Abstract
Cetuximab, a monoclonal antibody against the epidermal growth factor receptor (EGFR), has been successfully used to treat some patients with colorectal cancer and those with head and neck squamous cell carcinoma (HNSCC). For the effective treatment, it is essential to first identify cetuximab-responsive patients. The level of EGFR expression and/or the presence of mutations in signalling molecules downstream of the EGFR pathway have been reported to be determining factors for cetuximab responsiveness in colorectal cancer patients; however, limited data have been reported for HNSCC patients. We previously reported that the chemokine CXCL14 exhibits tumour-suppressive effects against xenografted HNSCC cells, which may be classified into two groups, CXCL14-expressing and non-expressing cells under serum-starved culture conditions. Here we employed CXCL14-expressing HSC-3 cells and CXCL14-non-expressing YCU-H891 cells as representatives of the two groups and compared their responses to cetuximab and their CXCL14 expression under various conditions. The growth of xenografted tumours initiated by HSC-3 cells, which expressed CXCL14 in vivo and in vitro, was suppressed by the injection of cetuximab into tumour-bearing mice; however, neither the expression of the chemokine nor the cetuximab-dependent suppression of xenograft tumour growth was observed for YCU-H891 cells. Both types of cells expressed EGFR and neither type harboured mutations in signalling molecules downstream of EGFR that have been reported in cetuximab-resistant colon cancer patients. The inhibition of the extracellular signal-regulated kinase (ERK) signalling increased the levels of CXCL14 messenger RNA (mRNA) in HSC-3 cells, but not in YCU-H891 cells. We also observed that the CXCL14 promoter region in YCU-H891 cells was hypermethylated, and that demethylation of the promoter by treatment with 5-aza-2′-deoxycytidine restored CXCL14 mRNA expression and in vivo cetuximab-mediated tumour growth suppression. Finally, we observed in vivo tumour growth suppression when YCU-H891 cells were engineered to express CXCL14 ectopically in the presence of doxycycline. These results indicate that CXCL14 expression may be a good predictive biomarker for cetuximab-dependent tumour suppression.
Highlights
Head and neck cancer is the sixth most common cancer worldwide
As a marker, we investigated whether DNA hypermethylation in YCU-MS861 and YCU-H891 contributes to the tumour-suppressive effect of cetuximab. cells, no expression of CXCL14 messenger RNA (mRNA) was detected, in the we investigated the use of DAC in head and neck squamous cell carcinoma (HNSCC) cells for presence or absence of in vitro cetuximab (Figure 1a, right panel)
We demonstrated that DAC increased Interestingly, YCU-OR891 cells the expression of CXCL14 messenger RNA and enhanced expressed a very small amount of CXCL14, but the level was not the tumour-suppressive effect of cetuximab
Summary
Head and neck cancer is the sixth most common cancer worldwide. Globally ~ 650 000 new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed each year.[1]The use of monoclonal antibodies for cancer therapy has achieved considerable success in recent years.[2,3] One such antibody is cetuximab, which is a human–mouse chimeric monoclonal IgG1 antibody targeted against the epidermal growth factor receptor (EGFR).[1,4,5] Recently, cetuximab has been used to treat patients with colorectal cancer and HNSCC. We demonstrated that DAC increased Interestingly, YCU-OR891 (oral floor carcinoma-derived) cells the expression of CXCL14 messenger RNA (mRNA) and enhanced expressed a very small amount of CXCL14, but the level was not the tumour-suppressive effect of cetuximab.
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