title: Differential regulation of a fibroblast growth factor-binding protein during skin carcinogenesis and wound healing.
abstract: The initiation of premalignant lesions is associated with subtle cellular and gene expression changes. Here we describe a severe combined immunodeficiency mouse xenograft model with human adult skin and compare chemical carcinogenesis and wound healing. We focus on a secreted binding protein for fibroblast growth factors (FGF-BP) that enhances the activity of locally stored FGFs and is expressed at high levels in human epithelial cancers. Carcinogen treatment of murine skin induced papilloma within 6 weeks, whereas the human skin grafts displayed no obvious macroscopic alterations. Microscopic studies of the human skin, however, showed p53-positive keratinocytes in the epidermis, increased angiogenesis in the dermis of the treated skin, enhanced proliferation of keratinocytes in the basal layer, and an increase of FGF-BP protein and mRNA expression. In contrast, after surgical wounding of human skin grafts or of mouse skin, FGF-BP expression was upregulated within a few hours and returned to control levels after 2 days with wound closure. Enhanced motility of cultured keratinocytes and dermal fibroblasts by FGF-BP supports a role in wound healing. We conclude that adult human skin xenografts can be used to identify early molecular events during malignant transformation as well as transient changes during wound healing.
authors.affiliation: Lombardi Cancer Center, Department of Oncology, Georgetown University, Washington, DC 20057, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kurtz
authors.forename: Achim
authors.initials: A
authors.lastname: Aigner
authors.forename: Rafael H
authors.initials: RH
authors.lastname: Cabal-Manzano
authors.forename: Robert E
authors.initials: RE
authors.lastname: Butler
authors.forename: Dozier R
authors.initials: DR
authors.lastname: Hood
authors.forename: Roy B
authors.initials: RB
authors.lastname: Sessions
authors.forename: Frank
authors.initials: F
authors.lastname: Czubayko
authors.forename: Anton
authors.initials: A
authors.lastname: Wellstein
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D012867:Skin / Q000187:drug effects; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D016038:Skin Transplantation; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*; D014945:Wound Healing / Q000235:genetics
chemical_list: D002273:Carcinogens; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; C070699:FGFBP1 protein, human; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate