Stem cell property epithelial-to-mesenchymal transition is a core transcriptional network for predicting cetuximab (Erbitux™) efficacy in KRAS wild-type tumor cells
| Autor: | Xavier Hernández-Yagüe, Javier A. Menendez, Alejandro Vazquez-Martin, Bernardo Queralt, Cristina Oliveras-Ferraros, Begoña Martin-Castillo, Raquel Guardeño, Luciana Báez, Sílvia Cufí, Joan Brunet |
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| Rok vydání: | 2011 |
| Předmět: |
Epithelial-Mesenchymal Transition
Cetuximab Down-Regulation Antineoplastic Agents Antibodies Monoclonal Humanized medicine.disease_cause Biochemistry Proto-Oncogene Proteins p21(ras) Amphiregulin Cancer stem cell Cell Line Tumor Proto-Oncogene Proteins medicine Humans Gene Regulatory Networks Neoplasms Squamous Cell Epithelial–mesenchymal transition Epidermal growth factor receptor Molecular Biology Vulvar Neoplasms biology CD44 Antibodies Monoclonal CD24 Antigen Cell Biology Actin cytoskeleton ErbB Receptors Hyaluronan Receptors Carcinoma Squamous Cell ras Proteins biology.protein Cancer research Female KRAS medicine.drug |
| Zdroj: | Journal of Cellular Biochemistry. 112:10-29 |
| ISSN: | 0730-2312 |
| Popis: | Beyond a well-recognized effect of KRAS mutations in determining de novo inefficacy of cetuximab (CTX) in metastatic colorectal cancer, we urgently need a biomarker signature for predicting CTX efficacy in KRAS wild-type (WT) tumors. CTX-adapted EGFR gene-amplified KRAS WT tumor cell populations were induced by stepwise-chronic exposure of A431 epidermoid cancer cells to CTX. Genome-wide analyses of 44K Agilent's whole human arrays were bioinformatically evaluated by Gene Set Enrichment Analysis (GSEA)-based screening of the KEGG pathway database. Molecular functioning of CTX was found to depend on: (i) The occurrence of a positive feedback loop on Epidermal Growth Factor Receptor (EGFR) activation driven by genes coding for EGFR ligands (e.g., amphiregulin); (ii) the lack of a negative feedback on mitogen-activated protein kinase (MAPK) activation regulated by dual-specificity phosphatases (e.g., DUSP6) and; (iii) the transcriptional status of gene pathways controlling the epithelial-to-mesenchymal transition (EMT) and its reversal (MET) program (actin cytoskeleton and cell-cell communication-e.g., keratins-focal adhesion signaling-e.g., integrins-and EMT-inducing cytokines - e.g., transforming growth factor-β). Quantitative real-time PCR, high-content immunostaining, and flow-cytometry analyses confirmed that CTX efficacy depends on its ability to promote: (i) Stronger cell-cell contacts by up-regulating the expression of the epithelial markers E-cadherin and occludin; (ii) down-regulation of the epithelial transcriptional repressors Zeb, Snail, and Slug accompanied by restoration of cortical F-actin; and (iii) complete prevention of the CD44(pos)/CD24(neg/low) mesenchymal immunophenotype. The impact of EGFR ligands/MAPK phosphatases gene transcripts in predicting CTX efficacy in KRAS WT tumors may be tightly linked with the ability of CTX to concurrently reverse the EMT status, a pivotal property of migrating cancer stem cells. |
| Databáze: | OpenAIRE |
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