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Frequent expression of genes for receptor tyrosine kinases and their ligands in human pancreatic cancer cells

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Summary

Limited information is available concerning the involvement of growth factor receptors and their ligands in the pathogenesis of human pancreatic cancer. We analyzed 12 human pancreatic cancer cell lines by Northern blot analysis for the expression of 9 receptor tyrosine kinases (RTKs) and 6 growth factors. The effect of a monoclonal antibody (MAb) against transforming growth factor-α (TGF-α) on in vitro pancreatic cancer cell growth was also assessed. mRNA for EGF-R, c-erbB-2 and c-erbB-3 was expressed in 12 (100%), 12 (100%), and 7 (58%), respectively, of the cell lines examined. In addition, 8 (67%) cell lines expressed the c-met/receptor for hepatocyte growth factor. As for ligands, TGF-α mRNA was detected in 10 (83%) cell lines; MAb against TGF-α inhibited growth of the 2 cell lines examined. Furthermore, mRNA for amphiregulin (AR) was expressed in 10 (83%) cell lines. Coexpression of TGF-α, AR, and EGF-R was observed in 9 (75%) cell lines. These results support the concept that several specified types of RTKs and their ligands are closely involved in regulation of the growth of human pancreatic cancer cells.

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References

  1. Yarden Y, Ullrich A. Growth factor receptor tyrosine kinases.Annu Rev Biochem 1988; 57: 443–478.

    Article  PubMed  CAS  Google Scholar 

  2. Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziani A, Kapeller R, Soltoff S. Oncogenes and signal transduction.Cell 1991; 64: 281–302.

    Article  PubMed  CAS  Google Scholar 

  3. Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, Lee J, Yarden Y, Libermann TA, Schlessinger A, Downward J, Mayes ELV, Whittle N, Waterfield MD, Seeburg PH. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells.Nature 1984; 309: 418–425.

    Article  PubMed  CAS  Google Scholar 

  4. Shih C, Padhy LC, Murray M, Weinberg RA. Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts.Nature 1981; 290: 261–264.

    Article  PubMed  CAS  Google Scholar 

  5. Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A, Schlessinger J. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumors of glial origin.Nature 1985; 313: 144–147.

    Article  PubMed  CAS  Google Scholar 

  6. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, Press MF. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244: 707–712.

    Article  PubMed  CAS  Google Scholar 

  7. Slamon DJ, Clark GM, Wong SG, Lewin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.Science 1987; 235: 177–182.

    Article  PubMed  CAS  Google Scholar 

  8. Harris AL. The epidermal growth factor receptor as a target for therapy.Cancer Cells 1990; 2: 321–323.

    PubMed  CAS  Google Scholar 

  9. Nagata N, Akatsu T, Kugai N, Yasutomo Y, Kinoshita T, Kosano H, Shimauchi T, Takatani O, Ueyama Y. The tumor cells (FA-6) established from a pancreatic cancer associated with humoral hypercalcemia of malignancy: a simultaneous production of parathyroid hormone-like activity and transforming growth factor activity.Endocrinol Jpn 1989; 36: 75–85.

    PubMed  CAS  Google Scholar 

  10. Yamada H, Yoshida T, Sakamoto H, Terada M, Sugimura T. Establishment of a human pancreatic adenocarcinoma cell line (PSN-1) with amplifications of bothc-myc and activated c-Ki-ras by a point mutation.Biochem Biophys Res Commun 1986; 140: 167–173.

    Article  PubMed  CAS  Google Scholar 

  11. Ikeda Y, Ezaki M, Hayashi I, Yasuda D, Nakayama K, Kono A. Establishment and characterization of human pancreatic cancer cell lines in tissue culture and in nude mice.Jpn J Cancer Res 1990; 81: 987–993.

    PubMed  CAS  Google Scholar 

  12. Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.Anal Biochem 1987; 162: 156–159.

    Article  PubMed  CAS  Google Scholar 

  13. Kuribayashi K, Hikata M, Hiraoka O, Miyamoto C, Furuichi Y. A rapid and efficient purification of poly(A)-mRNA by oligo(dT)30-latex.Nucleic Acids Res Symp Ser 1988; 19: 61–64.

    CAS  Google Scholar 

  14. Honda S, Yamaguchi K, Suzuki M, Sato Y, Adachi I, Kimura S, Abe K. Expression of parathyroid hormone-related protein mRNA in tumors obtained from patients with humoral hypercalcemia of malignancy.Jpn J Cancer Res 1988; 79: 677–681.

    PubMed  CAS  Google Scholar 

  15. Bell GI, Fong NM, Stempien MM, Wormsted MA, Caput D, Ku L, Urdea MS, Rall LB, Sanchez-Pescador R. Human epidermal growth factor precursor: cDNA sequence, expression in vitro and gene organization.Nucleic Acids Res 1986; 14: 8427–8444.

    Article  PubMed  CAS  Google Scholar 

  16. Derynck R, Roberts AB, Winkler ME, Cheng EY, Goeddel DV. Human transforming growth factor-alpha: precursor structure and expression inE. coli.Cell 1984; 38: 287–297.

    Article  PubMed  CAS  Google Scholar 

  17. Plowman GD, Green JM, Mcdonald VL, Neubauer MG, Disteche CM, Todaro GJ, Shoyab M. The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor inhibitory activity.Mol Cell Biol 1990; 10: 1969–1981.

    PubMed  CAS  Google Scholar 

  18. Ciccodicola A, Dono R, Obici S, Simeone A, Zollo M, Persico MG. Molecular characterization of a gene of the ‘EGF family’ expressed in undifferentiated human NETRA2 terato-carcinoma cells.EMBO J 1989; 8: 1987–1991.

    PubMed  CAS  Google Scholar 

  19. Higashiyama S, Abraham JA, Miller J, Fiddes JC, Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related, to EGF.Science 1991; 251: 936–939.

    Article  PubMed  CAS  Google Scholar 

  20. Sasada R, Ono Y, Taniyama Y, Shing Y, Folkman J, Igarashi K. Cloning and expression of cDNA encoding human betacellulin, a new member of the EGF family.Biochem Biophys Res Commun 1993; 190: 1173–1179.

    Article  PubMed  CAS  Google Scholar 

  21. Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U, Levinson A, Ullrich A. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location withneu oncogene.Science 1985; 230: 1132–1139.

    Article  PubMed  CAS  Google Scholar 

  22. Plowman GD, Whitney GS, Neubauer MG, Green JM, Mcdonald VL, Todaro GJ, Shoyab M. Molecular cloning and expression of an additional epidermal growth factor receptor-related gene.Proc Natl Acad Sci USA 1990; 87: 4905–4909.

    Article  PubMed  CAS  Google Scholar 

  23. Birchmeier C, Birnbaum D, Waitches G, Fasano O, Wigler M. Characterization of an activated human ros gene.Mol Cell Biol 1986; 6: 3109–3116.

    PubMed  CAS  Google Scholar 

  24. Martin-zanca D, Oskam R, Mitra G, Copeland T, Barbacid M. Molecular and biochemical characterization of the human trk proto-oncogene.Mol Cell Biol 1989; 9: 24–33.

    PubMed  CAS  Google Scholar 

  25. Hirai H, Maru Y, Hagiwara K, Nishida J, Takaku F. A novel putative tyrosine kinase receptor encoded by the eph gene.Science 1987; 238: 1717–1720.

    Article  PubMed  CAS  Google Scholar 

  26. Qiu F, Ray P, Brown K, Barker PE, Jhanwar S, Ruddle FH, Besmer P. Primary structure of c-kit: relationship with the CSF-1/PDGF receptor kinase family—oncogenic activation of v-kit involves deletion of extracellular domain and C terminus.EMBO J 1988; 7: 1003–1011.

    PubMed  CAS  Google Scholar 

  27. Coussens L, Beveren CV, Smith D, Chen E, Mitchell RL, Isacke CM, Verma IM, Ullrich A. Structural alteration of viral homologue of receptor proto-oncogenefms at carboxyl terminus.Nature 1986; 320: 277–280.

    Article  PubMed  CAS  Google Scholar 

  28. Chan AML, King HWS, Tempest PR, Deakin EA, Cooper CS, Brookes P. Primary structure of the met protein tyrosine kinase domain. Oncogene 1987; 1: 229–233.

    PubMed  CAS  Google Scholar 

  29. Lennard PR. Image analysis for all.Nature 1990; 347: 103104.

    Article  PubMed  CAS  Google Scholar 

  30. Sambrook J, Fritsch EF, Maniatis T.Molecular Cloning, a Laboratory Manual, 2nd ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989.

    Google Scholar 

  31. Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis.J Mol Biol 1975; 98: 503–517.

    Article  PubMed  CAS  Google Scholar 

  32. Xu Y, Ishii S, Clark AJL, Sullivan M, Wilson RK, Ma DP, Roe BA, Merlino GT, Pastan I. Human epidermal growth factor receptor cDNA is homologous to a variety of RNAs overproduced in A431 carcinoma cells.Nature 1984; 309: 806–810.

    Article  PubMed  CAS  Google Scholar 

  33. Semba K, Kamata N, Toyoshima K, Yamamoto T. A v-erbB-related protooncogene, c-erbB-2, is distinct from the c-erbB-1/epidermal growth factor-receptor gene and is amplified in human salivary gland adenocarcinoma.Proc Natl Acad Sci USA 1985; 82: 6497–6501.

    Article  PubMed  CAS  Google Scholar 

  34. Derynck R, Goeddel DV, Ullrich A, Gutterman JU, Williams RD, Bringman TS, Berger WH. Synthesis of messenger RNAs for transforming growth factor α and β and epidermal growth factor receptor by human tumors.Cancer Res 1987; 47: 707–712.

    PubMed  CAS  Google Scholar 

  35. Tanaka S, Imanishi K, Yoshihara M, Haruma K, Sumii K, Kajiyama G, Akamatsu S. Immunoreactive transforming growth factor alpha is commonly present in colorectal neoplasia.Am J Pathol 1991; 139: 123–129.

    PubMed  CAS  Google Scholar 

  36. Ohashi Y, Motokura M, Kinoshita Y, Mano T, Watanabe H, Kinoshita S, Manabe R, Oshiden K, Yanaihara C. Presence of epidermal growth factor in human tears.Invest Opthalmol Vis Sci 1989; 30: 1879–1882.

    CAS  Google Scholar 

  37. Imanishi K, Yamaguchi K, Kuranami M, Kyo E, Hozumi T, Abe K. Inhibition of growth of human lung adenocarcinoma cell lines by anti-transforming growth factor-α monoclonal antibody.J Natl Cancer Inst 1989; 81: 220–223.

    Article  PubMed  CAS  Google Scholar 

  38. Tsubouchi H, Niitani Y, Hirono S, Nakayama H, Gohda E, Arakaki N, Sakiyama O, Takahashi K, Kimoto M, Kawakami S, Setoguchi M, Tachikawa T, Shin S, Arima T, Daikuhara Y. Levels of the human hepatocyte growth factor in serum of patients with various liver disease determined by an enzyme-linked immunosorbent assay.Hepatology 1991; 13: 1–5.

    PubMed  CAS  Google Scholar 

  39. Lemoine NR, Hughes CM, Barton CM, Poulsom RA, Jeffrey RE, Kloppel G, Hall PA, Gullick WJ. The epidermal growth factor receptor in human pancreatic cancer.J Pathol 1992; 166: 7–12.

    Article  PubMed  CAS  Google Scholar 

  40. Williams TM, Winer DB, Greene MI, Maguire HC. Expression of c-erbB-2 in human pancreatic adenocarcinomas.Pathobiology 1991; 59: 46–52.

    Article  PubMed  CAS  Google Scholar 

  41. Yamanaka Y, Friess H, Kobrin MS, Buchler M, Kunz J, Beger HG, Korc M. Overexpression of HER2/neu oncogene in human pancreatic carcinoma.Hum Pathol 1993; 24: 1127–1134.

    Article  PubMed  CAS  Google Scholar 

  42. Lemoine NR, Lobresco M, Leung HY, Barton CM, Prigent SA, Gullick WJ, Kloppel G. The ERBB3 gene in human pancreatic cancer.J Pathol 1992; 168: 269–273.

    Article  PubMed  CAS  Google Scholar 

  43. Korc M, Chandrasekar B, Yamanaka Y, Friess H, Buchler M, Beger G. Overexpression of 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.

    Article  PubMed  CAS  Google Scholar 

  44. Hudziak RM, Schlessinger J, Ullrich A. Increased expression of the putative growth factor receptor p 185HER2 causes transformation and tumorigenesis of NIH3T3 cells.Proc Natl Acad Sci USA 1987; 84: 7159–7163.

    Article  PubMed  CAS  Google Scholar 

  45. Hall PA, Hughes CM, Staddon SL, Richman PI, Gullick WJ, Lemoine NR. The c-erbB-2 proto-oncogene in human pancreatic cancer.J Pathol 1990; 161: 195–200.

    Article  PubMed  CAS  Google Scholar 

  46. Klaus MH, Issing W, Miki T, Popescu NC, Aaronson SA. Isolation and characterization ofERBB3, a third member of theERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors.Proc Natl Acad Sci USA 1989; 86: 9193–9197.

    Article  Google Scholar 

  47. Ciardiello F, Kim N, Saeki T, Dono R, Persico MG, Plowman GD, Garrigues J, Radke S, Todaro GJ, Salomon DS. Differential expression of epidermal growth factor-related proteins in human colorectal tumors.Proc Natl Acad Sci USA 1991; 88: 7792–7796.

    Article  PubMed  CAS  Google Scholar 

  48. Stern DF, Kamps MP. EGF-stimulated tyrosine phosphorylation of p185neu: a potential model for receptor interaction.EMBO J 1988; 7: 995–1001.

    PubMed  CAS  Google Scholar 

  49. Hollywood DP, Hurst HC. A novel transcription factor, OB2-1, is required for overexpression of the proto-oncogene c-erbB-2 in mammary tumor lines.EMBO J 1993; 12: 2369–2375.

    PubMed  CAS  Google Scholar 

  50. Skinner A, Hurst HC. Transcriptional regulation of the c-erbB-3 gene in human breast carcinoma cell lines.Oncogene 1993; 8: 3393–3401.

    PubMed  CAS  Google Scholar 

  51. Korc M, Chandrasekar B, Shah GN. Differential binding and biological activities of epidermal growth factor and transforming growth factor α in a human pancreatic cancer cell line.Cancer Res 1991; 51: 6243–6249.

    PubMed  CAS  Google Scholar 

  52. Shoyab M, Plowman GD, McDonald VL, Bradley JG, Todaro GJ. Structure and function of human amphiregulin: a member of the epidermal growth factor family.Science 1988; 243: 1074–1077.

    Article  Google Scholar 

  53. Smith JJ, Derynck R, Korc M. Production of transforming growth factor α in human pancreatic cancer cells: evidence for a superagonist autocrine cycle.Proc Natl Acad Sci USA 1987; 84: 7657–7570.

    Google Scholar 

  54. Wong ST, Winchell LF, McCune BK, Earp HS, Teixido J, Massague J, Herman B, Lee DC. The TGF-α precursor expressed on the cell surface binds to the EGF receptor on adjacent cells, leading to signal transduction.Cell 1989; 56: 495–506.

    Article  PubMed  CAS  Google Scholar 

  55. Brachmann R, Lindquist PB, Nagashima M, Kohr W, Lipari T, Napier M, Derynck R. Transmembrane TGF-α precursors activate EGF/TGF-α receptors.Cell 1989; 56: 691–700.

    Article  PubMed  CAS  Google Scholar 

  56. Ebert M, Yokoyama M, Kobrin MS, Friess H, Lopez ME, Buchler MW, Johnson GR, Korc M. Induction and expression of amphiregulin in human pancreatic cancer.Cancer Res 1994; 54: 3959–3962.

    PubMed  CAS  Google Scholar 

  57. Johnson GR, Saeki T, Gordon AW, Shoyab M, Salomon DS, Stromberg K. Autocrine action of amphiregulin in a colon carcinoma cell line and immunocytochemical localization of amphiregulin in human colon.J Cell Biol 1992; 118: 741–751.

    Article  PubMed  CAS  Google Scholar 

  58. Shoyab M, McDonald VL, Bradley JG, Todaro GJ. Amphiregulin: a bifunctional growth-modulating glyco-protein produced by the phorbol 12-myristate 13-acetatetreated human breast adenocarcinoma cell line MCF-7.Proc Natl Acad Sci USA 1988; 85: 6528–6532.

    Article  PubMed  CAS  Google Scholar 

  59. Barton CM, Hall PA, Hughes CM, Gullick WJ, Lemoine NR. Transforming growth factor alpha and epidermal growth factor in human pancreatic cancer.J Pathol 1991; 163: 111–116.

    Article  PubMed  CAS  Google Scholar 

  60. Friess H, Yamanaka Y, Buchler M, Kobrin MS, Tahara E, 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.

    Article  PubMed  CAS  Google Scholar 

  61. Kobrin MS, Funatomi H, Friess H, Buchler MW, Stathis P, Korc M. Induction and expression of heparin-binding EGF-like growth factor in human pancreatic cancer.Biochem Biophys Res Commun 1994; 202: 1705–1709.

    Article  PubMed  CAS  Google Scholar 

  62. Bottaro DP, Rubin JS, Faletto DL, Chan AML, Kmiecik TE, Vande Woude GF, Aaronson SA. Identification of the hepatocyte growth factor receptor as the c-met oncogene product.Nature 1991; 251: 802–804.

    CAS  Google Scholar 

  63. Weidner KM, Behrens J, Vandekerckhove J, Birchmeier W. Scatter factor: molecular characteristics and effect on the invasiveness of epithelial cells.J Cell Biol 1990; 111: 2097–2108.

    Article  PubMed  CAS  Google Scholar 

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Oikawa, T., Hitomi, J., Kono, A. et al. Frequent expression of genes for receptor tyrosine kinases and their ligands in human pancreatic cancer cells. Int J Pancreatol 18, 15–23 (1995). https://doi.org/10.1007/BF02825417

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