title: Mitigation of Tumor-Associated Fibroblast-Facilitated Head and Neck Cancer Progression With Anti-Hepatocyte Growth Factor Antibody Ficlatuzumab.
abstract: OBJECTIVE
  Ficlatuzumab can be used to treat head and neck squamous cell carcinoma (HNSCC) by inhibiting c-Met receptor-mediated cell proliferation, migration, and invasion.
  
  
  OBJECTIVE
  To understand the effect of ficlatuzumab on HNSCC proliferation, migration, and invasion.
  
  
  METHODS
  The effects of ficlatuzumab on HNSCC proliferation, invasion, and migration were tested. Mitigation of c-Met and downstream signaling was assessed by immunoblotting. The tumor microenvironment has emerged as an important factor in HNSCC tumor progression. The most abundant stromal cells in HNSCC tumor microenvironment are tumor-associated fibroblasts (TAFs). We previously reported that TAFs facilitate HNSCC growth and metastasis. Furthermore, activation of the c-Met tyrosine kinase receptor by TAF-secreted hepatocyte growth factor (HGF) facilitates tumor invasion. Ficlatuzumab is a humanized monoclonal antibody that sequesters HGF, preventing it from binding to and activating c-Met. We hypothesized that targeting the c-Met pathway with ficlatuzumab will mitigate TAF-mediated HNSCC proliferation, migration, and invasion. Representative HNSCC cell lines HN5, UM-SCC-1, and OSC-19 were used in these studies.
  
  
  OBJECTIVE
  The HNSCC cell lines were treated with ficlatuzumab, 0 to 100 µg/mL, for 24 to 72 hours.
  
  
  METHODS
  Ficlatuzumab inhibited HNSCC progression through c-Met and mitogen-activated protein kinase (MAPK) signaling pathway.
  
  
  RESULTS
  Ficlatuzumab significantly reduced TAF-facilitated HNSCC cell proliferation (HN5, P < .001; UM-SCC-1, P < .001), migration (HN5, P = .002; UM-SCC-1, P = .01; and OSC-19, P = .04), and invasion (HN5, P = .047; UM-SCC-1, P = .03; and OSC-19, P = .04) through a 3-dimensional peptide-based hydrogel (PGmatrix). In addition, ficlatuzumab also inhibited the phosphorylation of c-Met at Tyr1234/1235 and p44/42 MAPK in HNSCC cells exposed to recombinant HGF.
  
  
  CONCLUSIONS
  We demonstrate that neutralizing TAF-derived HGF with ficlatuzumab effectively mitigates c-Met signaling and decreases HNSCC proliferation, migration, and invasion. Thus, ficlatuzumab effectively mitigates stromal influences on HNSCC progression.
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, Kansas City.
authors.forename: Dhruv
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, Kansas City.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kandl
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, Kansas City.
authors.forename: Chase D'Arcy
authors.initials: CD
authors.lastname: Hamilton
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, Kansas City.
authors.forename: Yelizaveta
authors.initials: Y
authors.lastname: Shnayder
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, Kansas City.
authors.forename: Terance Ted
authors.initials: TT
authors.lastname: Tsue
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, Kansas City.
authors.forename: Kiran
authors.initials: K
authors.lastname: Kakarala
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, Kansas City.
authors.forename: Levi
authors.initials: L
authors.lastname: Ledgerwood
authors.affiliation: Departments of Grain Science and Industry, and Biological and Agricultural Engineering, Kansas State University, Kansas City.
authors.forename: Xiuzhi Susan
authors.initials: XS
authors.lastname: Sun
authors.affiliation: PepGel LLC, Manhattan, Kansas.
authors.forename: Hongzhou John
authors.initials: HJ
authors.lastname: Huang
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, Kansas City.
authors.forename: Douglas
authors.initials: D
authors.lastname: Girod
authors.affiliation: Department of Otolaryngology, University of Kansas Medical Center, Kansas City4Department of Cancer Biology, University of Kansas Medical Center, Kansas City5Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City6Universi.
authors.forename: Sufi Mary
authors.initials: SM
authors.lastname: Thomas
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; C583360:ficlatuzumab