title: Inhibition of fibroblasts reduced head and neck cancer growth by targeting fibroblast growth factor receptor.
abstract: OBJECTIVE
  Head and neck squamous cell carcinoma (HNSCC) is a complex disease process involving interactions with carcinoma-associated fibroblasts and endothelial cells. We further investigated these relationships by suppressing stromal cell growth through the inhibition of fibroblast growth factor receptor (FGFR).
  
  
  METHODS
  Preclinical investigation.
  
  
  METHODS
  HNSCC cell lines (FADU, OSC19, Cal27, SCC1, SCC5, SCC22A), fibroblast (HS27), and endothelial cells (human umbilical vascular endothelial cell) were cultured individually or in coculture. Proliferation was assessed following treatment with a range of physiologic concentrations of FGFR inhibitor PD173074. Mice bearing established HNSCC xenografts were treated with PD173074 (12 mg/kg), and tumor histology was analyzed for stromal composition, proliferation (Ki67 staining), and apoptosis (TUNEL [terminal deoxynucleotidyl transferase dUTP nick end labeling] staining).
  
  
  RESULTS
  In vitro, inhibition of FGFR with PD173074 dramatically reduced proliferation of fibroblasts and endothelial cells compared to untreated controls. However, HNSCC cell proliferation was not affected by inhibition of FGFR. When cocultured with fibroblasts, HNSCC cells proliferation increased by 15% to 80% (P < .01). Furthermore, this fibroblast-enhanced tumor cell growth was suppressed by FGFR inhibition. Additionally, treatment of mice bearing HNSCC xenografts with PD173074 resulted in significant growth inhibition (P < .001). Additionally, those tumors from mice treated with PD173074 had a smaller stromal component, decreased proliferation, and increased apoptosis.
  
  
  CONCLUSIONS
  Targeting the FGFR pathway in head and neck cancer acts through the stromal components to decrease HNSCC growth in vivo and in vitro.
authors.affiliation: Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Larissa
authors.initials: L
authors.lastname: Sweeny
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Liu
authors.forename: William
authors.initials: W
authors.lastname: Lancaster
authors.forename: Justin
authors.initials: J
authors.lastname: Hart
authors.forename: Yolanda E
authors.initials: YE
authors.lastname: Hartman
authors.forename: Eben L
authors.initials: EL
authors.lastname: Rosenthal
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D051379:Mice; D011743:Pyrimidines / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D000077195:Squamous Cell Carcinoma of Head and Neck; D014407:Tumor Cells, Cultured
chemical_list: C115711:PD 173074; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor