Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas
| Autor: | Giacomo Manenti, Emanuela Virdis, Paolo G. Casali, Elena Tamborini, Tiziana Negri, Alessandro Gronchi, Silvia Brich, Marta Orsenigo, Silvia Stacchiotti, Silvana Pilotti, Elena Conca, Marco A. Pierotti |
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| Přispěvatelé: | Tamborini, Elena, Virdis, Emanuela, Negri, Tiziana, Orsenigo, Marta, Brich, Silvia, Conca, Elena, Gronchi, Alessandro, Stacchiotti, Silvia, Manenti, Giacomo, Casali, Paolo G., Pierotti, Marco A., Pilotti, Silvana |
| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Cancer Research Blotting Western Immunoblotting Gene Expression PDGFRB Bone Neoplasms Chordomas Signal transduction Receptor tyrosine kinase Growth factor receptor Epidermal growth factor Chordoma Receptor tyrosine kinases (RTKs) Humans Immunoprecipitation In Situ Hybridization Fluorescence Aged PDGFB Phosphoinositide 3-kinase biology Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling Receptor Protein-Tyrosine Kinases Middle Aged Immunohistochemistry Imatinib mesylate Oncology Basic and Translational Investigations biology.protein Cancer research mTOR Female Neurology (clinical) Platelet-derived growth factor receptor Signal Transduction |
| Zdroj: | Neuro-oncology. 12(8) |
| ISSN: | 1523-5866 |
| Popis: | We have previously demonstrated that chordomas express activated platelet-derived growth factor receptor (PDGFRB) and that treatment with imatinib, which is capable of switching off the activation of various receptor tyrosine kinases (RTKs) including PDGFRB, benefits a number of patients. The aim of this study was to identify the possible presence of other activated RTKs and their downstream signaling effectors. Cryopreserved material from 22 naive sporadic chordomas was investigated for the presence of activated RTKs and their cognate ligands and downstream signaling effectors by means of human phospho-RTK antibody arrays, Western blotting, and molecular analysis; immunohistochemistry and fluorescence in situ hybridization were used to analyze the corresponding formalin-fixed and paraffin-embedded samples. We detected activated PDGFRB, FLT3, and colony stimulating factor 1 receptor (CSF1R) of the PDGFR family and highly phosphorylated EGFR, HER2/neu, and (to a lesser extent) HER4 of the EGFR family. The detection of PDGFRB/PDGFB confirmed our previous data. The presence of activated EGFR was paralleled by the finding of high levels of epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha) and PDGFB co-expression and PDGFRB co-immunoprecipitation. Of the downstream effectors, the PI3K/AKT and RAS/MAPK pathways were both activated, thus leading to the phosphorylation of mammalian target of rapamycin (mTOR) and 4E-BP1 among the regulators involved in translational control. Taken together, our results (i) provide a rationale for tailored treatments targeting upstream activated receptors, including the PDGFR and EGFR families; (ii) support the idea that a combination of upstream antagonists and mTOR inhibitors enhances the control of tumor growth; and (iii) indicate that the 4E-BP1/eIF4E pathway is a major regulator of protein synthesis in chordoma. |
| Databáze: | OpenAIRE |
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