Regeneration of human epidermis on acellular dermis is impeded by small-molecule inhibitors of EGF receptor tyrosine kinase

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Forsberg, SofiUppsala universitet,Dermatologi och venereologi (författare)

Regeneration of human epidermis on acellular dermis is impeded by small-molecule inhibitors of EGF receptor tyrosine kinase

Artikel/kapitelEngelska2008

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2008-04-30
Springer Science and Business Media LLC,2008
printrdacarrier

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LIBRIS-ID:oai:DiVA.org:uu-89156
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-89156URI
https://doi.org/10.1007/s00403-008-0853-2DOI
http://kipublications.ki.se/Default.aspx?queryparsed=id:117632362URI

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Språk:engelska
Sammanfattning på:engelska

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Ämneskategori:art swepub-publicationtype

Anmärkningar

The family of human epidermal growth factor receptors (EGFR, HER2-4) exerts key functions in normal and malignant epithelial cells. Both EGFR and HER2 are valuable targets for anti-cancer drugs by interfering with ligand binding, receptor dimerization, or tyrosine kinase activity. A similar therapeutic strategy has been advocated for chronic psoriasis since plaque lesions overexpress EGFR and its ligands. Our aim was to characterize EGFR/HER2 protein expression in skin cultures and to evaluate the effects of tyrosine kinase inhibitors on epidermal outgrowth, morphology, and EGFR activation. Human skin explants were established on cell-free dermis and cultured at the air-liquid interface. The impact of small-molecule HER inhibitors on outgrowth was assayed by fluorescence-based image analysis and histometry. Effects of a dual EGFR/HER2 kinase inhibitor, PKI166, on neoepidermis were studied by immunohistochemistry and Western blot. Receptor immunostaining showed in vivo-like distributions with highest EGFR intensity in the proliferative layers whereas HER2 was mainly expressed by suprabasal keratinocytes. Reepithelialization was associated with EGFR autophosphorylation irrespective of exogenous ligand stimulation. PKI166 inhibited neoepidermal EGFR activation, keratinocyte proliferation, and outgrowth from normal and psoriatic skin explants. The rate of epidermalization in presence of other HER inhibitors varied suggesting that drug specificity, potency, and reversibility determine the dynamic outcome. Overall, agents predominantly targeting EGFR kinase were more efficient inhibitors of epidermal regeneration than an HER2-selective drug. The study illustrates the usefulness of a dynamic skin model and emphasizes the potential of HER-directed approaches to control epidermal growth in hyperproliferative skin disorders.

Ämnesord och genrebeteckningar

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Dermatologi och venereologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Dermatology and Venereal Diseases hsv//eng
Dermatology and venerology
Dermatologi och venerologi

Biuppslag (personer, institutioner, konferenser, titlar ...)

Östman, ArneKarolinska Institutet (författare)
Rollman, OlaUppsala universitet,Dermatologi och venereologi(Swepub:uu)olarollm (författare)
Uppsala universitetDermatologi och venereologi (creator_code:org_t)

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Ingår i:Archives of Dermatological Research: Springer Science and Business Media LLC300:9, s. 505-5160340-36961432-069X

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Av författaren/redakt...: Forsberg, Sofi; Östman, Arne; Rollman, Ola

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Dermatologi och ...

Artiklar i publikationen: Archives of Derm ...

Av lärosätet: Uppsala universitet; Karolinska Institutet

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