–551

    Google Scholar 

  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 163:111–116

    Google Scholar 

  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 64:1076–1082

    CAS  PubMed  Google Scholar 

  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 121:705–713

    Google Scholar 

  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 84:6770–6774

    Google Scholar 

  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 68:1507–1512

    PubMed  Google Scholar 

  9. Büchler M, Ebert M, Beger HG (1993) Grenzen chirurgischen Handelns beim Pankreaskarzinom. Langenbecks Arch Chir Suppl:460–464

  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 11:573–577

    Google Scholar 

  11. Burgess WH, Maciag T (1989) The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem 58:575–606

    Google Scholar 

  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 54:3568–3573

    Google Scholar 

  13. Caron de Fromentel C, Soussi T (1992) TP 53 Tumour suppressor gene: a model for investigating human mutagenesis. Genes Chromosom Cancer 4:1–15

    Google Scholar 

  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 69:151–160

    Google Scholar 

  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. Chen P-L, Chen Y, Brookstein R, Lee W-H (1990) Genetic mechanisms of tumor suppression by the human p53 gene. Science 250:1576–1580

    Google Scholar 

  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 8:1987–1991

    Google Scholar 

  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 74:225–234

    Google Scholar 

  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 230:1132–1139

    CAS  PubMed  Google Scholar 

  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 253:2061

    Article  CAS  PubMed  Google Scholar 

  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 138:221–226

    Google Scholar 

  22. Derynck R (1988) Transforming growth factor-alpha. Cell 54:593–595

    Google Scholar 

  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 237:178–182

    Google Scholar 

  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 10:5772–5781

    Google Scholar 

  25. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767

    Google Scholar 

  26. Folkman J, Klagsbrun M (1987) Angiogenic factors. Science 235:442–447

    Google Scholar 

  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: 17:24–26

    Google Scholar 

  28. Friess H, Büchler M, Krüger M, Beger HG (1992) Treatment of duct carcinoma of the pancreas with the LH-RH analogue buserelin. Pancreas 7:516–521

    CAS  PubMed  Google Scholar 

  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 7:737

    Google Scholar 

  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 8:540–544

    CAS  PubMed  Google Scholar 

  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 53:2704–2707

    CAS  PubMed  Google Scholar 

  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 105:1846–1856

    CAS  PubMed  Google Scholar 

  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 55:299

    Google Scholar 

  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 114:1261–1273

    Google Scholar 

  35. Givol D, Yayon A (1992) Complexity of FGF receptors: genetic basis for structural diversity and functional specificity. FASEB J 6:3362–3369

    Google Scholar 

  36. Glinsmann-Gibson BJ, Korc M (1991) Regulation of transforming growth factor-a mRNA expression in T3M4 human pancreatic carcinoma cells. Pancreas 6:142–149

    Google Scholar 

  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 51:4685–4692

    Google Scholar 

  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 19:1–17

    Google Scholar 

  39. Gospodarowicz D, Ferrara N, Schweigerer L, Neufeld G (1987) Structural characterization and biological functions of fibroblast growth factor. Endocrine Rev 8:95–114

    Google Scholar 

  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 43:1037–1041

    Google Scholar 

  41. Gudjonsson B (1987) Cancer of the pancreas. 50 years of surgery. Cancer 60:2284–2303

    CAS  PubMed  Google Scholar 

  42. Haines DS, Landers JE, Engle LJ, George DL (1994) Physical and fucntional interaction between wild-type p53 and mdm2 proteins. Mol Cell Biol 14:1171–1178

    Google Scholar 

  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 161:1995–2000

    Google Scholar 

  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 91:440–445

    Google Scholar 

  45. Hendler FJ, Ozanne BW (1984) Human squamous cell lung cancers express increased epidermal growth factor receptors. J Clin Invest 74:647–651

    Google Scholar 

  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 251:936–939

    Google Scholar 

  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 73:1589–1594

    Google Scholar 

  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 52:2616–2619

    Google Scholar 

  49. Hollenstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53

    CAS  PubMed  Google Scholar 

  50. Holmes WE, Sliwkowski MX, Akita RW (1992) Identification of heregulin, a specific activator of p185erbB2. Science 256:1205–1210

    Google Scholar 

  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 52:6696–6698

    Google Scholar 

  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 84:7159–7163

    Google Scholar 

  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 335:675–677

    Google Scholar 

  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 8:289–298

    CAS  PubMed  Google Scholar 

  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 54:972–977

    Google Scholar 

  56. Klagsbrun M (1989) The fibroblast growth factor family: structural and biological properties. Progr Growth Factor Res 1:207–235

    Google Scholar 

  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 53:4741–4744

    Google Scholar 

  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 264:14990–14999

    Google Scholar 

  59. Korc M, Magun B (1985) Recycling of epidermal growth factor in a human pancreatic carcinoma cell line. Proc Natl Acad Sci USA 82:6172–6175

    Google Scholar 

  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 83:5141–5144

    Google Scholar 

  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 90:1352–1360

    Google Scholar 

  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 86:9193–9197

    Google Scholar 

  63. Lane DP, Bechimol S (1990) p53: oncogene or anti-oncogene? Gene Dev 4:1–8

    Google Scholar 

  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 36:455–458

    Google Scholar 

  65. Lemoine NR (1990) ras oncogenes in human cancers. In: Sluyser M (ed) Molecular biology of cancer genes. Horwood, Chichester, pp 82–118

    Google Scholar 

  66. Lemoine NR, Hall PA (1990) Growth factors and oncogenes in pancreatic cancer. Baillieres Clin Gastroenterol 4:815–832

    Google Scholar 

  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 168:269–273

    Google Scholar 

  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 102:230–236

    Google Scholar 

  69. Levine A (1992) The p53 tumour suppressor gene and product. Cancer Surv 12:59–79

    Google Scholar 

  70. Levine AJ, Momand J, Finaly CA (1991) The p53 tumour suppressor gene. Nature 351:453–456

    Google Scholar 

  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 69:409–416

    Google Scholar 

  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 2:195–202

    Google Scholar 

  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 313:144–147

    CAS  PubMed  Google Scholar 

  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 68:775–785

    Google Scholar 

  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 67:785–795

    Google Scholar 

  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 106:1375–1384

    Google Scholar 

  77. Marchionni MA, Goodearl ADJ, Chen MS (1993) Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 362:312–318

    Google Scholar 

  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 80:622–266

    Google Scholar 

  79. Massague J (1990) The transforming growth factor-beta family. Annu Rev Cell Biol 6:597–641

    CAS  PubMed  Google Scholar 

  80. Massague J, Cheifetz S, Laiho M, Ralph DA, Weiss FMB, Zentella A (1992) Transforming growth factor beta. Cancer Surv 12:81–103

    Google Scholar 

  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:865–900

    Google Scholar 

  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 48:1705

    Google Scholar 

  83. National Cancer Institute (1991) Annual cancer statistics review 1973–1988. NIH publication no 91–2789, Department of Health and Human Services, Bethesda

    Google Scholar 

  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 1:366–368

    Google Scholar 

  85. Neoptolemos JP (ed) (1990) Cancer of the pancreas. Baillieres Clin Gastroenterol, London, 4:4

  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 342:705–708

    Google Scholar 

  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 12:961–971

    Google Scholar 

  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: 1556–1560

    Google Scholar 

  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 10:1969–1981

    Google Scholar 

  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 90:1746–1750

    Google Scholar 

  91. Prigent SA, Lemoine NR (1992) The type 1 (EGFR-related) family of growth factor receptors and their ligands. Progress in Growth Factor Research 4:1–24

    Google Scholar 

  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 83:4167–4171

    Google Scholar 

  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 7:1503–1511

    Google Scholar 

  94. Sainsbury JR, Farndon JR, Sherbet GV, Harris AL (1985) Epidermal-growth-factor receptors and oestrogen receptors in human breast cancer. Lancet 1:364–366

    Google Scholar 

  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 57:901–907

    Google Scholar 

  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 142:1534–1543

    Google Scholar 

  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 3:165–170

    Google Scholar 

  98. Schlessinger J, Ullrich A (1992) Growth factor signaling by receptor tyrosine kinases. Neuron 9:383–391

    Google Scholar 

  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 53:328–333

    Google Scholar 

  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 82:1263–1270

    Google Scholar 

  101. Silverberg, E, Lubera, J A (1989) Cancer statistics. Cancer J Clin 3:3–39

    Google Scholar 

  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 106:1645–1651

    Google Scholar 

  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 16:7773–7782

    Google Scholar 

  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 84:7567–7570

    Google Scholar 

  105. Sporn MB, Roberts AB (1992) Transforming growth factor-b: recent progress and new challenges. J Cell Biol 119:1017–1021

    Article  CAS  PubMed  Google Scholar 

  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 5:223–252

    Google Scholar 

  107. Steiner MS, Barrack ER (1992) Transforming growth factor-b1, overproduction in prostate cancer: effects on growth vivo and vitro. Mol Endocrinol 6:15–25

    Google Scholar 

  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 53:2472–2474

    Google Scholar 

  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 173:1239–1247

    Google Scholar 

  110. Ullrich A, Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61:203–212

    CAS  PubMed  Google Scholar 

  111. Vogelstein B, Kinzler KW (1992) p53 function and dysfunction. Cell 70:523–526

    Google Scholar 

  112. Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9:138–141

    Google Scholar 

  113. Warshaw AL, Fernandes-Del Castillo, C (1992) Pancreatic carcinoma. N Engl J Med 326:455–465

    CAS  PubMed  Google Scholar 

  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 84:961–965

    Google Scholar 

  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 71:1003–1014

    Google Scholar 

  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 42:746–756

    Google Scholar 

  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 53:5289–5296

    Google Scholar 

  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 13:565–570

    CAS  PubMed  Google Scholar 

  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 24:1127–1134

    Google Scholar 

  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 14:2477–284

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Visceral and Transplantation Surgery, University of Berne, Inselspital, CH-3010, Berne, Switzerland

    H. Friess, P. Berberat, M. Schilling, J. Kunz & M. W. Büchler

  2. Departments of Medicine and Biological Chemistry, Division of Endocrinology and Metabolism, University of California, Irvine, Calif., USA

    M. Korc

Authors
  1. H. Friess
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Berberat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Schilling
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Kunz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. W. Büchler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Korc
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Friess, H., Berberat, P., Schilling, M. et al. Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors. J Mol Med 74, 35–42 (1996). https://doi.org/10.1007/BF00202070

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00202070

Key words

Search

Navigation