EGFR inhibition promotes an aggressive invasion pattern mediated by mesenchymal-like tumor cells within squamous cell carcinomas
| Autor: | Nicole D. Facompre, Phyllis A. Gimotty, Devraj Basu, Meenhard Herlyn, Kathleen T. Montone, Anil K. Rustgi, Hiroshi Nakagawa, Kati Rasanen, Gregory S. Weinstein, Steven M. Sperry, Arnaud F. Bewley, J. Alan Diehl |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Epithelial-Mesenchymal Transition Cell Oncology and Carcinogenesis Cetuximab Antibodies Monoclonal Humanized Article Antibodies Cell Line Mesoderm Erlotinib Hydrochloride Cell Line Tumor Spheroids Cellular Monoclonal medicine Humans Neoplasm Invasiveness Cell Lineage Epithelial–mesenchymal transition Epidermal growth factor receptor Oncology & Carcinogenesis Humanized Cancer Neoplastic Tumor biology Cadherin Mesenchymal stem cell Carcinoma Pharmacology and Pharmaceutical Sciences Cadherins Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic ErbB Receptors medicine.anatomical_structure Oncology Squamous Cell Gene Expression Regulation Cell culture Immunology Cancer research biology.protein Carcinoma Squamous Cell Quinazolines Cellular Spheroids medicine.drug |
| Zdroj: | Molecular cancer therapeutics, vol 12, iss 10 |
| Popis: | Squamous cell carcinomas (SCC) with an infiltrative invasion pattern carry a higher risk of treatment failure. Such infiltrative invasion may be mediated by a mesenchymal-like subpopulation of malignant cells that we have previously shown to arise from epithelial–mesenchymal transition (EMT) and resist epidermal growth factor receptor (EGFR) targeting. Here, we show that SCCs with infiltrative, high-risk invasion patterns contain abundant mesenchymal-like cells, which are rare in tumors with low-risk patterns. This cellular heterogeneity was modeled accurately in three-dimensional culture using collagen-embedded SCC spheroids, which revealed distinct invasive fronts created by collective migration of E-cadherin–positive cells versus infiltrative migration of individual mesenchymal-like cells. Because EGFR expression by mesenchymal-like cells was diminished in the spheroid model and in human SCCs, we hypothesized that SCCs shift toward infiltrative invasion mediated by this subpopulation during anti-EGFR therapy. Anti-EGFR treatment of spheroids using erlotinib or cetuximab enhanced infiltrative invasion by targeting collective migration by E-cadherin–positive cells while sparing mesenchymal-like cells; by contrast, spheroid invasion in absence of mesenchymal-like cells was abrogated by erlotinib. Similarly, cetuximab treatment of xenografts containing mesenchymal-like cells created an infiltrative invasive front composed of this subpopulation, whereas no such shift was observed upon treating xenografts lacking these cells. These results implicate mesenchymal-like SCC cells as key mediators of the infiltrative invasion seen in tumors with locally aggressive behavior. They further show that EGFR inhibition can promote an infiltrative invasion front composed of mesenchymal-like cells preferentially in tumors where they are abundant before therapy. Mol Cancer Ther; 12(10); 2176–86. ©2013 AACR. |
| Databáze: | OpenAIRE |
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