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Expression of epidermal growth factor and platelet-derived growth factor receptors during cervical carcinogenesis

  • Cytokines/Growth Factors/Adhesion Factors
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Summary

Altered expression of epidermal growth factor receptor (EGFR) is common in a variety of epithelial malignancies, including cervical cancer. However, the prognostic significance of EGFR expression is controversial for cervical cancer. Platelet-derived growth factor receptor (PDGFR) expression status is unknown in cervical cancer. Our results demonstrated that expression of EGFR and PDGFR was greatly enhanced in vivo and in organotypic cultures of low-grade cervical dysplastic tissues, but levels were decreased in high-grade lesions. To our knowledge, this is the first report identifying the expression of PDGFR in human epithelium. When low-grade dysplastic organotypic culture tissues were induced to differentiate more completely, EGFR expression, but not PDGFR expression, was relocalized to the basal layer as seen in normal tissues. Differentiation also induced phosphorylation of EGFR but not PDGFR. Our results suggest a role for EGFR and PDGFR during the early stages of cervical carcinogensis, and demonstrate the facility of organotypic cultures to study the role of these growth factors in the development of cervical cancer.

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References

  • Antoniades, H.N.; Galanoppoulos, T.; Neville-Golden, J.; Kiritsy, C.P.; Lynch, S.E. Expression of growth factor and receptor mRNAs in skin epithelial cells following acute cutaneous injury. Am. J. Pathol. 142:1099–1110; 1993.

    PubMed  CAS  Google Scholar 

  • Asselineau, D.; Bernard, B.A.; Bailly, C.; Darmon, M.; Prunieras, M. Human epidermis reconstructed by culture: is it “normal”? J. Investig. Dermatol. 86:181–186; 1986.

    Article  PubMed  CAS  Google Scholar 

  • Ball, B. D.; Walker, G. K.; Bernstein, I. A. Histidine-rich proteins as molecular markers of epidermal differentiation. J. Biol. Chem. 253:5861–5868; 1978.

    PubMed  CAS  Google Scholar 

  • Carpenter, G. Receptors for epidermal growth factor and other polypeptide mitogens. Ann. Rev. Biochem. 56:881–9141; 1987.

    Article  PubMed  CAS  Google Scholar 

  • Carpenter, G.; Cohen, S. Epidermal growth factor. Ann. Rev. Biochem. 48:193–216; 1979.

    Article  PubMed  CAS  Google Scholar 

  • Cassel, D.; Glaser, L. Proteolytic cleavage of epidermal growth factor receptor. J. Biol. Chem. 257:9845–9848; 1982.

    PubMed  CAS  Google Scholar 

  • Chapman, W. B.; Lorinez, A. T.; Willett, G. D.; Wright, V. C.; Kurman, R. J. Epidermal growth factor receptor expression and the presence of human papilomavirus in cervical squamous intraepithelial lesoins. Int. J. Gynecol. Pathol. 11:221–226; 1992.

    Article  PubMed  CAS  Google Scholar 

  • Caesson-Welsh, L.; Eriksson, A.; Moren, A.; Severinsson, L.; Ek, B.; Ostman, A.; Betsholtz, C.; Heldin, C. cDNA cloning and expression of a human platelet-derived growth factor (PDGF) receptor specific for B-chain-containing PDGF molecules. Mol. Cell. Biol. 8:376–3486; 1988.

    Google Scholar 

  • Claesson-Welsh, L.; Eriksson, A.; Westermark, B.; Heldin, C. cDNA cloning and expression of the human A-type platelet-derived growth factor (PDGF) receptor establishes structural similarity to the B-type PDGF receptor. Proc. Natl. Acad. Sci. USA 86:4917–4921; 1989.

    Article  PubMed  CAS  Google Scholar 

  • Cohen, D. B.; Goldstein, D. J.; Tutledge, L.; Vass, W. C.; Lowy, D. R.; Schlegel, R.; Schiller, D. J.. Transformation-specific interaction of the bovine papillomavirus E5 oncoprotein with the platelet-derived growth factor receptor transmembrane domain and the epidermal growth factor receptor cytoplasmic domain. J. Virol. 67:5303–5311; 1993.

    PubMed  CAS  Google Scholar 

  • Cohen, S.; Ushiro, H.; Stoscheck, C.; Chinkers, M. A native 170,000 epidermal growth factor receptor-kinase complex from shed plasma membrane vesicles. J. Biol. Chem. 257:1523–1531; 1982.

    PubMed  CAS  Google Scholar 

  • Cuzick, J.; Sasieni, P.; Singer, A. Risk factors for invasive cervix cancer in young women. Eur. J. Cancer 32A:836–841; 1996.

    Article  PubMed  CAS  Google Scholar 

  • Dale, B. A.; Gown, A. M.; Fleckman, P.; Kimball, J. R.; Resing, K. A. Characterization of two monoclonal antibodies to human epidermal keratohyalin: reactivity with filaggrin and related proteins. J. Investig. Dermatol. 86:306–313; 1987.

    Article  Google Scholar 

  • Drummond-Barbosa, D. A.; Vaillancourot, R. R.; Kazauskas, A.; DiMaio, D. Ligand-independent activation of the platelet-derived growth factor beta receptor: requirements for bovine papillomavirus E5-induced mitogenic signaling. Mol. Cell. Biol. 15:2570–2581; 1995.

    PubMed  CAS  Google Scholar 

  • Eriksson, A.; Siegbahn, A.; Westermark, B.; Heldin, C. H.; Claesson-Welsh, L. Platelet-derived growth factor alpha- and beta-receptors activate unique and common signal transduction pathway. EMBO J. 11:543–550; 1992.

    PubMed  CAS  Google Scholar 

  • Fuchs, E.; Green, H. Changes in keratin gene expression during terminal differentiation of the keratinocyte. Cell 19:1033–1042; 1980.

    Article  PubMed  CAS  Google Scholar 

  • Gates, R. E.; King, L. E. J. Calcium facilitates endogenous proteolysis of the EGF receptor-kinasei. Mol. Cell. Endocrinol. 27:263–276; 1982.

    Article  PubMed  CAS  Google Scholar 

  • Gerwin, B. I.; Lechner, J. F.; Reddel, R. R.; Roberts, A. B.; Robbins, K. C.; Gabrielson, E. W.; Harris, C. C. Comparison of production of transforming growth factor-beta and platelet-derived growth factor by normal human mesothelial cells and mesothelioma cell lines. Cancer Res. 47:6180–6184; 1987.

    PubMed  CAS  Google Scholar 

  • Goppinger, A.; Wittmaack, F. M.; Wintzer, H. O.; Ikenberg, H.; Bauknecht, T. Localization of human epidermal growth factor receptor, in cervical intraepithelial neoplasias. J. Cancer Res. Clin. Oncol. 115:259–263; 1989.

    Article  PubMed  CAS  Google Scholar 

  • Greenfield, C.; Hils, I.; Waterfield, M. D.; Federwisch, W.; Wollmer, A.; Bludeli, T. L.: McDonald, N. EGF binding induces a, conformational change in the external domain of its receptor. EMBO J. 8:4115–4124; 1989.

    PubMed  CAS  Google Scholar 

  • Hale, R. J.; Buckley., C. H.; Gullick, W. J.; Fox, H.; Williams, J.; Wilcox, F. L. Prognostic value of epidermal growth factor receptor expression in cervical carcinoma. J. Clin. Pathol. 46:149–153; 1993.

    PubMed  CAS  Google Scholar 

  • Heldin, C. H.; Westermark, B. Platelet-derived grwoth factor-3 isoforms and 2 receptor types. Trends Genet. 5:108–111; 1989.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Humel, M.; Hudson, J. B.; Laimins, L. A. Differentiation-induced and constitutive transcription of human papillomavirus type 31b in cell lines containing viral episomes. J. Virol. 66:6070–6080; 1992.

    Google Scholar 

  • Inui, H.; Kitami, Y.; Tani, M.; Kondo, T.; Inagami, T. Differences in signal transduction between platelet-derived growth factor (PDGF) alpha and beta receptors in vascular muscle cells. J. Biol. Chem. 269:30,546–30,552; 1994.

    CAS  Google Scholar 

  • Johnsson, A.; Heldin, C. H.; Westermark, B.; Wasteson, A. Platelet-derived growth factor: identification of constituent polypeptide chains. Biochem. Biophys. Res. Commun. 104:66–74; 1982.

    Article  PubMed  CAS  Google Scholar 

  • Kersemaekers, A.-M. F.; Fleuren, G. J.; Kenter, G. G.; Van de Broek, L. J. C. M.; Uljee, M. S.; Hermans, J.; Van de Vijver, M. J. Oncogene alterations in carcinomas of the uterine cervix: overexpression of the epidermal growth factor receptor is associated with poor prognosis. Clin. Cancer Res. 5:577–586; 1999.

    PubMed  CAS  Google Scholar 

  • Kopan, R.; Traska, G.; Fuchs, E. Retinoids as important regulators of terminal differentiation: examining keratin expression in individual epidermal cells at various stages of keratinization. J. Cell Biol. 105:427–440; 1987.

    Article  PubMed  CAS  Google Scholar 

  • Marou, T.; Yamasaki, M.; Ladines-Llave, C. A.; Mochizuki, M. Immunohistochemical demonstration of elevated expression of epidermal growth factor receptor changes in the neoplastic changes of cervical squamous epithelium. Cancer 69:1182–1187; 1992.

    Article  Google Scholar 

  • Marquardt, H.; Hunkapiller, M. W.; Hood, L. E.; Todaro, G. J. Rat transforming growth factor type 1: structure and relation to epidermal growth factor. Science 223:1079–1082; 1984.

    Article  PubMed  CAS  Google Scholar 

  • Mayer, T. J.; Meyers, C. Temporal and spatial expression of the E5a protein during the differentiation-dependent life cycle of human papillomavirus type 31b. Virology 248:208–217; 1998.

    Article  PubMed  CAS  Google Scholar 

  • McCance, D. J.; Kopan, R.; Fuchs, E.; Laimins, L. A. Human papillomavirus type 16 alters human epithelial cell differentiation in vitro. Proc. Ntal. Acad. Sci. USA 85:7169–7173: 1988.

    Article  CAS  Google Scholar 

  • McCune, B. K.; Prokop, C. A.; Earp, H. S. Transient epidermal growth factor (EGF)-dependent suppression of EGF receptor autophosphorylation during internalization. J. Biol. Chem. 265:9715–9721; 1990.

    PubMed  CAS  Google Scholar 

  • Meyers, C. Organotypic (raft) epithelial tissue cultured system for the differentiation-dependent replication of papillomavirus. Methods Cell Sci. 18:201–210; 1996.

    Article  Google Scholar 

  • Meyers, C.; Frattini, M. G.; Hudson, J. B.; Laimins, L. A. Biosynthesis of human papillomavirus from a continous cell line upon epithelial differentiation. Science 257:971–973; 19992.

    Article  Google Scholar 

  • Meyers, C.; Frattini, M. G.; Laimins, L. A. Tissue culture techniques for the study of human papillomaviruses in stratified epithelial. In: Celis, J. E., ed. Cell biology: a laboratory handbook. San Diego, CA: Academic Press; 1994:491–499.

    Google Scholar 

  • Moll, R.; Franke, W. W.; Schiller, D. L.; Gerger, B.; Krepler, R. The catalog of human cytokeratins: patterns of expression in normal epithelial, tumors, and cultured cells. Cell 31:11–24; 1982.

    Article  PubMed  CAS  Google Scholar 

  • Nancy, L. B.; Magid, M.; Stoschek, C. M.; King, L. E. Comparison of epidermal growth factor binding and receptor distribution in normal human epidermis and epidermal appendages. J. Investig. Dermatol. 83:385–393; 1985.

    Google Scholar 

  • Neal, D. E.; Bennett, M. K.; Hall, R. R. Epidermal growth factor receptors in human bladder cancer: comparison of invasive and superficial tumors. Lancet 1:366–368; 1985.

    Article  PubMed  CAS  Google Scholar 

  • Nilson, L. A.; DiMaio, D. Platelet-derived growth factor receptor can mediate tumorigenic transformation by the bovine papillomavirus E5 protein. Mol. Cell. Biol. 13:4137–4145; 1993.

    PubMed  CAS  Google Scholar 

  • Ozanne, B.; Richards, C. S.; Hendler, F.; Burns, D.; Gusterson, B. Over-expression of the EGF receptor is a hallmark of squamous-cell carcinomas. J. Pathol. 149:9–14; 1986.

    Article  PubMed  CAS  Google Scholar 

  • Ozbun, M. A.; Meyers, C. Transforming growth factor betal induces differentiation in human papillomavirus-positive keratinocytes. J. Virol. 70:5437–5446; 1996.

    PubMed  CAS  Google Scholar 

  • Petti, L.; DiMaio, D. Activation of the platelet-derived growth factor receptor by the bovine papillomavirus E5 transforming protein. EMBO J. 10:845–855; 1991.

    PubMed  CAS  Google Scholar 

  • Petti, L.; DiMaio, D. Stable association between the bovine papillomavirus E5 transforming protein and activated platelet-derived growth factor receptor in transformed mouse cells. Proc. Natl. Acad. Sci. USA 89:6736–6740; 1992.

    Article  PubMed  CAS  Google Scholar 

  • Petti, L.; DiMaio, D. Specific interaction between the bovine papillomavirus E5 transforming protein and the beta receptor for platelet-derived growth factor in stably transformed and acutely transfected cells. J. Virol. 68:3582–3592; 1994.

    PubMed  CAS  Google Scholar 

  • Pfeiffer, D.; Stellwag, B.; Pfeiffer, A.; Borlinghaus, P.; Meier, W.; Scheidel, P. Clinial implications of the epidermal growth factor receptor in the squamous cell carcinoma of the uterine cervix. Gynecol. Oncol. 33:146–150; 1989.

    Article  PubMed  CAS  Google Scholar 

  • Rader, J. S.; Golub, T. R.; Hudson, J. B.; Patel, D.; Bedell, M. A.; Lamins, L. A. In vitro differentiation of epithelial cells from cervical neoplasias resembles in vivo lesions. Oncogene 5:571–576; 1990.

    PubMed  CAS  Google Scholar 

  • Rheinwald, J. G.; Beckettk, M. A. Tumorigenic keratinocyte lines requiring anchorage and fibroblast support ocultured from huamn squamous cell carcinomas. Cancer Res. 41:1657–1663: 1986.

    Google Scholar 

  • Richart, R. M. Cervical intraepithelial neoplasia. In: Sommers, S. C., ed. Pathology annual. New York: Appleton-Century-Crofts; 1973:301–328.

    Google Scholar 

  • Ross, R.; Raines, E. W.; Bowen-Pope, D. F. The biology of platelet-derived growth factor. Cell 46:155–169; 1986.

    Article  PubMed  CAS  Google Scholar 

  • Sainsbury, J.; Malcolm, A.; Appleton, D.; Farndon, J.; Harris, A. Presence of epidermal growth factor receptor as an indicator of poor prognosis in patients with breast cancer. J. Clin. Pathol. 38:1225–1228; 1985.

    PubMed  CAS  Google Scholar 

  • Schlessinger, J.; Schreiber, A. B.; Levi, A.; Lax, I.; Libermann, T. A.; Yarden, Y. Regulation of cell proliferation by epidermal growth factor. Crit. Rev. Biochem. 14:93–1111; 1983.

    CAS  Google Scholar 

  • Shoyab, M.; McDonald, V. L.; Bradley, J. G.; Todaro, G. J. Structure and function of amphiregulin: a member of the epidermal growth factor family. Science 243:1074–1076; 1989.

    Article  PubMed  CAS  Google Scholar 

  • Straight, S. W.; Hinkle, P. M.; Jewers, R. J.; McCance, D. J. The E5 oncoprotein of human papillomavirus type 16 transforms fibroblasts and effects the down-regulation of the epidermal growth factor receptor in keratinocytes. J. Virol. 67:4521–4532; 1993.

    PubMed  CAS  Google Scholar 

  • Ullrich, A.; Schlessinger, J. Signal transduction by reports with tyrosine kinase activity. Cell 61:203–212; 1990.

    Article  PubMed  CAS  Google Scholar 

  • Veale, D.; Kerr, N.; Gibson, G. H.; Harris, A. L. Characterization of epidermal growth factor receptor in primary human non-small-lung cancer. Cancer Res. 49:1313–1317; 1989.

    PubMed  CAS  Google Scholar 

  • Versnel, M. A.; Hagemeijer, A.; Bouts, M. J.; Van der Kwast, T.; Hoogsteden, H. C. Expression of c-sis (PDGF B-chain) and PDGF A-chain genes in ten human malignant mesothelioma cell lines derived from primary and metastatic tumors. Oncogene 2:601–605; 1988.

    PubMed  CAS  Google Scholar 

  • Visalli, R. B.; Courtney, R. J.; Meyers, C. Infection and replication of herpes simplex virus type 1 in an organotypic epithelial culture system. Virology 230:236–243; 1997.

    Article  PubMed  CAS  Google Scholar 

  • Williams, L. T. Signal transduction by the platelet-derived growth factor receptor. Science 243:1564–1570; 1989.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, 17033, Pennsylvania

    T. J. Mayer & C. Meyers

  2. Department of Pathology, Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, 17033, Hershey, Pennsylvania

    E. E. Frauenhoffer

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  1. T. J. Mayer
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  2. E. E. Frauenhoffer
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  3. C. Meyers
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Correspondence to C. Meyers.

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Mayer, T.J., Frauenhoffer, E.E. & Meyers, C. Expression of epidermal growth factor and platelet-derived growth factor receptors during cervical carcinogenesis. In Vitro Cell.Dev.Biol.-Animal 36, 667–676 (2000). https://doi.org/10.1290/1071-2690(2000)036<0667:EOEGFA>2.0.CO;2

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