title: Creating oral squamous cancer cells: a cellular model of oral-esophageal carcinogenesis.
abstract: Immortalization and malignant transformation are important steps in tumor development. The ability to induce these processes from normal human epithelial cells with genetic alterations frequently found in the corresponding human cancer would significantly enhance our understanding of tumor development. Alterations in several key intracellular regulatory pathways (the pRB, p53, and mitogenic signaling pathways and the telomere maintenance system) appear to be sufficient for the neoplastic transformation of normal human cells. Nevertheless, in vitro transformation models to date depend on viral oncogenes, most prominently the simian virus 40 early region, to induce immortalization and malignant transformation of normal human epithelial cells. Here, we demonstrate a transformation model creating oral-esophageal cancer cells by using a limited set of genetic alterations frequently observed in the corresponding human cancer. In a stepwise model, cyclin D1 overexpression and p53 inactivation led to immortalization of oral keratinocytes. Additional ectopic epithelial growth factor receptor overexpression followed by c-myc overexpression as well as consecutive reactivation of telomerase induced by epithelial growth factor receptor sufficed to transform oral epithelial cells, truly recapitulating the development of the corresponding human disease.
authors.affiliation: Department of Medicine and Institute for Molecular Medicine and Cell Research, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
authors.forename: Gitta
authors.initials: G
authors.lastname: Goessel
authors.forename: Michael
authors.initials: M
authors.lastname: Quante
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: Hideki
authors.initials: H
authors.lastname: Harada
authors.forename: Steffen
authors.initials: S
authors.lastname: Heeg
authors.forename: Yasir
authors.initials: Y
authors.lastname: Suliman
authors.forename: Michaela
authors.initials: M
authors.lastname: Doebele
authors.forename: Alexander
authors.initials: A
authors.lastname: von Werder
authors.forename: Christine
authors.initials: C
authors.lastname: Fulda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Opitz
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000209:etiology*; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000032:analysis; D066246:ErbB Receptors / Q000032:analysis; D004938:Esophageal Neoplasms / Q000209:etiology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D009061:Mouth Mucosa / Q000166:cytology; D009062:Mouth Neoplasms / Q000209:etiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis; D016615:Telomere; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt