Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase-Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells
2012 (English)In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 10, no 9, 1158-1168 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
American Association for Cancer Research , 2012. Vol. 10, no 9, 1158-1168 p.
National CategoryMedical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-86135DOI: 10.1158/1541-7786.MCR-12-0030ISI: 000310648300003OAI: oai:DiVA.org:liu-86135DiVA: diva2:574938
Funding Agencies|Johan and Jakob Soderberg Foundation||Foundation Olle Engqvist Byggmastare||Swedish Laryng Foundation||Borgholm Rotary Club||Swedish National Board of Health and Welfare||Lions Research Foundation||Lars Hierta Memorial Foundation||Tore Nilsson Foundation for Medical Research||Swedish Society for medical research||County Council of Ostergotland||Cancer Foundation of Ostergotland||Merck Serono||Swedish Research Council|349-2008-6578|Swedish Cancer Society|CAN 2009/1136CAN 2010/545|2012-12-072012-12-072013-11-11