title: Targeted inhibition of CD133+ cells in oral cancer cell lines.
abstract: Resistance to treatment and the appearance of secondary tumors in head and neck squamous cell carcinomas (HNSCC) have been attributed to the presence of cells with stem-cell-like properties in the basal layer of the epithelium at the site of the lesion. In this study, we tested the hypothesis that these putative cancer stem cells (CSC) in HNSCC could be specifically targeted and inhibited. We found that 9 of 10 head and neck tumor biopsies contained a subpopulation of cells that expressed CD133, an unusual surface-exposed membrane-spanning glycoprotein associated with CSC. A genetically modified cytolethal distending toxin (Cdt), from the periodontal pathogen Aggregatibacter actinomycetemcomitans, was conjugated to an anti-human CD133 monoclonal antibody (MAb). The Cdt-MAb complex preferentially inhibited the proliferation of CD133(+) cells in cultures of established cell lines derived from HNSCC. Inhibition of the CD133(+) cells was rate- and dose-dependent. Saturation kinetics indicated that the response to the Cdt-MAb complex was specific. Healthy primary gingival epithelial cells that are native targets of the wild-type Cdt were not affected. Analysis of these data provides a foundation for the future development of new therapies to target CSC in the early treatment of HNSCC.
  
  
  BACKGROUND
  Cdt, cytolethal distending toxin; CSC, cancer stem cells; HNSCC, head and neck squamous cell carcinoma; MAb, monoclonal antibody.
authors.affiliation: Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: M
authors.initials: M
authors.lastname: Damek-Poprawa
authors.forename: A
authors.initials: A
authors.lastname: Volgina
authors.forename: J
authors.initials: J
authors.lastname: Korostoff
authors.forename: T P
authors.initials: TP
authors.lastname: Sollecito
authors.forename: M S
authors.initials: MS
authors.lastname: Brose
authors.forename: B W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: S O
authors.initials: SO
authors.lastname: Akintoye
authors.forename: J M
authors.initials: JM
authors.lastname: DiRienzo
mesh_terms: D000071916:AC133 Antigen; D016976:Aggregatibacter actinomycetemcomitans / Q000502:physiology; D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000096:biosynthesis*; D001427:Bacterial Toxins / Q000235:genetics / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D000922:Immunotoxins / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D058990:Molecular Targeted Therapy; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D016297:Mutagenesis, Site-Directed; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010455:Peptides
chemical_list: D000071916:AC133 Antigen; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001427:Bacterial Toxins; D006023:Glycoproteins; D000922:Immunotoxins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; C067044:cytolethal distending toxin