title: CD271 is a functional and targetable marker of tumor-initiating cells in head and neck squamous cell carcinoma.
abstract: Tumor-initiating cells (TICs) in squamous cell carcinoma of the head and neck (SCCHN) are best characterized by their surface expression of CD44. Although there is great interest in identifying strategies to target this population, no marker of these cells has been found to be functionally active. Here, we examined the expression of the purported marker of normal human oral epithelial stem cells, CD271. We show that CD271 expression is restricted to a subset of the CD44+ cells. Using xenograft assays, we show that the CD44+CD271+ subpopulation contains the most tumorigenic cells. Loss of CD271 function results in a block in the G2-M phase of the cell cycle and a profound negative impact on the capacity of these cells to initiate tumor formation in vivo. Incubation with recombinant NGF results in enhanced phosphorylation of Erk, providing additional evidence that CD271 is functionally active. Finally, incubation of SCCHN cells with antibody to CD271 results in decreased Erk phosphorylation and decreased tumor formation in vivo. Thus, our data are the first to demonstrate that CD271 more specifically identifies the TIC subpopulation within the CD44+ compartment in SCCHN and that this receptor is a functionally active and targetable molecule.
authors.affiliation: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA. Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA. .
authors.forename: Oihana
authors.initials: O
authors.lastname: Murillo-Sauca
authors.affiliation: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA. Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA.
authors.forename: Man Ki
authors.initials: MK
authors.lastname: Chung
authors.affiliation: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA. Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA. .
authors.forename: June Ho
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: Karamboulas
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Shirley
authors.initials: S
authors.lastname: Kwok
authors.affiliation: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA. Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Jung
authors.affiliation: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Richard
authors.initials: R
authors.lastname: Oakley
authors.affiliation: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: James R
authors.initials: JR
authors.lastname: Tysome
authors.affiliation: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA. Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA.
authors.forename: Lovisa O
authors.initials: LO
authors.lastname: Farnebo
authors.affiliation: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kaplan
authors.affiliation: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Davud
authors.initials: D
authors.lastname: Sirjani
authors.affiliation: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA. .
authors.forename: Vasu
authors.initials: V
authors.lastname: Divi
authors.affiliation: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA. .
authors.forename: F Christopher
authors.initials: FC
authors.lastname: Holsinger
authors.affiliation: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Chafeek
authors.initials: C
authors.lastname: Tomeh
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Victoria Hospital, Schulich School of Medicine and Dentistry, London, Ontario, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Nichols
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA. .
authors.forename: Quynh T
authors.initials: QT
authors.lastname: Le
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: A Dimitrios
authors.initials: AD
authors.lastname: Colevas
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Kong
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Uppaluri
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO. .
authors.forename: James S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, Canada.
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Ailles
authors.affiliation: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA. Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA.
authors.forename: John B
authors.initials: JB
authors.lastname: Sunwoo
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000276:immunology; D010766:Phosphorylation; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis* / Q000276:immunology; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D018960:Hyaluronan Receptors; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor