Skip to main content
SpringerLink
Log in

Immunohistochemical localization of heparin-binding epidermal growth factor-like growth factor in normal skin and skin cancers

  • Published:
The Histochemical Journal Aims and scope Submit manuscript

Summary

Heparin-binding epidermal growth factor (EGF)-like growth factor is a 22-kDa glycoprotein that was originally identified as a secreted product of cultured human macrophages. Although the growth factor mRNA has been identified in various cells and tissues, the tissue distribution of the protein itself has rarely been demonstrated. In this study, the EGF-like growth factor was detected immunohistochemically in a variety of human skin samples by indirect immunofluorescence using a polyclonal rabbit antiserum raised against residues 26–41 of mature heparin-binding EGF. The keratinocytes of a variety of epithelium-derived structures demonstrated reproducible, specific staining for the EGF. In normal tissues, this staining was prominent in the basal cells of the epidermis and in the epithelial cells lining epidermal appendages such as hair follicles, sebaceous sweat glands and eccrine sweat glands. In addition, specific staining was detected in skin cancers derived from the basal epithelial cell layer, including basal and squamous cell carcinomas of the skin, with no staining detected in melanoma specimens. Immunoreactive heparin-binding EGF was characteristically associated with the surface of cells. With minor exceptions, the immunoreactive sites are identical to the known EGF receptor distribution in the skin, and suggest that keratinocyte-derived heparin-binding EGF may act in concert with other EGF family members in processes such as skin morphogenesis and wound repair, as well as in the development of skin cancers

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.

Similar content being viewed by others

References

  • Abraham, J.A., Damm, D., Bajardi, A., Miller, J., Klagsbrun, M. & Ezekowitz, R.A.B. (1993) Heparin-binding EGF-like growth factor: characterization of rat and mouse CDNA clones, protein domain conservation across species, and transcript expression in tissues. Biochem. Biophys. Res. Commun.190, 125-33.

    Article  PubMed  CAS  Google Scholar 

  • Aviezer, D. & Yayon, A. (1994) Heparin-dependent binding and autophosphorylation of epidermal growth factor (EGF) receptor by heparin-binding EGF-like growth factor but not by EGF. Proc. Natl Acad. Sci. USA.91, 12173-7.

    Article  PubMed  CAS  Google Scholar 

  • Bauknecht, T., Gross, G. & Hagedorn, M. (1985) Epidermal growth factor receptors in different skin tumors. Dermatologica171, 16-20.

    Article  PubMed  CAS  Google Scholar 

  • Besner, G.E., Higashiyama, S. & Klagsbrun, M. (1990) Isolation and characterization of a macrophage-derived heparin-binding growth factor. Cell Regul.1, 811-9.

    PubMed  CAS  Google Scholar 

  • Besner, G.E., Whelton, D., Crissman-combs, M., Steffen, C., Kim, G., & Brigstock, D.R. (1992) Interaction of heparin-binding EGF-like growth factor (HB-EGF) with the epidermal growth factor receptor: modulation by heparin, heparinase or synthetic heparin-binding HB-EGF fragments. Growth Factors7, 289-96.

    Article  PubMed  CAS  Google Scholar 

  • Brown, G.L., Nanney, L.B., Griffen, J., Cramer, A.B., Yancey, J.M., Curtsinger, L.J., Holtzin, L., Schultz, G.S., Kurkiewicz, M.J. & Lynch, J.B. (1989) Enhancement of wound healing by topical treatment with epidermal growth factor. N. Engl. J. Med.321, 76-9.

    Article  PubMed  CAS  Google Scholar 

  • Cook, P., Damm, D., Garrick, B., Wood, K., Karkaria, C., Higashiyama, S., Klagsbrun, M. & Abraham, J. (1995a). Carboxyl-terminal truncation of Leucine76 converts heparin-binding EGF-like growth factor from a heparin-enhancible growth factor to a heparin-suppressible growth factor. J. Cell Physiol.163, 407-17.

    Article  PubMed  CAS  Google Scholar 

  • Cook, P., Ashton, M., Karkaria, C., Seiss, D. & Shipley, G. (1995b) Differential effects of a heparin antagonist (hexadimethrine) or chlorate on amphiregulin, basic fibroblast growth factor, and heparin-binding EGF-like growth factor activity. J. Cell Physiol.163, 418-29.

    Article  PubMed  CAS  Google Scholar 

  • Davis, K.M., Brigstock, D.R., Johnson, P.R., Crissman-combs, M.A., Mccarthy, D.W., Downing, M.T. & Besner, G.E. (1996) Production of glycosylated heparin-binding EGF-like growth factor in HeLa cells usin vaccinia virus. Prot. Express. Purifica.8, 57-7.

    Article  CAS  Google Scholar 

  • Dominey, A.M., Wang, X.J., King, L.E., Nanney, L.B., Gagne, T.A., Sellheter, K., Bundman, D.S., Longley, M.A., Rothnagel, J.A. & Greenhalgh, D.A. (1993) Targeted overexpression of transforming growth factor α in the epidermis of transgenic mice elicits hyperplasia, hyperkeratosis, and spontaneous, squamous papillomas. Cell Growth Diff.4, 1071-82.

    PubMed  CAS  Google Scholar 

  • Elder, J.T., Fisher, G.J., Lindquist, P.B., Bennett, G.L., Pittelkow, M.R., Coffey, R.J., Ellingsworth, L., Derynck, R. & Voorhees, J.J. (1989) Overexpression of transforming growth factor alpha in psoriatic epidermis. Science243, 811-14.

    Article  PubMed  CAS  Google Scholar 

  • Elder, J.T., Klein, S.B., Tavakkol, A., Fisher, G.J., Nickoloff, B.J. & Voorhees, J.J. (1990) Growth factor and proto-oncogene expression in psoriasis. J. Invest. Dermatol.95, 7S-9S.

    Article  Google Scholar 

  • Hashimoto, K., Higashiyama, S., Asada, H., Hashimura, E., Kobayashi, T., Sudo, K., Nakagawa, T., Damm, D., Yoshikawa, K. & Taniguchi, N. (1994) Heparin-binding epidermal growth factor-like growth factor is an autocrine growth factor for human keratinocytes. J. Biol. Chem.269, 20060-6.

    PubMed  CAS  Google Scholar 

  • Higashiyama, S., Abraham, J.A., Miller, J., Fiddes, J.C. & Klagsbrun, M. (1991) A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science251, 936-9.

    Article  PubMed  CAS  Google Scholar 

  • Higashiyama, S., Lau, K., Besner, G.E., Abraham, J.A. & Klagsbrun, M. (1992) Structure of heparin-binding EGF-like growth factor. Multiple forms primary structure, and glycosylation of the mature protein. J. Biol. Chem.267, 6205-12.

    PubMed  CAS  Google Scholar 

  • Higashiyama, S., Abraham, J. & Klagsbrun, M. (1993) Heparin-binding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate. J. Cell. Biol.122, 933-40.

    Article  PubMed  CAS  Google Scholar 

  • Kim, G., Besner, G., Steffen, C., Mccarthy, D., Downing, M., Luquette, M., Abad, M. & Brigstock, D. (1995) Purification of heparin-binding EGF-like growth factor from pig uterine luminal flushings, and its production by endometrial tissues. Biol. Reprod.52, 561-71.

    Article  PubMed  CAS  Google Scholar 

  • Kiso, S., Kawata, S., Tamura, S., Higashiyama, S., Ito, N., Tsushima, H., Taniguchi, N. & Matsuzawa, Y. (1995) Role of heparin-binding epidermal growth factor-like growth factor as a hepatotrophic factor in rat liver regeneration after partial hepatectomy. Hepatology22, 1584-90.

    PubMed  CAS  Google Scholar 

  • Kobrin, M.S., Funatomi, H., Friess, H., Buchler, M.W., Stathis, P. & Korc, M. (1994) Induction and epxression of heparin-binding EGF-like growth factor in human pancreatic cancer. Biochem. Biophys. Res. Commun.202, 1705-9.

    Article  PubMed  CAS  Google Scholar 

  • Marikovsky, M., Breuing, K., Liu, P.Y., Eriksson, E., Higashiyama, S., Farber, P., Abraham, J. & Klagsbrun, M. (1993) Appearance of heparin-binding EGF-like growth factor in wound fluid as a response to injury. Proc. Natl Acad. Sci. USA.90, 3889-93.

    Article  PubMed  CAS  Google Scholar 

  • Marikovsky, M., Vogt, P., Eriksson, E., Rubin, J.S., Taylor, W.G., Sasse, J. & Klagsbrun, M. (1996) Wound fluid derived heparin-binding EGF-like growth factor (HB-EGF) is synergistic with insulin-like growth factor-1 for Balb/MK keratinocyte proliferation. J. Investig. Dermatol.106, 616-21.

    Article  PubMed  CAS  Google Scholar 

  • Miyoshi, E., Higashiyama, S., Nakagawa, T., Suzuki, K., Horimoto, M., Hayashi, N., Fusamoto, H., Kamada, H., Kamada, T. & Taniguchi, N. (1996) High expression of heparin-binding EGF-like growth factor in rat hepatocarcinogenesis. Int. J. Cancer68, 215-18.

    Article  PubMed  CAS  Google Scholar 

  • Murayama, Y., Miyagawa, J.-I., Higashiyama, S., Kondo, S., Yabu, M., Isozaki, K., Kayanoki, Y., Kanayama, S., Shinomura, Y., Taniguchi, N. & Matsuzawa, Y. (1995) Localization of heparin-binding epidermal growth factor-like growth factor in human gastric mucosa. Gastroenterology109, 1051-9.

    Article  PubMed  CAS  Google Scholar 

  • Naef, M., Yokoyama, M., Friess, H., Buchler, M.W. & Korc, M. (1996) Co-expression of heparin-binding EGF-like growth factor and related peptides in human gastric carcinoma. Int. J. Cancer66, 315-21.

    Article  PubMed  CAS  Google Scholar 

  • Naglich, J.G., Metherall, J.E., Russell, D.W. & Eidels, L. (1992) Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell69, 1051-61.

    Article  PubMed  CAS  Google Scholar 

  • Nanney, L.B., Magid, M., Stoscheck, C.M. & King, L.E. (1994) Comparison of epidermal growth factor binding and receptor distribution in normal human epidermis and epidermal appendages. J. Investig. Dermatol.83, 385-93.

    Article  Google Scholar 

  • Nanney, L.B., Stoscheck, C.M., Magid, M. & King, L.E. (1986) Altered 125I-epidermal growth factor binding and receptor distribution in psoriasis. J. Invest. Dermatol.86, 260-5.

    Article  PubMed  CAS  Google Scholar 

  • Ono, M., Raab, G., Lau, K., Abraham, J. & Klagsbrun, M. (1994) Purification and characterization of transmembrane froms of herapin-binding EGF-like growth factor. J. Biol. Chem.269, 31315-21.

    CAS  Google Scholar 

  • Ozanne, B. & Richards, C.S. (1986) Over-expression of the EGF receptor is a hallmark of squamous cell carcinomas. J. Pathol.149, 9-14.

    Article  PubMed  CAS  Google Scholar 

  • Powell, P.P., Klagsbrun, M., Abraham, J.A. & Jones, R. (1993) Eosinophils expressing heparin-binding EGF-like growth factor mRNA localize around lung microvessels in pulmonary hypertension. Am. J. Pathol.143, 784-93.

    PubMed  CAS  Google Scholar 

  • Prigent, S.A. & Lemoine, N.R. (1992) The type 1 (EGFR-related) family of growth factor receptors and their ligands. Prog. Growth Factor Res.4, 1-24.

    Article  PubMed  CAS  Google Scholar 

  • Schultz, G., Rotatori, S. & Clark, W. (1991) EGF and TGF-α in wound healing and repair. J. Cell. Biochem.45, 346-52.

    Article  PubMed  CAS  Google Scholar 

  • Turbitt, M.L., Akhurst, R.J., White, S.I. & Mackie, R.M. (1990) Localization of elevated transforming growth factor-alpha in psoriatic epidermis. J. Invest. Dermatol.95, 229-32.

    Article  PubMed  CAS  Google Scholar 

  • Vassar, R. & Fuchs, E. (1991) Transgenic mice provide new insights into the role of TGF-α during epidermal development and differentiation. Genes Develop.5, 714-27.

    Article  PubMed  CAS  Google Scholar 

  • Vassar, R., Hutton, E. & Fuchs, E. (1992) Transgenic overexpression of transforming growth factor α bypasses the need for c-HA-ras mutations in mouse skin tumorigenesis. Mol. Cell Biol.12, 4643-53.

    PubMed  CAS  Google Scholar 

  • Vaughan, T.J., Pascall, J.C. & Brown, K.D. (1992) Tissue distribution of mRNA for heparin-binding epidermal growth factor. Biochem. J.287, 681-4.

    PubMed  CAS  Google Scholar 

  • Yates, R.A., Nanney, L.B., Gates, R.E. & King, L.E. (1991) Epidermal growth factor and related growth factors. Inter. J. Dermatol.30, 687-94.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, The Ohio State University and Children's Hospital Columbus, U.S.A

    Marc T. Downing, David R. Brigstock, Missy Crissman-Combs & Gail E. Besner

  2. Pathology, The Ohio State University and Children's Hospital Columbus, U.S.A

    Mark H. Luquette

Authors
  1. Marc T. Downing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David R. Brigstock
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark H. Luquette
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Missy Crissman-Combs
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gail E. Besner
    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

Downing, M.T., Brigstock, D.R., Luquette, M.H. et al. Immunohistochemical localization of heparin-binding epidermal growth factor-like growth factor in normal skin and skin cancers. J Mol Hist 29, 735–744 (1997). https://doi.org/10.1023/A:1026417202351

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026417202351

Keywords

Search

Navigation