Cancer and Metastasis Reviews

, Volume 12, Issue 3–4, pp 255–274 | Cite as

EGF receptor in neoplasia and metastasis

  • Khashayarsha Khazaie
  • Volker Schirrmacher
  • Rosemarie B. Lichtner


EGFR is a member of the tyrosine kinase family of cell surface receptors with a wide range of expression throughout development and in a variety of different cell types. The receptor can transmit signals to cells: i) upon interaction with ligands such as EGF, TGFα, amphiregulin or heparin binding EGF, ii) upon truncation or mutation of extracellular and/or intracellular domains, iii) upon amplification of a basal receptor activity (in the absence of ligand) through cooperation with other cellular signaling pathways or nuclear events (e.g. expression of v-erbA). The activated EGFR can exert pleiotropic functions on cells, depending on their tissue origin and state of differentiation. Under certain conditions it can also contribute to neoplasia and development of metastases. Such conditions can exist upon aberrant receptor/ligand expression and activation (e.g. in the wrong cell; at the wrong time; in the wrong amounts). Aberrant signalling can also occur through constitutive EGFR activation. Oncogenic potential of EGFR has been demonstrated in a wide range of experimental animals. EGFR is also implicated in human cancer, where it may contribute both to the initiation (glioblastoma) and progression (epithelial tumors) of the disease. EGFR may influence key steps in the processes of tumor invasion and dissemination. Involvement of EGFR in tumor spread may indicate a potential use of this receptor as a target for antimetastatic therapy.

Key words

EGFR neoplasia metastasis 


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  1. 1.
    Carpenter G, Cohen S: Epidermal growth factor. J Biol Chem 265: 7709–7712, 1990Google Scholar
  2. 2.
    Plowman GD, Culouscou J-M, Whitney GS, Green JM, Carlton GW, Foy L, Neubauer MG, Shoyab M: Ligandspecific activation of HER4/p180erbB4, a fourth member of the Epidermal Growth Factor Receptor family. Proc Natl Acad Sci 90: 1746–1750, 1993Google Scholar
  3. 3.
    Ullrich A, Schlessinger J: Signal transduction by receptors with tyrosine kinase activity. Cell 61: 203–212, 1990Google Scholar
  4. 4.
    Honegger AM, Dull TJ, Felder S, Van Obberghen E, Bellot F, Szapary D, Schmidt A, Ullrich A, Schlessinger J: Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activation and alters cellular routing. Cell 51: 199–209, 1987Google Scholar
  5. 5.
    Moolenaar WA, Bierman AJ, Tilly BC, Verlaan I, Defize LHK, Honegger AM, Ullrich A, Schlessinger J: A point mutation at the ATP-binding site of the EGF-receptor abolishes signal transduction. EMBO J 7: 707–710, 1988Google Scholar
  6. 6.
    Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, Lee J, Yarden Y, Libermann TA, Schlessinger J, Downward J, Mayes ELV, Whittle N, Waterfield MD, Seeburg PH: Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified genes in A431 epidermoid carcinoma cells. Nature (London) 309: 418–425, 1984Google Scholar
  7. 7.
    Downward J, Parker P, Waterfield MD: Autophosphorylation sites on the epidermal growth factor receptor. Nature 311: 483–485, 1984Google Scholar
  8. 8.
    Carpenter G, Wahl MI: Handb Exp Pharmacol 951: 69–171, 1990Google Scholar
  9. 9.
    Lin CR, Chen WS, Lazar CW, Carpenter CD, Gill GN, Evans RM, Rosenfeld MG: Protein kinase C phosphorylation at Thr 654 of the unoccupied Epidermal Growth Factor-receptor and EGF binding regulate functional receptor loss by independent mechanisms. Cell 44: 839–848, 1986Google Scholar
  10. 10.
    Segatto O, Lonardo F, Wexler D, Fazioli F, Pierce JH, Bottaro DP, White MF, DiFiore PP: The juxtamembrane regions of the Epidermal Growth Factor-Receptor and gp185erB-2 determine the specificity of signal transduction. Mol Cell Biol 11: 3191–3202, 1991Google Scholar
  11. 11.
    Countaway JL, Nairn AC, Davis RJ: Mechanism of desensitisation of the EGFR protein-tyrosine kinase. J Biol Chem 267: 1129–1140, 1992Google Scholar
  12. 12.
    Theroux SJ, Taglienti Sian C, Nair N, Countaway JL, Robinson HL, Davis RJ: Increased oncogenic potential of erbB is associated with the loss of a COOH-terminal domain serine phosphorylation site. J Biol Chem 267: 7967–7970, 1992Google Scholar
  13. 13.
    Honegger AM, Schmidt A, Ullrich A, Schlessinger J: Evidence for Epidermal Growth Factor Receptor-induced intermolecuar autophosphorylation of the EGF-receptors in living cells. Mol Cell Biol 10: 4035–4044, 1990Google Scholar
  14. 14.
    Honegger AM, Dull TJ, Bellot F, van Obberghen E, Szapary D, Schmidt A, Ullrich A, Schlessinger J: Biological activities of EGF-receptor mutants with individually altered autophosphorylation sites. EMBO J 7:3045–3052, 1988Google Scholar
  15. 15.
    Honegger A, Dull TJ, Szapary D, Komoriya A, Kris R, Ullrich A, Schlessinger J: Kinetic parameters of the protein tyrosine kinase activity of EGF-receptor mutants with individually altererd autophosphorylation sites. EMBO J 7: 3053–3060, 1988Google Scholar
  16. 16.
    Walton GM, Chen WS, Rosenfeld MG, Gill GN: Analysis of deletions of the carboxyl terminus of the Epidermal Growth Factor Receptor reveals self-phosphorylation at tyrosine 992 and enhanced in vivo tyrosine phosphorylation of cell substrates. J Biol Chem 265: 1750–1754, 1990Google Scholar
  17. 17.
    Khazaie K, Dull TJ, Graf T, Schlessinger J, Ullrich A, Beug H, Vennstrjm B: Trunction of the human EGFR leads to differential transforming potentials in primary avian fibroblasts and erythroblasts. EMBO J 7: 3061–3071, 1988Google Scholar
  18. 18.
    Massoglia S, Gray A, Dull TJ, Munemitsu S, Kung H-J, Schlessinger J, Ullrich A: Epidermal growth factor receptor cytoplasmic domain mutations trigger ligand-independent transformation. Mol Cell Biol 10: 3048–3055, 1990Google Scholar
  19. 19.
    Lichtner RB, Wiedemuth M, Kittmann A, Ullrich A, Schirrmacher V, Khazaie K: Ligand-induced activation of EGFR in intact rat mammary adenocarcinoma cells without detectable receptor phosphorylation. J Biol Chem 267: 11872–11880, 1992Google Scholar
  20. 20.
    Vega QC, Cochet C, Filhol O, Chang C-P, Rhee SG, Gill GN: A site of tyrosine phosphorylation in the C terminus of the Epidermal Growth Factor Receptor is required to activate phospholipase C. Mol Cell Biol 12: 128–135, 1992Google Scholar
  21. 21.
    Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziani A, Kapeller R, Soltoff S: Oncogenes and signal transduction. Cell 64: 281–302, 1991Google Scholar
  22. 22.
    Panayotou G, Waterfield M: Phosphatidylinositol 3-kinase: a key enzyme in diverse sinalling processes. Trends in Cell Biol Dec: 358–360, 1992Google Scholar
  23. 23.
    Panayotou G, Waterfield M: The assembly of signalling complexes by receptor tyrosine kinases. BioEssays, March 1993, in pressGoogle Scholar
  24. 24.
    Merlino GT, Ishii S, Whang-Peng J, Knutsen T, Xu Y-H, Clark AJ, Stratton RH, Wilson RK, Ma DP, Roe BA, Hunts JH, Shimizu N, Pastan I: Structure and localization of genes encoding aberrant and normal epidermal growth factor receptor RNAs from A431 human carcinoma cells. Mol Cell Biol 5: 1722–1734, 1985Google Scholar
  25. 25.
    Petch LA, Harris J, Raymond VW, Blasband A, Lee DC, Earp HS: A truncated, secreted form of the epidermal growth factor receptor is encoded by an alternatively spliced transcript in normal rat tissue. Mol Cell Biol 10: 2973–2982, 1990Google Scholar
  26. 26.
    Vennström B, Bishop JM: Isolation and characterization of chicekn DNA homologous to the two putative oncogenes of avian erythroblastosis virus. Cell 28: 135–143, 1982Google Scholar
  27. 27.
    Gamou S, Hirai M, Rikimaru K, Enomoto S, Shimizu N: Biosynthesis of the epidermal growth factor receptor in human squamous cell carcinoma lines: secretion of the truncated receptor-hyperproducing cells. Cell Struct Func 13: 25–38, 1988Google Scholar
  28. 28.
    Basu A, Raghunath M, Bishayee S, Das M: Inhibition of tyrosine kinase activity of the epidermal growth factor (EGF) receptor by a truncated receptor form that binds to EGF: role for interreceptor interaction in kinase regulation. Mol Cell Biol 9: 671–677, 1989Google Scholar
  29. 29.
    Redemann N, Holzmann B, von Rüden T, Wagner EF, Schlessinger J, Ullrich A: Anti-oncogenic activity of signalling-defective epidermal growth factor receptor mutants. Mol Cell Biol 12: 491–498, 1992Google Scholar
  30. 30.
    Cohen S, Elliott G: J Invest Dermatol 40: 1–5, 1963Google Scholar
  31. 31.
    Gregory H: Isolation and structure of urogastrone and its relationship to epidermal growth factor. Nature 257: 325–327, 1975Google Scholar
  32. 32.
    Cohen S, Carpenter G: Human epidermal growth factor: Isolation and chemical and biological properties. Proc Natl Acad Sci USA 72: 1317–1321, 1975Google Scholar
  33. 33.
    Roberts AB, Sporn MB: Transforming growth factors. Cancer Surveys 4: 683–705, 1985Google Scholar
  34. 34.
    Derynck R: Transforming growth factor α. Cell 54: 593–595, 1988Google Scholar
  35. 35.
    Prigent S, Lemoine NR: The type 1 (EGFR-related) family of growth factor receptors and their ligands. Progress in Growth Factor Research 4: 1–24, 1992Google Scholar
  36. 36.
    Higashiyama S, Lau K, Besner GE, Abraham JA, Klagsbrun M: Structure of heparin-binding EGFR-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein. J Biol Chem 267: 6205–6212, 1992Google Scholar
  37. 37.
    Wong ST, Winchell LF, McCune BK, Earp HS, Teixido J, Massagué 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 56: 495–506, 1989Google Scholar
  38. 38.
    Blasband AJ, Gilligan DM, Winchell LF, Wong ST, Luetteke NC, Rogers KT, Lee DC: Expression of the TGFα integral membrane precursor induces transformation of NRK cells. Oncogene 5: 1213–1221, 1990Google Scholar
  39. 39.
    Anklesaria P, Teixido J, Laiho M, Pierce JH, Greenberger JS, Massagué J: Cell-cell adhesion mediated by binding of membrane-anchored transforming growth factor α to epidermal growth factor receptors promotes cell proliferation. Proc Natl Acad Sci USA 87: 3289–3293, 1990Google Scholar
  40. 40.
    Fukuyama R, Shimizu N: Expression of EGF and the EGFR in human tissues. J Exp Zool 258: 336–343, 1991Google Scholar
  41. 41.
    Harris RC: Potential physiological roles for EGF in the kidney. Am J Kidney Dis 17: 627–630, 1991Google Scholar
  42. 42.
    Fine LG, Hammerman MR, Abboud HE: Evolving role of growth factors in the renal response to acute and chronic disease. J Am Soc Nephrol 2: 1163–1170, 1992Google Scholar
  43. 43.
    Fuse H, Sakamoto M, Okumura M, Katayama T: EGF contents in seminal plasma as a marker of prostatic functions. Arch Androl 29: 79–85, 1992Google Scholar
  44. 44.
    Nishi N, Shimizu C, Okutani T, Kagawa Y, Takasuga H, Suno M, Wada F: Rat prostatic growth factors: purification and characterization of high and low molecular weight Epidermal Growth Factor receptors from rat dorsolateral prostate. Biochim Biophys Acta 1095: 268–275, 1991Google Scholar
  45. 45.
    Plata-Salaman CR: Epidermal growth factor and the nervous system. Pepetides 12: 653–663, 1991Google Scholar
  46. 46.
    Madtes DK, Raines EW, Sakariassen KS, Assoian RK, Sporn MB, Bell GI, Ross R: Induction of transforming growth factor-α in activated human alveolar macrophages. Cell 53: 285–293, 1988Google Scholar
  47. 47.
    Laurence DJR, Gusterson BA: The epidermal growth factor receptor: a review of structural and functional relationships in the normal organism and in cancer cells. Tumor Biol 11: 229–261, 1990Google Scholar
  48. 48.
    Panayotou G, End P, Aumailley M, Timpl R, Engel H: Domains of laminin with growth factor activity. Cell 56: 93–101, 1989Google Scholar
  49. 49.
    Kubota S, Tashiro K, Yamada Y: Signaling site of laminin with mitogenic activity. J Biol Chem 267: 4285–4288, 1992Google Scholar
  50. 50.
    Gospodarowicz D: Epidermal and nerve growth factors in mammalian development. Ann Rev Physiol 43: 251–263, 1981Google Scholar
  51. 51.
    Dardik A, Schultz RM: Blastocoel expansion in the preimplantation mouse embryo: stimulatory effect of TGF-α and EGF. Development 113: 919–930, 1991Google Scholar
  52. 52.
    Rappoll D, Brenner CA, Schultz R, Mark D, Werb Z: Developmental expression of PDGF, TGF-α, and TGF-β genes in preimplantation mouse embryos. Science 241: 1823–1825, 1988Google Scholar
  53. 53.
    Arnholdt H, Diebold J, Kuhlmann B, Lohrs U: Receptor mediated processing of epidermal growth factor in the trophoblast of the human placenta. Virchows Arch B Cell Pathol 61: 75–80, 1991Google Scholar
  54. 54.
    Zhang Y, Paria BC, Dey SK, Davis DL: Characterisation of the Epidermal Growth Factor Receptor in preimplantation pig conceptuses. Dev Biol 151: 617–621, 1992Google Scholar
  55. 55.
    Warburton D, Seth R, Shum L, Horcher PG, Hall FL, Werb Z, Slavkin HC: Epigenetic role of epidermal growth factor expression and signalling in embryonic mouse lung morphogenesis. Dev Biol 149: 123–133, 1992Google Scholar
  56. 56.
    Abbott BD, Pratt RM: Retinoic acid alters epithelial differentiation during palatogenesis. J Craniofac Genet Dev Biol 11: 315–325, 1991Google Scholar
  57. 57.
    Lee D, Han VKM: The expression of growth factors and their receptors in development. In: Sporn MB, Roberts AB (eds) Handbook of Experimental Pharmacology. Springer Verlag, Berlin, 1990, pp 611–654Google Scholar
  58. 58.
    Joh T, Darland T, Samuels M, Wu JX, Adamson ED: Regulation of epidermal growth factor receptor gene expression in murine embryonal carcinoma cells. Cell Growth Differ 3: 315–325, 1992Google Scholar
  59. 59.
    den Hertog J, de Laat SW, Schlessinger J, Kruijer W: Neuronal differentiation in response to epidermal growth factor of transfected P19 embryonal carcinoma cells expressing human epidermal growth factor receptors. Cell Growth Differ 2: 155–164, 1991Google Scholar
  60. 60.
    Reynolds BA, Weiss S: Generation of neurones and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255: 1707–1710, 1992Google Scholar
  61. 61.
    Simpson DL, Morrison R, de Vellis J, Herschman HR: Epidermal growth factor binding and mitogenic activity on purified populations of cells from the central nervous system. J Neurosci Res 8: 453–462, 1982Google Scholar
  62. 62.
    Leutz A, Schachner M: Epidermal growth factor stimulates DNA-synthesis of astrocytes in primary cerebellar cultures. Cell Tissue Res 220: 393–404, 1981Google Scholar
  63. 63.
    Junier M-P, Ma YJ, Costa ME, Hoffman G, Hill DF, Ojeda SR: Transforming growth factor-α contributes to the mechanism by which hypothalamic injury induces precocious puberty. Proc Natl Acad Sci USA 88: 9743–9747, 1991Google Scholar
  64. 64.
    Nelson KG, Takahashi T, Bossert NL, Walmer DK, McLachlan JA: Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation. Proc Natl Acad Sci 88: 21–25, 1991Google Scholar
  65. 65.
    Ignar-Trowbridge DM, Nelson KG, Bidwell MC, Curtis SW, Washburn TF, McLachlan JA, Korach KS: Coupling of dual signaling pathways: Epidermal growth factor action involves the estrogen receptor. Proc Natl Acad Sci 89: 4658–4662, 1992Google Scholar
  66. 66.
    Daniel CW, Silberstein GB, Strickland P: Direct action of 17 beta-estradiaol on mouse mammary ducts analyzed by substained release implants and steroid autoradiography. Cancer Res 47: 6052–6057, 1987Google Scholar
  67. 67.
    Coleman S, Silberstein GB, Daniel CW: Ductal morphogenesis in the mouse mammary gland: evidence supporting a role for Epidermal growth factor. Dev Biol 127: 304–315, 1988Google Scholar
  68. 68.
    Daniel CW, Silberstein GB: In: Neville MC, Daniel CW (eds) The mammary gland, development, regulation and function. Plenum, New York, 1987, pp 3–36Google Scholar
  69. 69.
    Lippman ME, Dickson RB, Kasid A, Gelmann E, Davidson N, McManaway M, Huff K, Bronzert D, Bates S, Swain S, Knabbe C: Autocrine and paracrine growth regulation of human breast cancer. J Steroid Biochem 24: 147–154, 1986Google Scholar
  70. 70.
    Snedeker SM, Brown CF, DiAugustine RP: Expression and functional properties of transforming growth factor-α and epidermal growth factor during mouse mammary gland ductal morphogenesis. Proc Natl Acad Sci USA 88: 276–280, 1991Google Scholar
  71. 71.
    Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, Waterfield MD: Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 307: 521–527, 1984Google Scholar
  72. 72.
    Beug H, Kahn P, Djderlein G, Hayman MJ, Graf T: Characterization of hematopoietic cells transformed in vitro by AEV-H, an erbB containing avian erythroblastosis virus. In: Neth, Gallo, Greaves, Janka (eds) Modern Trends in Human Leukemia VI, 29. Springer-Verlag, Berlin-Heidelberg, 1985, pp 290–297Google Scholar
  73. 73.
    Beug H, Hayman M, Vennstrom, B: Mutational analysis of v-erbB oncogene function. In: Graf T, Kahn P (eds) Oncogenes and Growth Control. Springer-Verlag, Berlin-Heidelberg, 1988Google Scholar
  74. 74.
    Sap J, Munoz A, Damm K, Goldberg Y, Ghysdael J, Leutz A, Beug H, Vennstrjm B: The c-erb-A protein is a high affinity receptor for thyroid hormone. Nature 324: 635–640, 1986Google Scholar
  75. 75.
    Weinberger C, Thompson CC, Ong ES, Lebo R, Gruol DJ, Evans RM: The c-erb-A gene encodes a thyroid hormone receptor. Nature 324: 641–646, 1986Google Scholar
  76. 76.
    Schroeder C, Gibson L, Nordstrjm C, Beug H: The estrogen receptor cooperates with the TGFα receptor (c-erbB) in regulation of chicken erythroid progenitor self-renewal. EMBO J 12: 951–960, 1993Google Scholar
  77. 77.
    Pain B, Woods CM, Saez J, Flickinger T, Raines M, Peyrol S, Moscovici C, Moscovici MG, Kung H-J, Jurdic P, Lazarides E, Samarut J: EGF-R as a hemopoietic growth factor receptor: the c-erbB product is present in chicken erythrocytic progenitors and controls their self-renewal. Cell 65: 37–46, 1991Google Scholar
  78. 78.
    Pierce JH, Ruggiero M, Fleming TP, DiFiore PP, Greenberger JS, Varticovski L, Schlessinger J, Rovera G, Aaronson SA: Signal transduction through the EGF receptor transfected in IL-3 dependent hematopoietic cells. Science 239: 628–631, 1988Google Scholar
  79. 79.
    Collins M, Downward J, Miyajima A, Maruyama K, Arai KI, Mulligan R: Transfer of functional EGFRs to an IL3-dependent cell line. J Cell Physiol 137: 293–298, 1988Google Scholar
  80. 80.
    Shibuya H, Yoneyama M, Ninomiya-Tsuji J, Matsumoto K, Taniguchi T: IL-2 and EGF receptors stimulate the hematopoietic cell cycle via different signalling pathways: demonstration of a novel role for c-myc. Cell 70: 57–67, 1992Google Scholar
  81. 81.
    Oval J, Hershberg R, Gansbacher B, Gilboa E, Schlessinger J, Taetle R: Expression of functional epidermal growth factor receptors in a human hematopoietic cell line. Cancer Res 51: 150–156, 1991Google Scholar
  82. 82.
    Metz T, Graf T, Leutz A: Activation of cMGF expression is a critical step in avian myeloid leukemogenesis. EMBO J 10: 837–844, 1991Google Scholar
  83. 83.
    Velu TJ, Beguinot L, Vass WC, Willingham MC, Merlino GT, Pastan I, Lowy DR: Epidermal growth factor-dependent transformation by a human EGF-receptor proto-oncogene. Science 238: 1408–1410, 1987Google Scholar
  84. 84.
    DiFiore PP, Pierce JH, Fleming TP, Hazan R, Ullrich A, King CR, Schlessinger J, Aaronson SA: Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells. Cell 51: 1063–1070, 1987Google Scholar
  85. 85.
    Khazaie K, Panayotou G, Aguzzi A, Samarut J, Gazzolo L, Jurdic P: EGF promotesin vivo sarcomagenic growth of early passage chicken embryo fibroblasts expressing v-myc and enhancesin vitro transformation by the v-erbA oncogene. Oncogene 6: 21–28, 1991Google Scholar
  86. 86.
    Sandgren EP, Luetteke NC, Palmiter RD, Brinster RL, Lee DC: Overexpression of TGFα in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 61: 1121–1135, 1990Google Scholar
  87. 87.
    Pelley RJ, Moscovici C, Hughes S, Kung H-J: Proviral activated c-erbB is leukemogenic but not sarcomagenic: characterization of a replication-competent retrovirus containing the activated c-erbB. J Virol 62: 1840–1844, 1988Google Scholar
  88. 88.
    Raines MA, Maihle NJ, Moscovici C, Moscovici MG, Kung H-J: Molecular characterisation of three erbB transducing viruses generated during avian leukosis virus-induced erythroleukemia: extensive internal deletion near the kinase domain activates the fibrosarcoma - and hemangioma - inducing potentials of erbB. J Virol 62: 2444–2452, 1988Google Scholar
  89. 89.
    Gamett D, Tracy S, Robinson H: Differences in sequences encoding the carboxy-terminal domain of the epidermal factor receptor correlate with differences in the disease potential of viralerbB genes. Proc Natl Acad Sci USA 83: 6053–6057, 1986Google Scholar
  90. 90.
    Rosenthal A, Lindquist PB, Bringman TS, Goeddel DV, Derynck R: Expression in rat fibroblasts of a human transforming growth factor-α cDNA results in transformation. Cell 46: 301–309, 1986Google Scholar
  91. 91.
    Stern DF, Hare DL, Cecchini MA, Weinberg RA: Construction of a novel oncogene based on synthethic sequences encoding epidermal growth factor. Science 235: 321–324, 1987Google Scholar
  92. 92.
    Land H, Parada LF, Weinberg RA: Cellular oncogenes and multistep carcinogenesis. Science 222: 771–778, 1983Google Scholar
  93. 93.
    Decker SJ, Alexander C, Habib T: Epidermal growth factor-stimulated tyrosine phosphorylation and Epidermal growth factor receptor degradation in cells expressing EGF receptors truncated at residue 973. J Biol Chem 267: 1104–1108, 1992Google Scholar
  94. 94.
    Clark S, Dunlop M: Modulation of phospholipase A2 activity by EGF in CHO cells transfected with human EGFR. Role of receptor cytoplasmic subdomain. Biochem J 15: 715–721, 1991Google Scholar
  95. 95.
    DiFiore PP, Helin K, Kraus MH, Pierce JH, Artrip J, Segatto J, Bottaro DP: A single amino acid substitution is sufficient to modify the mitogenic properties of the epidermal growth factor receptor to resemble that of gp185erbB-2. EMBO J 11: 3927–3933, 1992Google Scholar
  96. 96.
    Jhappan C, Stahle C, Harkins RN, Fausto N, Smith GH, Merlino GT: TGFα overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell 61: 1137–1146, 1990Google Scholar
  97. 97.
    Fuchs E, Vassar R: Trangenic mice provide new insights into the role of TGF-α during epidermal development and differentiation. Genes Dev 5: 714–727, 1991Google Scholar
  98. 98.
    Elder JT, Fisher GJ, Lindquist PB, Bennett GL, Pittelkow MR, Coffey RJ Jr, Ellingsworth L, Derynck R, Voorhees JJ: Overexpression of TGF-α in psoriatic epidermis. Science 243: 811–814, 1989Google Scholar
  99. 99.
    Krane JF, Gottlieb AB, Carter DM, Krueger JG: The Insulin growth factor-I receptor is overexpressed in psoriatic epidermis, but is differentially regulated from the epidermal growth factor receptor. J Exp Med 175: 1081–1090, 1992Google Scholar
  100. 100.
    Cook PW, Pittelkow MR, Shipley GD: Growth factor independent proliferation of normal human keratinocytes: production of autocrine and paracrine acting mitogenic factors. J Cell Physiol 146: 277–289, 1991Google Scholar
  101. 101.
    Imamoto A, Beltran LM, DiGiovanni J: Evidence for autocrine/paracrine growth stimulation by TGF-α during the process of skin tumor promotion. Mol Carcinog 4: 52–60, 1991Google Scholar
  102. 102.
    te-Pas MF, van Bergen en Henegouwen PM, Boonstra J, Ponec M: Regulation of EGFR expression in normal and transformed keratinocytes. Arch Dermatol Res 283: 125–130, 1991Google Scholar
  103. 103.
    Colburn NH: Genes and membrane signals involved in neoplastic transformation. In: Huberman E, Barr SH (eds) Carcinogenesis, Vol 10. Raven Press, New York, 1985, pp 235–248Google Scholar
  104. 104.
    Ben-Ari ET, Bernstein LR, Colburn NH: Differential cjun expression in response to tumor promoters in JB6 cells sensitive or resistant to neoplastic transformation. Mol Carcinog 5: 62–74, 1992Google Scholar
  105. 105.
    Sun Y, Pommier Y, Colburn NH: Acquisition of a growthinhibitory response to phorbol ester involves DNA damage. Cancer Res 52: 1907–1915, 1992Google Scholar
  106. 106.
    Sainsbury JRC, Farndon JR, Needham GK, Malcolm AJ, Harris AL: Epidermal growth factor receptor status as predictor of early recurrence of and death from breast cancer. Lancet i: 1398–1402, 1987Google Scholar
  107. 107.
    Grimaux M, Romain S, Remvikos Y, Martin PM, Magdalenat H: Prognostic value of EGFR in node-positive breast cancer. Breast Cancer Res Treat 14: 77–90, 1989Google Scholar
  108. 108.
    Bolufer P, Miralles F, Rodriquez A, Vanquez C, Lluch A, Garcia-Conde J, Olmos T: Epidermal growth factor receptor in human breast cancer: correlation with cytosolic and nuclear ER receptors and with biological and histological tumor characteristics. Eur J Cancer 26: 283–290, 1990Google Scholar
  109. 109.
    Toi M, Osaki A, Yamada H, Toge T: Epidermal growth factor receptor expression as a prognostic indicator in breast cancer. Eur J Cancer 27: 977–980, 1991Google Scholar
  110. 110.
    Klijn JG, Berns PM, Schmitz PI, Foekens JA: The clinical significance of EGFR in human breast cancer: a review on 5232 patients. Endocr Rev 13: 3–17, 1992Google Scholar
  111. 111.
    Battaglia F, Scambia G, Rossi G, Benedetti P, Bellatone R, Pollizi G, Querzoli P, Negrinie R, Jacobelli S, Crucittie F, Mancuso S: Epidermal growth factor receptor in human breast cancer: correlation with steroid hormone receptors and axillary lymph node involvement. Eur J Cancer Clin Oncol 24: 1685–1690, 1988Google Scholar
  112. 112.
    Cappelletti V, Brivio M, Miodini P, Granata G, Coradini D, DiFronzo G: Simultaneous estimation of epidermal growth factor receptors and steroid receptors in a series of 136 resectable primary breast tumors. Tumor Biol 9: 200–211, 1988Google Scholar
  113. 113.
    Delarue JC, Friedman S, Mouriesse H, May-Levin F, Sancho-Garnier H, Contesso G: Epidermal growth factor receptor in human breast cancer: correlation with estrogen and progesterone receptors. Breast Cancer Res Treat 11: 173–178, 1988Google Scholar
  114. 114.
    Foekens JA, Portengen H, Putten WLJ, Trapman AMAC, Reubi J, Alexieva FG, Klijn JGM: Prognostic value of receptors for insulin-like growth factor I, somatostatin, and epidermal growth factor in human breast cancer. Cancer Res 49: 7002–7009, 1989Google Scholar
  115. 115.
    Bolla M, Chedin M, Souvignet C, Marron J, Arnould C, Chambaz E: Estimation of epidermal growth factor receptor in 177 breast cancers: correlation with prognostic factors. Breast Canc Res Treat 16: 97–102, 1990Google Scholar
  116. 116.
    Spyratos F, Delarue D, Andrieu C, Lidereau R, Champème MH, Hacène K, Brunet M: Epidermal growth factor receptors and prognosis in primary breast cancer. Breast Cancer Res Treat 17: 83–89, 1990Google Scholar
  117. 117.
    Koenders PG, Beex LVAM, Geurts-Moespot A, Heuvel JJTM, Kienhuis CBM, Benraad TJ: Epidermal growth factor receptor-negative tumors are predominantly confined to the subgroup of estradiol receptor-positive human primary breast cancers. Cancer Res 51: 4544–4548, 1991Google Scholar
  118. 118.
    Bilous M, Milliken J, Mathijs J-M: Immunocytochemistry andin situ hybridisation of Epidermal growth factor receptor and relation to prognostic factors in breast cancer. Eur J Cancer 28: 1033–1037, 1992Google Scholar
  119. 119.
    Rios MA, Fernandez A, Tormo B, Quintero S, Perez I, Skoog L, Perez R: Heterogenous expression of the EGF-receptor in human breast carcinoma. Anticancer Res 12: 205–208, 1992Google Scholar
  120. 120.
    Fernandez-Pol JA: Modulation of EGFR protooncogene expression by growth factors and hormones in human breast carcinoma cells. Critical Reviews in Oncogenesis 2: 173–185, 1991Google Scholar
  121. 121.
    van de Vijver MJ, Nusse R: The molecular biology of breast cancer. Biochim Biophys Acta 1072: 33–50, 1991Google Scholar
  122. 122.
    Long B, McKibben BM, Lynch M, van den Berg HW: Changes in epidermal growth factor-receptor expression and response to ligand associated with acquired tamoxifen resistance or estrogen independence in the ZR-75-1 human breast cancer cell lines. Br J Cancer 65: 865–869, 1992Google Scholar
  123. 123.
    van Agthoven T, van Agthoven TLA, Portengen H, Foekens JA, Dorssers LCJ: Ectopic expression of epidermal growth factor receptors induces hormone independence in ZR-75-1 human breast cancer cells. Cancer Res 52: 5082–5088, 1992Google Scholar
  124. 124.
    Carlin CR, Simon D, Mattison J, Knowles BB: Expression and biosynthetic variation of the epidermal growth factor receptor in human hepatocellular carcinoma-derived cell lines. Mol Cell Biol 8: 25–34, 1988Google Scholar
  125. 125.
    Baskin G, Schenker S, Frosto T, Henderson G: Transforming growth factor-β 1 inhibits EGFR endocytosis and down-regulation in cultured fetal rat hepatocytes. J Biol Chem 266: 13238–13242, 1991Google Scholar
  126. 126.
    Meyer DH, Bachem MG, Gressner AM: Bidirectional effects of Kupffer cells on hepatocyte proliferation in vitro. FEBS Lett 283: 150–154, 1991Google Scholar
  127. 127.
    Aumüller G: Benign prostatic hyperplasia and growth factors: mechanisms and hypotheses. Urologe A 31: 159–165, 1992Google Scholar
  128. 128.
    Manni A: Somatostatin and growth hormone regulation in cancer. Biotherapy 4: 31–36, 1992Google Scholar
  129. 129.
    Atlas I, Mendelsohn J, Baselga J, Fair WR, Masui H, Kumar R: Growth regulation of human renal carcinoma cells: role of transforming growth factor-α. Cancer Res 52: 3335–3339, 1992Google Scholar
  130. 130.
    Walker C, Everitt J, Freed JJ, Knudson AG Jr, Whiteley LO: Altered expression of transforming growth factor-α in hereditary rat renal cell carcinoma. Cancer Res 51: 2973–2978, 1991Google Scholar
  131. 131.
    Neal DE, Marsh C, Bennett MK, Abel PD, Hall RR, Sainsbury JRC, Harris A: Epidermal growth factor receptors in human bladder cancer: comparison of invasive and superficial tumors. Lancet, Feb 16: 166–368, 1985Google Scholar
  132. 132.
    Shirasuna K, Hayashido Y, Sugiyama M, Yoshioka H, Matsuya T: Immunohistochemical localization of EGF and EGFR in human mucosa and its malignancy. Virchows-Arch-A-Pathol-Anat-Histopathol 418: 349–353, 1991Google Scholar
  133. 133.
    Maurizi M, Scambia G, Benedetti Panici P, Ferrandina G, Almadori G, Paludetti G, De Vincenzo R, Distefano M, Brinchi D, Cadoni G, Mancuso S: Epidermal growth factor receptor expression in primary laryngeal cancer: correlation with clinico-pathological features and prognostic significance. Int J Cancer 52: 862–866, 1992Google Scholar
  134. 134.
    Ozawa S, Ueda M, Ando N, Abe O, Hirai M, Shimizu N: Stimulation by EGF of the growth of EGF receptor-hyper-producing tumor cells in athymic mice. Int J Cancer 40: 706–710, 1987Google Scholar
  135. 135.
    Mukaida H, Toi M, Hirai T, Yamashita Y, Toge T: Clinical significance of the expression of EGF and its receptor in esophageal cancer. Cancer 68: 142–148, 1991Google Scholar
  136. 136.
    Chen S-C, Chou C-K, Wong F-H, Chang C, Hu C-P: Over expression of epidermal growth factor and Insulin growth factor-I receptors and autocrine stimulation in human espohageal carcinoma cells. Cancer Res 51: 1898–1903, 1991Google Scholar
  137. 137.
    Lemoine NR, Jain S, Sivestre F, Lopes C, Hughes CM, McLealland E, Gullick WJ, Filipe MI: Amplification and overexpression of the EGF-receptor and c-erbB-2 protooncogenes in human stomach cancer. Br J Cancer 64: 79–83, 1991Google Scholar
  138. 138.
    Gross ME, Zorbas MA, Danels YJ, Garcia R, Gallick GE, Olive M, Brattain MG, Boman BM, Yeoman LC: Cellular growth response to EGF in colon carcinoma cells with an amplified growth factor derived from a familial adenomatous polyposis patient. Cancer Res 51: 1452–1459, 1991Google Scholar
  139. 139.
    Huang S, Trujillo JM, Chakrabarty S: Proliferation of human colon cancer cells: role of EGF and transforming growth factor-α. Int J Cancer 52: 978–986, 1992Google Scholar
  140. 140.
    Scambia G, Benedetti Panici P, Battaglia F, Ferrandina G, Baiocchi G, Greggi S, De-Vincenzo R, Manuco S: Significance of EGFR in advanced ovarian cancer. J Clin Oncol 10: 529–535, 1992Google Scholar
  141. 141.
    Damstrup L, Rygaard K, Spang-Thomsen M, Poulsen HS: Expression of the EGFR in human small cell lung cancer cell lines. Cancer Res 52: 3089–3093, 1992Google Scholar
  142. 142.
    Leung FC, Bohn LR, Dagle GE: Elevated EGFR binding in plutonium-induced lung tumors from dogs. Proc Soc Exp Biol Med 196: 385–389, 1991Google Scholar
  143. 143.
    Yamazaki H, Yasuhisa F, Ueyama Y, Tamaoli N, Kawamoto T, Taniguchi S, Shibuya M: Amplification of the structurally and functionally altered epidermal growth factor receptor gene (c-erbB) in human brain tumors. Mol Cell Biol 8: 1816–1820, 1988Google Scholar
  144. 144.
    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 tumours of glial origin. Nature 313: 144–147, 1985Google Scholar
  145. 145.
    Tuzi NL, Venter DJ, Kumar S, Staddon SL, Lemoine NR, Gullick WJ: Expression of growth factor receptors in human brain tumours. Br J Cancer 63: 227–233, 1991Google Scholar
  146. 146.
    Chaffanet M, Chauvin C, Laine M, Berger F, Chedin M, Rost N, Nissou MF, Benabid AL: EGFR amplification and expression in human brain tumors. Eur J Cancer 28: 11–17, 1992Google Scholar
  147. 147.
    Humphrey PA, Wong AJ, Vogelstein B, Zalutsky MR, Fuller GN, Archer GE, Friedman HS, Kwatra MM, Bigner SH, Bigner DD: Antisynthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci USA 87: 4207–4211, 1990Google Scholar
  148. 148.
    Hart IR: “Seed and soil” revisited: mechanisms of site specific metastasis. Cancer Met Rev 1: 5–16, 1982Google Scholar
  149. 149.
    Nicolson GL: Cell surface molecules and tumor metastasis. Regulation of metastatic phenotype diversity. Exp Cell Res 150: 3–22, 1984Google Scholar
  150. 150.
    Schirrmacher V: Cancer metastasis: experimental approaches, theoretical concepts, and impacts for treatment strategies. Adv Cancer Res 43: 1–73, 1985Google Scholar
  151. 151.
    Dong X-F, Berthois Y, Martin P-M: Effect of epidermal growth factor on the proliferation of human epithelial cancer cell lines: correlation with the level of occupied EGF receptor. Anticancer Res 11: 737–744, 1991Google Scholar
  152. 152.
    Minke JMHM, Schuuring E, van den Berghe R, Stolwijk JAM, Boonstra J, Cornelisse C, Hilkens J, Misdorp W: Isolation of two distinct epithelial cell lines from a single feline mammary carcinoma with different tumorigenic potential in nude mice and expressing different levels of epidermal growth factor-receptors. Cancer Res 51: 4028–4037, 1991Google Scholar
  153. 153.
    Lee K, Tanaka M, Hatanaka M, Kuze F: Reciprocal effects of epidermal growth factor receptor and transforming grwoth factor-β on the anchorage-dependent and -independent growth of A431 epidermoid carcinoma cells. Exp Cell Res 173: 156–162, 1987Google Scholar
  154. 154.
    Agrilles A, Kraft N, Ootaka T, Hutchinson P, Atkins RC: Epidermal growth factor and transforming growth factor-a stimulate or inhibit proliferation of a human renal adenocarcinoma cell line depending on cell status: differentiation of the two pathways by G protein involvement. Cancer Res 52: 4356–4360, 1992Google Scholar
  155. 155.
    Santon JB, Cronin MT, MacLeod CL, Mendelsohn J, Masui H, Gill GN: Effects of epidermal growth factor receptor concentration on tumorigenicity of A431 cells in nude mice. Cancer Res 46: 4701–4705, 1986Google Scholar
  156. 156.
    Filmus J, Trent JM, Pollak MN, Buick RN: Epidermal growth factor receptor gene-amplified MDA-A468 breast cancer cell line and its nonamplified variants. Mol Cell Biol 7: 251–257, 1987Google Scholar
  157. 157.
    Inui T, Tsubura A, Morii S: Incidence of precancerous foci of mammary glands and growth rate of transplantable mammary cancers in sialoadenectomized mice. J Natl Cancer Inst 81: 1660–1663, 1989Google Scholar
  158. 158.
    Yoneda T, Alsina MM, Watatani K, Bellot F, Schlessinger J, Mundy GR: Dependence of a human squamous carcinoma and associated paraneoplastic syndromes on the epidermal growth factor receptor pathway in nude mice. Cancer Res 51: 2438–2443, 1991Google Scholar
  159. 159.
    Müller BM, Romerdahl CA, Trent JM, Reisfeld RA: Suppression of spontaneous melanoma metastasis in scid mice with an antibody to the epidermal growth factor receptor. Cancer Res 51: 2193–2198, 1991Google Scholar
  160. 160.
    Aboud-Pirak E, Hurwitz E, Pirak ME, Bellot F, Schlessinger J, Sela M: Efficacy of antibodies to epidermal growth factor receptor against Kb carcinomain vitro and in nude mice. J Natl Cancer Inst 80: 1605–1611, 1988Google Scholar
  161. 161.
    Koenuma M, Yamori T, Tsuruo T: Insulin and insulin-like growth factor I stimulate proliferation of metastatic variants of colon carcinoma 26. Jpn J Cancer Res 80: 51–58, 1989Google Scholar
  162. 162.
    Cavanaugh PG, Nicolson GL: Lung-derived growth factor that stimulates the growth of lung-metastasizing tumor cells: identification as transferrin. J Cell Biochem 47: 261–271, 1991Google Scholar
  163. 163.
    Lichtner RB, Gallick GE, Nicolson GL: Pyrimido-pyrimidine modulation of EGF growth-promoting activity and p21 ras expression in rat mammary adenocarcinoma cells. J Cell Physiol 137: 285–292, 1988Google Scholar
  164. 164.
    Breillout F, Antoine E, Lascaux V, Rolland Y, Poupon M-F: Promotion of micrometastasis proliferation in a rat rhabdomyosarcoma model by EGF. J Natl Canc Inst 81: 702–705, 1989Google Scholar
  165. 165.
    Lester BR, McCarthy JB: Tumor cell adhesion to the extracellular matrix and signal transduction mechanisms implicated in tumor cell motility, invasion and metastasis. Cancer Met Rev 11: 31–44, 1992Google Scholar
  166. 166.
    van Roy F, Mareel M: Tumor invasion: effects of cell adhesion and motility. Trends in Cell Biol 2: 163–169, 1992Google Scholar
  167. 167.
    Briles EB, Kornfeld S: Isolation and metastatic properties of detachment variants of B16 melanoma cells. J Natl Cancer Inst 60: 1217–1222, 1978Google Scholar
  168. 168.
    Chinkers M, McKanna JA, Cohen S: Rapid induction of morphological changes in human carcinoma cell A431 by EGF. J Cell Biol 83: 260–265, 1979Google Scholar
  169. 169.
    Rieber M, Gil F, Rieber MS, Urbina C: Substrate-dependent effect of epidermal growth factor on intercellular adhesion and synthesis of triton-insoluble proteins in human carcinoma A431 cells. Int J Cancer 37: 411–418, 1986Google Scholar
  170. 170.
    Lichtner RB, Wiedemuth M, Noeske-Jungblut C, Schirrmacher V: Rapid effects of EGF on cytoskeletal structures and adhesive properties of highly metastatic rat mammary adenocarcinoma cells. Clin Exp Metastasis 11: 113–125, 1993Google Scholar
  171. 171.
    Chinkers M, McKanna JA, Cohen S: Rapid rounding of human epidermoid carcinoma cells A431 induced by EGF. J Cell Biol 88: 422–429, 1981Google Scholar
  172. 172.
    Westermark B, Magnusson A, Heldin CH: Effect of epidermal growth factor on membrane motility and cell locomotion in cultures of human clonal glioma cells. Prog Clin Biol Res 118: 491–507, 1983Google Scholar
  173. 173.
    Basson MD, Modlin IM, Madri JA: Human enterocyte (Caco-2) migration is modulatedin vitro by extracellular matrix composition and epidermal growth factor. J Clin Invest 90: 15–23, 1992Google Scholar
  174. 174.
    Bellas RE, Bendori R, Farmer SR: Epidermal growth factor activation of Vinculin and β1-integrin gene transcription in quiescent swiss 3T3 cells. J Biol Chem 266: 12008–12014, 1991Google Scholar
  175. 175.
    Tamkun JW, DeSimone DW, Fonda D, Patel RS, Buck C, Horwitz AF, Hynes RO: Structure of integrin, a glycoprotein involved in the transmembrane linkage between fibronetin and actin. Cell 46: 271–282, 1986Google Scholar
  176. 176.
    Kornberg LJ, Earp HS, Turner CE, Prockop C, Juliano RL: Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of β1 integrins. Proc Natl Acad Sci USA 88: 8392–8396, 1991Google Scholar
  177. 177.
    Hirst R, Horwitz A, Buck C, Rohrschneider L: Phosphorylation of the fibronectin receptor complex in cells transformed by oncogenes that encode tyrosine kinases. Proc Natl Acad Sci USA 83: 6470–6474, 1986Google Scholar
  178. 178.
    Freed E, Gailit J, van der Geer P, Ruoslahti E, Hunter T: A novel integrin β subunit is associated with the vitronectin receptor α subunit (αv) in a human osteosarcoma cell line and is a substrate for protein kinase C. EMBO J 8: 2955–2965, 1989Google Scholar
  179. 179.
    Hibbs ML, Jakes S, Stacker SA, Wallace RW, Springer TA: The cytoplasmic domain of the integrin lymphocyte function-associated antigen 1 β subunit: sites required for binding to intercellular adhesion molecule 1 and the phorbol ester-stimulated phosphorylation site. J Exp Med 174: 1227–1238, 1991Google Scholar
  180. 180.
    Hillery CA, Smyth SS, Parise LV: Phosphorylation of human platelet glycoprotein IIIa (GPIIIa). J Biol Chem 266: 14663–14669, 1991Google Scholar
  181. 181.
    Guan JL, Shalloway D: Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature 358: 690–692, 1992Google Scholar
  182. 182.
    Hanks SK, Calalb MB, Harper MC, Patel SK: Focal adhesion protein-tyrosine kinase phosphorylation in response to cell attachment to fibronectin. Proc Natl Acad Sci 89: 8487–8491, 1992Google Scholar
  183. 183.
    Hynes RO: Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69: 11–25, 1992Google Scholar
  184. 184.
    Zachary I, Rozengurt E: Focal adhesion kinase (p125FAK): a point of convergence in the action of neuropeptides, integrins, and oncogenes. Cell 71: 891–894, 1992Google Scholar
  185. 185.
    Bade EG, Feindler S: Liver epithelial cell migration induced by epidermal growth factor or transforming growth factor alpha is associated with changes in the gene expression of secreted proteins. In Vitro Cell Dev Biol 24: 149–154, 1988Google Scholar
  186. 186.
    Thorne HJ, Jose DJ, Zhang HY, Dempsey PJ, Whitehead RH: Epidermal growth factor stimulates the synthesis of cell attachment proteins in the human breast cancer cell line PMC42. Int J Cancer 40: 207–212, 1987Google Scholar
  187. 187.
    Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, Ljchner D, Birchmeier W: E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 113: 173–185, 1991Google Scholar
  188. 188.
    Behrens J, Frixen U, Schipper J, Weidner M, Birchmeier W: Cell adhesion in invsion and metastasis. Semin Cell Biol 3: 169–178, 1992Google Scholar
  189. 189.
    Fukuyama R, Shimizu N: Detection of EGFRs and E-cadherins in the basolateral membrane of A431 cells by laser scanning fluorescence microscopy. Jpn J Cancer Res 82: 8–11, 1991Google Scholar
  190. 190.
    Behrens J, Vakaet L, Friis R, Winterhager E, Van Roy F, Mareel MM, Birchmeier W: Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/β-catenin complex in cells transformed witha temperature sensitive v-src gene. J Cell Biol 120: 757–766, 1993Google Scholar
  191. 191.
    Reichmann E, Schwarz H, Deiner EM, Leitner I, Eiler M, Berger J, Busslinger M, Beug H: Activation of an inducible c-FosER fusion protein causes loss of epithelial polarity and triggers epithelial-fibroblastoid cell conversion. Cell 71: 1103–1116, 1992Google Scholar
  192. 192.
    Behrens J, Weidner KM, Frixen UH, Schipper JH, Sachs M, Arakaki N, Daikura Y, Birchmeir W: The role of E-cadherin and scatter factor in tumor invasion and cell motility. In: Goldberg ID (ed) Cell Motility Factors. Birkhäuser Verlag, Basel, 1991, pp 109–127Google Scholar
  193. 193.
    Schoenenberger CA, Matlin KS: Cell polarity and epithelial oncogenesis. Trends in Cell Biology 1: 87–92, 1991Google Scholar
  194. 194.
    Lichtner RB, Schirrmacher V: Cellular distribution and biological activity of epidermal growth factor receptors in A431 cells are influenced by cell-cell contact. J Cell Physiol 144: 303–312, 1990Google Scholar
  195. 195.
    Roy LM, Gittinger CK, Landreth GE: Characterisation of the Epidermal growth factor receptor associated with cytoskeletons of A431 cells. J Cell Physiol 140: 295–304, 1989Google Scholar
  196. 196.
    van Bergen en Henegouwen PMP, Defize LHK, de Kroon J, van Damme H, Verkleij AJ, Boonstra J: Ligand-induced association of epidermal growth factor receptor to the cytoskeleton of A431 cells. J Cell Biochem 39: 455–465, 1989Google Scholar
  197. 197.
    Akiyama K, Kadowaki T, Nishida E, Kadooka T, Ogawara H, Fukami Y, Sakai H, Takaku F, Kasuga M: Substrate specificities of tyrosine-specific protein kinases toward cytoskeletal proteinsin vitro. J Biol Chem 261: 14797–14803, 1986Google Scholar
  198. 198.
    Fava RA, Cohen S: Isolation of a calcium-dependent 35 kilodalton substrate for the epidermal growth factor receptor kinase from A-431 celss. J Biol Chem 259: 2636–2645, 1984Google Scholar
  199. 199.
    Bretscher A: Rapid phosphorylation and reorganisation of ezrin and spectrin accompany morphological changes induced in A431 cells by epidermal growth factor. J Cell Biol 108: 921–930, 1989Google Scholar
  200. 200.
    Wiegant FAC, Blok FJ, Defize LKH, Linnemans WAM, Verkleij AJ, Boonstra J: Epidermal growth factor receptors associated to cytoskeletel elements of epidermoid carcinoma (A431) cells. J Cell Biol 103: 87–94, 1986Google Scholar
  201. 201.
    Ruoslahti E: Control of cell motility and tumor invasion by extracellular matrix interactions. Br J Cancer 66: 239–242, 1992Google Scholar
  202. 202.
    Stoker M, Gherardi E: Regulation of cell movement: the motogenic cytokines. Biochim Biophys Acta 1072: 81–102, 1991Google Scholar
  203. 203.
    Vallés A, Boyer B, Thiery JP: Adhesion systems in embryonic epithelial to mesenchyme tranformations and in cancer invasion and metastasis. In: Goldberg ID (ed) Cell Motility Factors. Birkhäuser Verlag, Basel, 1991, pp 17–34Google Scholar
  204. 204.
    Blay J, Brown KD: Epidermal growth factor receptor promotes the chemotactic migration of cultured rat intestinal epithelial cells. J Cell Physiol 124: 107–122, 1985Google Scholar
  205. 205.
    Engström W: Differential effects of epidermal growth factor (EGF) on cell locomotion and cell proliferation in a cloned human embryonic carcinoma-derived cell line in vitro. J Cell Sci 86: 47–55, 1986Google Scholar
  206. 206.
    Barrandon Y, Green H: Cell migration is essential for sustained growth of keratinocyte colonies: the roles of transforming growth factor-α and epidermal growth factor. Cell 50: 1131–1137, 1987Google Scholar
  207. 207.
    Koyasu S, Kadowaki T, Nishida E, Tobe K, Abe E, Kasuga M, Sakai H, Yahara I: Alterations in growth, cell morphology, and cytoskeletal structures of KB cells induced by EGF and transforming growth factor-beta. Exp Cell Res 176: 107–116, 1988Google Scholar
  208. 208.
    Lund-Johansen M, Bjerkvig R, Humphrey PA, Bigner SH, Bigner DD, Laerum O-D: Effect of EGF on glioma cell growth, migration, and invasion in vitro. Cancer Res 50: 6039–6044Google Scholar
  209. 209.
    Nakajima M, Chop AM: Tumor invasion and extracellular matrix degradative enzymes: regulation of activity by organ factors. Semin Cancer Biol 2: 115–127, 1991Google Scholar
  210. 210.
    Laiho M, Keski-Oja J: Growth factors in the regulation of pericellular proteolysis: a review. Cancer Res 49: 2533–2553, 1989Google Scholar
  211. 211.
    Niedbala MJ, Sartorelli AC: Regulation by EGF of human squamous cell carcinoma plasminogen activator mediated proteolysis of extracellular matrix. Cancer Res 40: 3302–3309, 1989Google Scholar
  212. 212.
    Keski-Oja J, Blasi F, Leof EB, Moses HL: Regulation of the synthesis and activity of urokinase plaminogen activator in A549 human lung carcinoma cells by transforming growth factor β. J Cell Biol 106: 451–459, 1988Google Scholar
  213. 213.
    Boyd D: Examination of the effects of epidermal growth factor receptor on the production of urokinase and the expression of plasminogen activator receptor in a human colon cancer cell line. Cancer Res 49: 2427–2432, 1989Google Scholar
  214. 214.
    Chua CC, Geiman DE, Keller GH, Ladda RL: Induction of collagenase secretion in human fibroblast cultures by growth promoting factors. J Biol Chem 260: 5213–5216, 1985Google Scholar
  215. 215.
    Korczak B, Kerbel R, Dennis J: Growth factor dependent regulation of proteinases: expression and secretion in non-metastatic and metastatic mouse mammary andenocarcinoma SP1 cells (meeting abstract). Proc Ann Meet Am Assoc Cancer Res 31: A438, 1990Google Scholar
  216. 216.
    Gavrilovic J, Moens G, Thiery JP, Jouanneau J: Expression of transfected transforming growth factor α induces a motile fibroblast-like phenotype with extracellular matrix-degrading potential in a rat bladder carcinoma cell line. Cell Reg 1: 1003–1014, 1990Google Scholar
  217. 217.
    Sundareshan P, Misiorowski RL, Davis JR, Korc M, Hendrix MJ: Effects of epidermal growth factor on growth response, morphology, and invasive potential of human endometrial carcinoma cell-line RL95-2. Cancer Commun 3: 149–158, 1991Google Scholar
  218. 218.
    Mizoguchi H, Komiyama S, Matsui K, Hamanaka R, Ono M, Kiue A, Kobayashi M, Shimizu N, Welgus HG, Kuwano M: The response to epidermal growth factor of human maxillary tumor cells in terms of tumor growth, invasion and expression of proteinase inhibitors. Int J Cancer 49: 738–743, 1991Google Scholar

Copyright information

© Kluwer Academic Publishers 1993

Authors and Affiliations

  • Khashayarsha Khazaie
    • 1
  • Volker Schirrmacher
    • 1
  • Rosemarie B. Lichtner
    • 2
  1. 1.Deutsches KrebsforschungszentrumHeidelbergGermany
  2. 2.Research Laboratories of Schering AGBerlin 65Germany

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