Mitigation of Tumor-Associated Fibroblast-Facilitated Head and Neck Cancer Progression With Anti–Hepatocyte Growth Factor Antibody Ficlatuzumab | Head and Neck Cancer | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
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Original Investigation
December 2015

Mitigation of Tumor-Associated Fibroblast-Facilitated Head and Neck Cancer Progression With Anti–Hepatocyte Growth Factor Antibody Ficlatuzumab

Author Affiliations
  • 1Department of Otolaryngology, University of Kansas Medical Center, Kansas City
  • 2Departments of Grain Science and Industry, and Biological and Agricultural Engineering, Kansas State University, Kansas City
  • 3PepGel LLC, Manhattan, Kansas
  • 4Department of Cancer Biology, University of Kansas Medical Center, Kansas City
  • 5Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City
  • 6University of Kansas Cancer Center, Kansas City
JAMA Otolaryngol Head Neck Surg. 2015;141(12):1133-1139. doi:10.1001/jamaoto.2015.2381
Abstract

Importance  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.

Design, Setting, and Participants  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.

Exposures for Observational Studies  The HNSCC cell lines were treated with ficlatuzumab, 0 to 100 µg/mL, for 24 to 72 hours.

Main Outcomes and Measures  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 and Relevance  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.

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