Evaluation of tyrosine receptor kinases in the interactions of head and neck squamous cell carcinoma cells and fibroblasts.
OBJECTIVE
Despite treatment advancements, disease-free survival of head and neck squamous cell carcinoma (HNSCC) has not significantly improved. This may be a result of tumor-fibroblasts interactions providing protective pathways for oncogenic cells to resist therapy. Further understanding of these relationships in HNSCC may improve effectiveness of targeted therapies. In this article, we investigated the role of several receptor tyrosine kinases (RTKs) in the interactions between HNSCC cells and supporting cells (fibroblasts).


METHODS
HNSCC cell lines and human tumor samples were evaluated for FGFR1/2/3, and PDGF-beta expression levels. Cell lines (FADU, SCC1, OSC19, Cal27, SCC22A) were treated with a range of physiological concentrations of dovitinib and assessed for proliferation, cytotoxicity, and apoptosis. Mice bearing HNSCC xenografts were treated with dovitinib (20 mg/kg).


RESULTS
Evaluation of HNSCC tumor specimens, cell lines and fibroblasts found variable expression of multiple RTKs (fibroblasts growth factor receptor, platelet derived growth factor receptor and vascular endothelial growth factor receptor) and their ligands, supporting previous theories of paracrine and autocrine signaling within the microenvironment. In a dose-dependent fashion, RTK inhibition reduced proliferation of HNSCC cell lines and fibroblast in vitro. When HNSCC cells were cocultured with fibroblasts, RTK inhibition resulted in a smaller reduction in the proliferation relative to untreated conditions. In vivo, RTK inhibition resulted in significant tumor regression and growth inhibition (p<0.05) and reduced the incidence of regional lymph node metastasis.


CONCLUSIONS
Effective treatment of HNSCC, therefore, may require inhibition of multiple RTKs in order to adequately inhibit the microenvironment's various signaling pathways.
Department of Surgery, Division of Otolaryngology - Head and Neck Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Larissa
L
Sweeny
Terence M
TM
Zimmermann
Zhiyong
Z
Liu
Eben L
EL
Rosenthal
D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005455:Fluorescent Antibody Technique; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
D020794:Receptor Protein-Tyrosine Kinases