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Expression of Epithelial Antigens Exo-1 and EPM-1 in Human Epidermal Keratinocyte Maturation and Benign and Malignant Neoplasia1

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Expression of Epithelial Antigens Exo-1 and EPM-1 in Human Epidermal Keratinocyte Maturation and Benign and Malignant Neoplasia1 [CANCER RESEARCH 50. 7668-7676. December I, 19901 Expression of Epithelial Antigens Exo-1 and EPM-1 in Human Epidermal Keratinocyte Maturation and Benign and Malignant Neoplasia1 Reinhard Klingel,2 Petra Boukamp, Roland Moll, Wolfgang Tilgen, Norbert E. Fusenig, Karl-Hermann Meyer zum Büschenfelde, and Wolfgang G. Dippold First Department of Internal Medicine, University of Mainz, D-6500 Main: [R. K., K-H. M. :. B., W. tí.I).I: Division of Differentiatinn and Carcinogenesis in Vitro, Institute of Biochemistry, Deutsches Krebsforschungs:entrum, D-6900 Heidelberg ¡P.B., N. E. F.J; Department of Pathology, University of Main:, D-6500 Mainz [R. M.I; and Department of Dermatology, University of Heidelberg, D-6900 Heidelberg ¡W.T.], Federal Republic ofdermany ABSTRACT lated but still tissue restricted (5-7). In human skin, proliferation and differentiation of keratino Exo-1, a polar neutral glycolipid, and EPM-1, a high molecular weight cytes and the development of benign and malignant neoplasia glycoprotein, are developmental antigens of human epithelial cells, ini are reflected by characteristic changes in tissue architecture. In tially described as components both on the cell surface and in secretions of gastrointestinal epithelia and respective tumors. In order to assess the turn, modifications in cell shape can act as a signal for terminal biological significance of both antigens for epithelial cell differentiation differentiation and inhibition of proliferation (8). Maturation and neoplastic transformation, their expression during human skin de and differentiation in human epidermis can be evaluated by velopment and benign and malignant neoplasia was analyzed in fresh determination of synthesis and modification of structural pro frozen tissue specimens of skin biopsies and of human epidermal keratin- teins and of alterations in the expression of cell surface antigens, ocytes growing in experimental model systems. Antigen expression was receptors, and epidermal lipids. Differentiation-related struc assessed immunohistochemically with specific monoclonal antibodies. tural proteins that are best defined include the keratins (9-12), During fetal development Exo-1 was temporarily expressed in interme filaggrin (13), and the cornified envelope proteins, e.g., involu- diate cells but was absent in normal adult human skin. Exo-1 expression crin (14), which are expressed and modified in a specific se reemerged in neoplasias, both benign and malignant, but was restricted to spinous-like differentiated cells. Similarly, Exo-1 was not expressed quence which closely parallels the morphological changes in in transplants of normal keratinocytes mimicking the normal epidermis human epidermis (11, 12, 15, 16). Similarly, changes in cell but was clearly visible in differentiated areas of transplants of malignantly surface carbohydrates occur during maturation of the epidermis transformed keratinocytes. EPM-1 appeared first in basal epidermal and can, for example, be visualized by different blood group cells in the second half of gestation and remained detectable in the antigens, which allow the distinction of different epidermal cell stratum basale of adult skin. While squamous cell carcinomas continued compartments (17-21). We recently identified and character to express EPM-1, it was not detectable in basal cell epitheliomas and ized two new antigens of normal and neoplastic human epithelia in normal epidermis after invasion by neuroectodermal tumor cells. In by monoclonal antibodies. These antigens were primarily ob experimental models, EPM-1 was present in the basal layers of normal served in normal and neoplastic gastrointestinal epithelia. Exo- human keratinocytes and of transformed keratinocytes with benign 1, a polar neutral glycolipid (22), and EPM-1, a high molecular growth characteristics whenever a well stratified and keratinized epider mis-like epithelium had formed in transplants. In transformed keratino weight glycoprotein (23), were present both on cell surfaces and cytes with malignant growth behavior, EPM-1 was expressed irregularly, in secretions. Other recently described differentiation-, devel as in squamous cell carcinomas in xita. Thus, expression of Exo-1 is a opment-, or tumor-associated markers of human epithelia, in marker for an early embryonic differentiation pathway of human keratin cluding the epithelial membrane antigen EMA, the high molec ocytes and in adult tissue reveals abnormal differentiation associated ular weight glycoproteins CA 19-9 and DU-PAN-2, and the H, with certain stages of hyperproliferation. EPM-1 expression is part of Le X, and Le Y blood group antigens, are different from Exo- developmental programs and is influenced by microenvironmental inter 1 and EPM-1 (18, 19, 24-31). The receptors for transferrin and actions and alterations of tissue homeostasis. epidermal growth factor, both detectable in epidermal basal cells, do not show characteristic changes during differentiation INTRODUCTION and transformation events in human skin (32, 33). In this paper, we report on the expression of Exo-1 and Glycolipids and carbohydrate structures of cell membrane EPM-1 in different stages of development and carcinogenesis glycoproteins undergo significant changes in their expression of human skin keratinocytes. Our particular interest was to during embryonic and fetal development and malignant trans analyze whether Exo-1 and EPM-1 expression patterns would formation of human cells (1-3). Glycosylation plays an impor indicate membrane changes associated with fetal maturation tant role in cytokine-mediated processes of normal tissue re and proliferation, as well as differentiation in the adult tissue. modeling and the maintenance of tissue homeostasis (4). The Disease entities of human skin as well as benign and malignant phenotype of cancer cells is a result of many genetic and tumors were studied to evaluate the influence of alterations in epigenetic changes, as well as altered microenvironmental in growth and differentiation occurring during hyperproliferation teractions. When cells are at ectopie sites, as is the case for and different stages of neoplastic transformation. In addition, metastatic tumors or tissue culture models, their phenotype normal keratinocytes and cell lines were analyzed in culture reflects the expression of genetic programs which are deregu- and transplantation models. These systems mimic in a tissue- specific way the in vivo situation of different phases of epithelial Received 4/20/90; accepted 7/13/90. regeneration and early tumor development. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. MATERIALS AND METHODS 1This work was supported by grants from the Bundesministerium fürFor schung und Technologie (DI 01 GA 054/6) and Deutsche Forschungsgemein Tissue Samples. Tissue samples of normal skin, various neoplastic schaft (Kl 578/2-1). This work was also partly supported by a Fellowship from lesions, and experimental models were snap-frozen and stored in liquid the DKFZ (Stiftung Sondervermögen) to P. B. 2To whom requests for reprints should be addressed, at First Department of nitrogen. Cryostat sections (4-6 ¿im)wereobtained according to stand Internal Medicine, University of Mainz. Langenbeckstr. I. D-6500 Mainz, FRG. ard procedures. 7668 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1990 American Association for Cancer Research. EPITHELIAL ANTIGENS IN KERATINOCYTE MATURATION AND NEOPLASIA Table 1 Exo-l and EPM-I expression in normal adult skin, fetal skin, and skin Monoclonal Antibodies. Mouse monoclonal antibody Pa-25 (IgM) appendages recognizes the high molecular weight glycoprotein EPM-1, and mono Reactivity for clonal antibody Pa-G-14 (IgM) the polar neutral glycolipid Exo-1 (22, Number 23). Both monoclonal antibodies were raised against the human pan Tissue tested Exo-l EPM-I creatic cancer cell line Capan-1, and pools of (5x) concentrated hybrid- Adult skin 25 oma culture supernatant (immunoglobulin concentration, 200 /¿g/ml) Basal cell layer + were used throughout the whole study. Spinous cell layer Immunocytochemical Staining. Fresh frozen, nonfixed tissue sections Skin appendages (4-6 ¿im)werestained with Pa-25 and Pa-G-14 by an indirect immu- Hair follicle noperoxidase method, essentially as described previously (34). The Outer root sheath + immunochemical reaction was developed with the red dye 3-amino-9- Inner root sheath + ethyl-carbazole and counterstained with blue Meyer's Hemalum solu Sebaceous gland Peripheral germinative cells — + tion (Merck, Darmstadt, FRG).3 A monoclonal antibody to the mouse Centrally located vacuolated cells lymphocyte antigen Lyt.l.l (IgM) served as a negative control and the Eccrine sweat gland + + anti-HLA-ABC monoclonal antibody W6/32 as a positive control for Fetal skin 17 the immunostaining (35). Additionally, the indirect immunofluores- Periderm + cence method was used as described previously (36). As second anti Basalcells body, we used fluorescein isothiocyanate-labeled anti-mouse 7-globulin Before 17-week EGA 17-24-week EGA +/-" (Fab fragment; Dianova). After 24-week EGA + Cell Lines. The spontaneously immortalized human skin keratino- Intermediate cells/upper suprabasal layers cyte cell line designated HaCaT, described in detail previously (36), Before 14/15-week EGA exhibited a transformed phenotype in vitro but was
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