Abstract

A growing body of evidence suggests that components of the tumor microenvironment, including cancer-associated fibroblasts (CAF), may modulate the treatment sensitivity of tumor cells. Here, we investigated the possible influence of CAFs on the sensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines to cetuximab, an antagonistic epidermal growth factor receptor (EGFR) antibody. Cetuximab treatment caused a reduction in the proliferation rate of HNSCC cell lines, whereas the growth of HNSCC-derived CAF cultures was unaffected. When tumor cells were cocultured with CAFs in a transwell system, the cetuximab-induced growth inhibition was reduced, and a complete protection from growth inhibition was observed in one of the tumor cell lines investigated. Media that had been conditioned by CAFs offered protection from cetuximab treatment in a concentration-dependent manner, suggesting that the resistance to treatment was mediated by CAF-derived soluble factors. The coculture of HNSCC cell lines with CAFs resulted in an elevated expression of matrix metalloproteinase-1 (MMP-1) in both the tumor cells and CAFs. Moreover, the CAF-induced resistance was partly abolished by the presence of an MMP inhibitor. However, CAFs treated with siRNA targeting MMP-1 still protected tumor cells from cetuximab treatment, suggesting that several MMPs may cooperate to facilitate resistance or that the protective effect is mediated by another member of the MMP family. These results identify a novel CAF-dependent modulation of cetuximab sensitivity and suggest that inhibiting MMPs may improve the effects of EGFR-targeted therapy.

Highlights

  • Cancer of the head and neck is the sixth most common form of cancer worldwide with 650,000 new cases each year

  • When the tumor cells were cocultured with HNSCC-derived cancerassociated fibroblasts (CAF) in a transwell system, they were less susceptible to cetuximab treatment

  • CAF cultures were completely resistant to cetuximab treatment, which indicates that mitogenic pathways other than EGF receptor (EGFR) are dominant in these cells (Fig. 1E)

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Summary

Introduction

Cancer of the head and neck is the sixth most common form of cancer worldwide with 650,000 new cases each year. The majority of all head and neck cancers are squamous cell carcinomas (HNSCC) with origins in the mucosa of the oral cavity, throat, nose or sinuses. Clinical drug resistance remains a major problem, and the overall survival rate for patients with HNSCC has not increased over the past. The receptor dimerizes, which leads to the autophosphorylation and activation of the intracellular tyrosine kinase domain [1]. Kinase activation triggers multiple downstream signaling pathways involving MAPK, PI3K/Akt, STATs, Src, and PLCg, which regulate key cellular processes including proliferation and survival. EGFR is frequently overexpressed in a number of human solid tumors, including HNSCC, where the high expression of EGFR correlates with a poor clinical outcome [2,3]

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