title: Targeting a glioblastoma cancer stem-cell population defined by EGF receptor variant III.
abstract: The relationship between mutated proteins and the cancer stem-cell population is unclear. Glioblastoma tumors frequently express EGFRvIII, an EGF receptor (EGFR) variant that arises via gene rearrangement and amplification. However, expression of EGFRvIII is restricted despite the prevalence of the alteration. Here, we show that EGFRvIII is highly coexpressed with CD133 and that EGFRvIII(+)/CD133(+) defines the population of cancer stem cells (CSC) with the highest degree of self-renewal and tumor-initiating ability. EGFRvIII(+) cells are associated with other stem/progenitor markers, whereas markers of differentiation are found in EGFRvIII(-) cells. EGFRvIII expression is lost in standard cell culture, but its expression is maintained in tumor sphere culture, and cultured cells also retain the EGFRvIII(+)/CD133(+) coexpression, self-renewal, and tumor initiating abilities. Elimination of the EGFRvIII(+)/CD133(+) population using a bispecific antibody reduced tumorigenicity of implanted tumor cells better than any reagent directed against a single epitope. This work demonstrates that a mutated oncogene can have CSC-specific expression and be used to specifically target this population.
authors.affiliation: Authors' Affiliations: Brain Tumor Research Laboratories, Program in Cancer Biology, Stanford University Medical Center, Stanford; Department of Pathology, Stanford University Medical Center, Stanford; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University Medical Center, Stanford; Department of Neurosurgery, Stanford University School of Medicine, Stanford; Veterans Affairs Palo Alto Health Care System, Palo Alto, California; Department of Physiology and Pharmacology, Institute for Biomedical Research, School of Medicine, University of Salamanca, Salamanca, Spain; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; and Department of Gastroenterology, Henan Provincial People's Hospital, Zhengzhou, Henan, People's Republic of China.
authors.forename: David R
authors.initials: DR
authors.lastname: Emlet
authors.forename: Puja
authors.initials: P
authors.lastname: Gupta
authors.forename: Marina
authors.initials: M
authors.lastname: Holgado-Madruga
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Del Vecchio
authors.forename: Siddhartha S
authors.initials: SS
authors.lastname: Mitra
authors.forename: Shuang-Yin
authors.initials: SY
authors.lastname: Han
authors.forename: Gordon
authors.initials: G
authors.lastname: Li
authors.forename: Kristin C
authors.initials: KC
authors.lastname: Jensen
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Linda Wei
authors.initials: LW
authors.lastname: Xu
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Skirboll
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Wong
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D018033:Antibodies, Bispecific / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D002469:Cell Separation; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000276:immunology; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000071916:AC133 Antigen; D018033:Antibodies, Bispecific; D015703:Antigens, CD; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D006023:Glycoproteins; D018796:Immunoconjugates; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors