Cancer-associated fibroblasts induce matrix metalloproteinase-mediated cetuximab resistance in head and neck squamous cell carcinoma cells.
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.
Division of Otorhinolaryngology and Head and Neck Surgery, Department of Clinical and Experimental Medicine, Linköping University, Linköping SE-581 85, Sweden. ann-charlotte.johansson@liu.se
Ann-Charlotte
AC
Johansson
Anna
A
Ansell
Fredrik
F
Jerhammar
Maja Bradic
MB
Lindh
Reidar
R
Grénman
Eva
E
Munck-Wikland
Arne
A
Östman
Karin
K
Roberg
D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000068818:Cetuximab; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D005347:Fibroblasts / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D034622:RNA Interference; D012334:RNA, Neoplasm / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D014407:Tumor Cells, Cultured
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D012334:RNA, Neoplasm; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D000068818:Cetuximab