Keratinocyte growth factor/fibroblast growth factor 7, a homeostatic factor with therapeutic potential for epithelial protection and repair.
Keratinocyte growth factor (KGF) is a paracrine-acting, epithelial mitogen produced by cells of mesenchymal origin. It is a member of the fibroblast growth factor (FGF) family, and acts exclusively through a subset of FGF receptor isoforms (FGFR2b) expressed predominantly by epithelial cells. The upregulation of KGF after epithelial injury suggested it had an important role in tissue repair. This hypothesis was reinforced by evidence that intestinal damage was worse and healing impaired in KGF null mice. Preclinical data from several animal models demonstrated that recombinant human KGF could enhance the regenerative capacity of epithelial tissues and protect them from a variety of toxic exposures. These beneficial effects are attributed to multiple mechanisms that collectively act to strengthen the integrity of the epithelial barrier, and include the stimulation of cell proliferation, migration, differentiation, survival, DNA repair, and induction of enzymes involved in the detoxification of reactive oxygen species. KGF is currently being evaluated in clinical trials to test its ability to ameliorate severe oral mucositis (OM) that results from cancer chemoradiotherapy. In a phase 3 trial involving patients who were treated with myeloablative chemoradiotherapy before autologous peripheral blood progenitor cell transplantation for hematologic malignancies, KGF significantly reduced both the incidence and duration of severe OM. Similar investigations are underway in patients being treated for solid tumors. On the basis of its success in ameliorating chemoradiotherapy-induced OM in humans and tissue damage in a variety of animal models, additional clinical applications of KGF are worthy of investigation.
Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892, USA.
Paul W
PW
Finch
Jeffrey S
JS
Rubin
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D002277:Carcinoma / Q000473:pathology; D002468:Cell Physiological Phenomena / Q000187:drug effects; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000009:adverse effects / Q000737:chemistry / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000188:drug therapy; D006493:Heparin / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009928:Organ Specificity; D011487:Protein Conformation; D011509:Proteoglycans / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D013280:Stomatitis / Q000139:chemically induced / Q000188:drug therapy; D019172:Transplantation Conditioning / Q000009:adverse effects; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
D000970:Antineoplastic Agents; C496453:FGF7 protein, human; C496454:Fgf7 protein, mouse; D011509:Proteoglycans; D017468:Receptors, Fibroblast Growth Factor; C036090:heparin proteoglycan; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D006493:Heparin; D051497:Receptor, Fibroblast Growth Factor, Type 2