CD271 is a functional and targetable marker of tumor-initiating cells in head and neck squamous cell carcinoma
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Oihana Murillo-Sauca1,5,6, Man Ki Chung1,5,6, June Ho Shin1,5,6, Christina Karamboulas7, Shirley Kwok4, Young Ho Jung1,5,6, Richard Oakley1,5, James R. Tysome1,5, Lovisa O. Farnebo1,5,6, Michael J. Kaplan1,5, Davud Sirjani1,5, Vasu Divi1,5, F. Christopher Holsinger1,5, Chafeek Tomeh1,5, Anthony Nichols8, Quynh T. Le2,5, A. Dimitrios Colevas3,5, Christina S. Kong4,5, Ravindra Uppaluri9, James S. Lewis Jr.9,10, Laurie E. Ailles7 and John B. Sunwoo1,5,6
1 Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA
2 Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA
3 Department of Medicine, Stanford University School of Medicine, Stanford, CA
4 Department of Pathology, Stanford University School of Medicine, Stanford, CA
5 Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA
6 Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA
7 Ontario Cancer Institute, University Health Network, Toronto, Canada
8 Department of Otolaryngology – Head and Neck Surgery, Victoria Hospital, Schulich School of Medicine and Dentistry, London, Ontario, Canada
9 Department of Otolaryngology – Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO
10 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
John B. Sunwoo, email:
Keywords: HNSCC, cancer stem cells, NGFR, p75NTR, cancer-initiating cell, CD44
Received: May 22, 2014 Accepted: July 26, 2014 Published: July 26, 2014
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.
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