Anti-VEGFR2 driven nuclear translocation of VEGFR2 and acquired malignant hallmarks are mutation dependent in glioblastoma
| Autor: | Isk, Bhagelu R. Achyut, er Asm, Ali S. Arbab, Meenu Jain, Adarsh Shankar, Syed A Arbab, Roxan Ara, Mei Jing Lim, Kartik Angara |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Pathology medicine.medical_specialty Vatalanib medicine.medical_treatment Cancer Chromosomal translocation Cell cycle Biology medicine.disease In vitro Article Targeted therapy 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology Apoptosis 030220 oncology & carcinogenesis medicine Cancer research Immunohistochemistry |
| Popis: | Objective: Anti-Angiogenic Therapies (AATs), targeting VEGF-VEGFR pathways, are being used as an adjuvant to normalize Glioblastoma (GBM) vasculature. Unexpectedly, clinical trials have witnessed transient therapeutic effect followed by aggressive tumor recurrence. In pre-clinical studies, targeting VEGFR2 with vatalanib, increased GBM growth under hypoxic microenvironment. There is limited understanding of these unanticipated results. Here, we investigated tumor cell associated phenotypes in response to VEGFR2 blockade. Methods: Human U251 cells were orthotopically implanted in mice (day 0) and were treated with vehicle or vatalanib on day 8. Tumor specimens were collected for immunohistochemistry and protein array. Nuclear translocation of VEGFR2 was analyzed through IHC and western blot. In vitro studies were performed in U251 (p53 and EGFR mutated) and U87 (p53 and EGFR wild type) cells following vehicle or vatalanib treatments under normoxia (21% O2) and hypoxia (1% O2). Proliferation, cell cycle and apoptosis assays were done to analyze tumor cell phenotypes after treatments. Results: Vatalanib treated animals displayed distinct patterns of VEGFR2 translocation into nuclear compartment of U251 tumor cells. In vitro studies suggest that vatalanib significantly induced nuclear translocation of VEGFR2, characterized in chromatin bound fraction, especially in U251 tumor cells grown under normoxia and hypoxia. Anti-VEGFR2 driven nuclear translocation of VEGFR2 was associated with increased cell cycle and proliferation, decreased apoptosis, and displayed increased invasiveness in U251 compared to U87 cells. Conclusion: Study suggests that AAT-induced molecular and phenotypic alterations in tumor cells are associated with mutation status and are responsible for aggressive tumor growth. Therefore, mutation status of the tumor in GBM patients should be taken in to consideration before applying targeted therapy to overcome unwanted effects. |
| Databáze: | OpenAIRE |
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