Abstract 1433: Tumor-associated fibroblasts increase HNSCC invasion in the presence of carcinogen NNK via activation of EGFR and c-Met

Abstract

Abstract Tobacco smoking is a major risk factor for head and neck squamous cell carcinoma (HNSCC); one of the leading causes of cancer mortality. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) a major product of cigarette smoke and is a well known carcinogen. Approximately 20 − 40% of former smokers continue to smoke 1 year post-HNSCC diagnosis. The role of NNK in tumor progression remains unknown. We hypothesize that exposure to carcinogens such as NNK contributes to the invasive and metastatic ability of HNSCC. In addition we believe it affects the surrounding stromal tissue, facilitating tumor progression. In order to examine the effects of NNK on HNSCC and stomal fibroblast invasion, we used Matrigel-coated transwell invasion chambers, where the cells were plated on top of the Matrigel for 24 h following which the invaded cells were fixed, stained, and counted. Our data demonstrate that NNK (10 nM) increases invasion in both HNSCC cells as well as surrounding stromal fibroblasts though Matrigel. Further, we demonstrate that NNK treatment resulted in activation of the epidermal growth factor receptor (EGFR) and c-met in HNSCC cells. EGFR activates downstream molecules increasing HNSCC invasion. Inhibition of EGFR using the EGFR specific antibody cetuximab abrogates NNK-induced invasion in HNSCC cells. Neutralizing antibodies to HGF abrogates NNK induces invasion in the presence of tumor associated stromal fibroblasts. These findings provide important insights into mechanism whereby NNK contributes to tumor progression. Further, inhibition of EGFR abrogates NNK-mediated invasion of HNSCC and may facilitate loco-regional spread of the disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1433.