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• W2034177039 abstract "malignant acanthosis nigricans To the Editor: The homeostasis of the epidermis is regulated by a multitude of factors that act via specific receptors on the keratinocyte surface. These factors are normally released in a paracrine or autocrine way. There is a rare condition, however, in which epidermal growth is thought to be regulated by an endocrine mechanism, i.e., by growth factors synthesized in tissues other than the skin and released into the circulation: paraneoplastic or malignant acanthosis nigricans (MAN). The pathogenesis of MAN is still unclear. A current hypothetical mechanism is the secretion of large amounts of transforming growth factor α (TGF-α) by the tumor into the circulation that is thought to stimulate keratinocyte growth via an endocrine route (Koyama et al., 1997Koyama S. Ikeda K. Sato M. et al.Transforming growth factor-α (TGF-α) -producing gastric carcinoma with acanthosis nigricans: an endocrine effect of TGF-α in the pathogenesis of cutaneous paraneoplastic syndrome and epithelial hyperplasia of the esophagus.J Gastroenterol. 1997; 32: 71-77Crossref PubMed Scopus (89) Google Scholar). Increased production of TGF-α has been found in the vast majority of primary bladder carcinomas and in cells isolated from such tumors (Mellon et al., 1996Mellon J.K. Cook S. Chambers P. Neal E. Transforming growth factor α and epidermal growth factor levels in bladder cancer and their relationship to epidermal growth factor receptor.Br J Cancer. 1996; 73: 654-658Crossref PubMed Scopus (44) Google Scholar;Gazzaniga et al., 1998Gazzaniga P. Gradilone A. Silvestri I. et al.High levels of transforming growth factor-a (TGF-α) mRNA may predict local relapses in early stage urinary bladder cancer.Eur J Cancer. 1998; 34: 934-936Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar;Ruck and Paulie, 1998Ruck A. Paulie S. EGF, TGF α, AR and HB-EGF are autocrine growth factors for human bladder carcinoma cell lines.Anticancer Res. 1998; 18: 1447-1452PubMed Google Scholar;Tungekar and Linehan, 1998Tungekar M.F. Linehan J. Patterns of expressions of transforming growth factor and epidermal growth factor receptor in squamous cell lesions of the urinary bladder.J Clin Pathol. 1998; 51: 583-587Crossref PubMed Scopus (16) Google Scholar), and there seems to be a positive correlation between tumor stage and expression levels of this growth factor (Ravery et al., 1997Ravery V. Grignon D. Angulo J. Pontes E. Montie J. Crissman J. Chopin D. Evaluation of epidermal growth factor receptor, transforming growth factor α, epidermal growth factor and c-erbB2 in the progression of invasive bladder cancer.Urol Res. 1997; 25: 9-17Crossref PubMed Scopus (76) Google Scholar;Kee et al., 2001Kee K.H. Lee M.J. Ro J.Y. Oncoprotein changes in the flat lesions with atypia and invasive neoplasms of the urinary bladder.Oncol Rep. 2001; 8: 579-583PubMed Google Scholar). TGF-α is a primary mediator of benign and malignant keratinocyte hyperproliferation in vivo: upregulation of TGF-α production and epidermal growth factor receptor (EGFR) expression have been found in samples of psoriatic human skin (Nanney et al., 1986Nanney L.B. Stoscheck C.M. Magid M. King Jr, L.E. Altered [125I] epidermal growth factor binding and receptor distribution in psoriasis.J Invest Dermatol. 1986; 86: 260-265Crossref PubMed Scopus (264) Google Scholar;Elder et al., 1989Elder J.T. Fisher G.J. Lindquist P.B. et al.Overexpression of transforming growth factor a in psoriatic epidermis.Science. 1989; 243: 811-814Crossref PubMed Scopus (504) Google Scholar) and in squamous cell carcinomas (Donnelly et al., 1993Donnelly M.J. Patel V. Yeudall W.A. Game S.M. Scully C. Prime S.S. Autocrine production of TGF-α and TGF-β during tumour progression of rat oral keratinocytes.Carcinogenesis. 1993; 14: 981-985Crossref PubMed Scopus (15) Google Scholar;Jones et al., 1993Jones G.J. Heiss N.S. Veale R.B. Thornley A.L. Amplification and expression of the TGF-α, EGF receptor and c-myc genes in four human oesophageal squamous cell carcinoma lines.Biosci Rep. 1993; 13: 303-312Crossref PubMed Scopus (21) Google Scholar). When overexpressed in the epidermis of transgenic mice TGF-α induces epidermal thickening caused by keratinocyte hyperproliferation (Vassar and Fuchs, 1991Vassar R. Fuchs E. Transgenic mice provide new insights into the role of TGF-α during epidermal development and differentiation.Genes Dev. 1991; 5: 714-727Crossref PubMed Scopus (367) Google Scholar). TGF-α is closely related to epidermal growth factor (EGF) and binds to the same receptor, EGFR (Kramer et al., 1994Kramer R.H. Lenferink A.E. van Bueren-Koornneef I.L. van der Meer A. van de Poll M.L. van Zoelen E.J. Identification of the high affinity binding site of transforming growth factor-α (TGF-α) for the chicken epidermal growth factor (EGF) receptor using EGF/TGF-a chimeras.J Biol Chem. 1994; 269: 8708-8711Abstract Full Text PDF PubMed Google Scholar). This binding induces activation of the classical mitogen-activated protein kinase (MAPK, ERK) pathway, a module of three protein kinases that is organized in a hierarchical fashion and is known to regulate basic cellular functions such as proliferation, differentiation, and migration (Marshall, 1994Marshall C.J. MAP kinase kinase kinase, MAP kinase kinase and MAP kinase.Curr Opin Genet Dev. 1994; 4: 82-89Crossref PubMed Scopus (898) Google Scholar). Our previous studies of ERK activation in primary human keratinocytes have revealed a role for this pathway in the regulation of keratinocyte proliferation and differentiation: sustained activity of ERK suppresses and ERK inhibition induces differentiation (Haase et al., 2001Haase I. Hobbs R.M. Romero M.R. Broad S. Watt F.M. A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis.J Clin Invest. 2001; 108: 527-536Crossref PubMed Scopus (148) Google Scholar). Given the role of ERK in the development of hyperproliferative skin lesions we asked whether alterations of ERK activity would play a role in the pathogenesis of MAN. Biopsies were taken after obtaining informed consent from a patient suffering from MAN associated with metastatic bladder carcinoma. The MAN lesions were most pronounced at areas of cornified epithelium bordering the mucosa of lips and eyelids. Investigations were carried out in samples from the lip of this patient and in samples of normal skin and normal buccal mucosa obtained from different individuals. In normal skin and normal mucosa EGFR is constitutively expressed in the basal keratinocyte layer and variably in the first and second suprabasal keratinocyte layer (Figure 1a and data not shown). This expression pattern was altered dramatically in MAN skin: EGFR was present on the cell surface of basal and most suprabasal keratinocytes (Figure 1b, c). Assessment of cell proliferation using immunostaining against Ki67 and PCNA showed increased proliferation of basal but not suprabasal keratinocytes in MAN skin (data not shown). These changes were accompanied by dramatic alterations in the expression of keratin 14 (K14), which is normally confined to basal keratinocytes (Figure 1d, e). In MAN lesions K14 was present in all viable, i.e., basal and suprabasal keratinocytes. Similar changes in keratin expression have also been found in other hyperproliferative skin conditions (Wongwaisayawan et al., 1991Wongwaisayawan H. Yoshiike T. Aikawa Y. Briggaman R.A. Ogawa H. Antikeratin 14 monoclonal antibody staining in psoriasis and seborrhoeic keratosis: immunofluorescence and two colour FACS studies.Arch Dermatol Res. 1991; 283: 405-410Crossref PubMed Scopus (8) Google Scholar) and indicate a delayed onset of terminal differentiation. Using a combination of Western blotting and confocal laser scanning microscopy with antibodies that detect phosphorylation-specific epitopes of ERK we analyzed activation of MAPK signaling in normal skin and mucosa and in MAN lesions. Western blot analysis of two samples from normal skin and one sample from MAN skin showed a dramatic increase in the proportion of phosphorylated, i.e., activated, ERK2 in MAN skin (Figure 2e and data not shown). This activation was specific for ERK as jun-N terminal kinase (JNK) whose activity is also regulated by EGFR-dependent signaling (Hashimoto et al., 1999Hashimoto A. Kurosaki M. Gotoh N. Shibuya M. Kurosaki T. Shc regulates epidermal growth factor-induced activation of the JNK signaling pathway.J Biol Chem. 1999; 274: 20139-20143Crossref PubMed Scopus (52) Google Scholar) showed no significant increase in phosphorylation in the same sample (Figure 2e). We then used the phosphorylation-specific antibody to localize ERK activity in cryostate sections of MAN skin and control samples. As reported previously (Haase et al., 2001Haase I. Hobbs R.M. Romero M.R. Broad S. Watt F.M. A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis.J Clin Invest. 2001; 108: 527-536Crossref PubMed Scopus (148) Google Scholar), incubation of sections of three different samples of normal skin and one sample of normal buccal mucosa with the antibody against activated ERK did not yield any staining above background levels (Figure 2c, d, and data not shown). In contrast, sections of MAN skin showed focal staining of nuclei of keratinocytes but not stromal cells (Figure 2a, b). Keratinocytes in proximity to the stromal parts of the MAN lesion exhibited most pronounced ERK activation. In Figure 2(b), which is the same section as in Figure 2(a), nuclei were visualized using a fluorescent nuclear dye, ToProIII (red staining). The overlap of the green staining for phosphorylated ERK and the red nuclear staining results in a yellow signal for nuclei containing activated ERK (Figure 2b). Binding of TGF-α to EGFR leads to the stimulation of ERK in many systems (see, for example,Oliver et al., 1995Oliver B.L. Sha'afi R.I. Hajjar J.J. Transforming growth factor-α and epidermal growth factor activate mitogen-activated protein kinase and its substrates in intestinal epithelial cells.Proc Soc Exp Biol Medical. 1995; 210: 162-170Crossref PubMed Scopus (40) Google Scholar). Our Western blot analysis clearly shows that levels of total ERK activity were indeed elevated in MAN skin (Figure 2e). The finding that activated ERK was not only present in the basal compartment but also in suprabasal cells within the lesion suggests that EGFR expressed suprabasally is functional. In this context it appears interesting that, in spite of increased ERK activity in basal and suprabasal cells, proliferation was restricted to basal keratinocytes. This is consistent with in vitro findings demonstrating that ERK activation is not sufficient to stimulate anchorage-independent growth in primary human keratinocytes (Haase et al., 2001Haase I. Hobbs R.M. Romero M.R. Broad S. Watt F.M. A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis.J Clin Invest. 2001; 108: 527-536Crossref PubMed Scopus (148) Google Scholar) and suggests that additional, probably adhesion-dependent, factors are required in order to translate the growth stimulating effect of ERK activity. The distribution of activated ERK within the MAN lesion also raises the question of which function this pathway exerts in suprabasal keratinocytes. We have shown recently that, though ERK activation is not sufficient to stimulate proliferation of suspended keratinocytes, it can delay the program of terminal differentiation (Haase et al., 2001Haase I. Hobbs R.M. Romero M.R. Broad S. Watt F.M. A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis.J Clin Invest. 2001; 108: 527-536Crossref PubMed Scopus (148) Google Scholar). In agreement with that we found dramatic alterations in the expression of keratin 14 in MAN skin. A disturbed balance between proliferation and differentiation of epidermal keratinocytes is a feature of several skin diseases and we are only just beginning to understand the intracellular signaling pathways involved. There is now accumulating evidence for a role of ERK activation in epidermal hyperproliferation (Albanell et al., 2001Albanell J. Codony-Servat J. Rojo F. et al.Activated extracellular signal-regulated kinases: association with epidermal growth factor receptor/transforming growth factor α expression in head and neck squamous carcinoma and inhibition by anti-epidermal growth factor receptor treatments.Cancer Res. 2001; 61: 6500-6510PubMed Google Scholar;Haase et al., 2001Haase I. Hobbs R.M. Romero M.R. Broad S. Watt F.M. A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis.J Clin Invest. 2001; 108: 527-536Crossref PubMed Scopus (148) Google Scholar). Here we demonstrate activation of ERK signaling in a case of MAN and provide further evidence for a pathogenic role of this pathway in hyperproliferative skin disease." @default.
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• W2034177039 title "Activation of Epidermal Growth Factor Receptor/ERK Signaling Correlates with Suppressed Differentiation in Malignant Acanthosis Nigricans" @default.
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