Activation of ERBB4 in glioblastoma can contribute to increased tumorigenicity and influence therapeutic response
| Autor: | Sameer A. Greenall, Lauren T. Kerr, Timothy E. Adams, Naomi W. Alexander, Viviane Tabar, Jacqueline F. Donoghue, Nicholas G. Gottardo, Anthony Longano, Rong Wang, Terrance Grant Johns, Paul S. Mischel |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Angiogenesis EGFR Oncology and Carcinogenesis lcsh:RC254-282 GBM Article Receptor tyrosine kinase 03 medical and health sciences Rare Diseases Growth factor receptor Clinical Research Medicine neoplasms ERBB4 Cancer Messenger RNA therapy Oncogene biology business.industry Neurosciences lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Brain Disorders nervous system diseases Brain Cancer cell_developmental_biology Orphan Drug 030104 developmental biology Oncology 5.1 Pharmaceuticals Cytoplasm Cancer research biology.protein Immunohistochemistry Phosphorylation prognosis business Tyrosine kinase |
| Zdroj: | Cancers, vol 10, iss 8 Cancers, Vol 10, Iss 8, p 243 (2018) Cancers Volume 10 Issue 8 |
| Popis: | Glioblastoma (GBM) is often resistant to conventional and targeted therapeutics. ErbB2 Receptor Tyrosine Kinase 4 (ERBB4) is expressed throughout normal brain and is an oncogene in several pediatric brain cancers therefore, we investigated ERBB4 as a prognostic marker and therapeutic target in GBM. Using RT-qPCR, we quantified mRNA encoding total ERBB4 and known ERBB4 variants in GBM and non-neoplastic normal brain (NNB) samples. Using immunohistochemistry, we characterized the localization of total and phosphorylated ERBB4 (p-ERBB4) and EGFR protein in archived GBM samples and assessed their association with patient survival. Furthermore, we evaluated the effect of ERBB4 phosphorylation on angiogenesis and tumorigenicity in GBM xenograft models. Total ERBB4 mRNA was significantly lower in GBM than NNB samples, with the juxtamembrane JM-a and cytoplasmic CYT-2 variants predominating. ERBB4 protein was ubiquitously expressed in GBM but was not associated with patient survival. However, high p-ERBB4 in 11% of archived GBM samples, independent of p-EGFR, was associated with shorter patient survival (12.0 ± 3.2 months) than was no p-ERBB4 (22.5 ± 9.5 months). Increased ERBB4 activation was also associated with increased proliferation, angiogenesis, tumorigenicity and reduced sensitivity to anti-EGFR treatment in xenograft models. Despite low ERBB4 mRNA in GBM, the functional effects of increased ERBB4 activation identify ERBB4 as a potential prognostic and therapeutic target. |
| Databáze: | OpenAIRE |
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