Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes
| Autor: | Edward K. Geissler, Christian Moser, Hans J. Schlitt, Akira Mori, Philipp Schachtschneider, Christina Hackl, Sven A. Lang, Oliver Stoeltzing, David Bryant Batt, Andreas Gaumann |
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| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
Male Cancer Research medicine.medical_specialty Mice Nude Antineoplastic Agents Biology Metastasis Mice Pancreatic tumor Cell Movement Pancreatic cancer Internal medicine Cell Line Tumor Survivin medicine Animals Humans Neoplasm Metastasis Protein kinase B Neovascularization Pathologic Cancer Endothelial Cells Kinase insert domain receptor medicine.disease Isoquinolines Vascular Endothelial Growth Factor Receptor-2 Pancreatic Neoplasms Endocrinology Oncology Cancer research raf Kinases Pericytes Signal Transduction |
| Zdroj: | Molecular cancer therapeutics. 7(11) |
| ISSN: | 1535-7163 |
| Popis: | The Ras/Raf/MEK pathway represents an important oncogenic signaling pathway in gastrointestinal malignancies, including pancreatic cancer. Although activating B-Raf mutations are infrequent in pancreatic cancer, we hypothesized that targeting Raf could be valuable for therapy of this cancer entity. Moreover, as vascular endothelial growth factor receptor 2 (VEGFR2) is involved in tumor angiogenesis, we sought to investigate the effects of dual inhibition of Raf and VEGFR2 on pancreatic tumor growth, vascularization, and metastasis. Effects of a Raf/VEGFR2 inhibitor (NVP-AAL881) on pancreatic cancer cells, endothelial cells, and vascular smooth muscle cells were determined by Western blotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, and migration assays, respectively. Changes in the expression of VEGF-A or survivin were investigated by ELISA and/or real-time PCR. The growth-inhibitory effects of Raf/VEGFR2 inhibition were additionally evaluated in orthotopic tumor models. Results showed that various Raf isoforms were activated in pancreatic cancer cells and NVP-AAL881 diminished the activation of MEK, Akt, Erk, and also STAT3. Moreover, dual inhibition of Raf/VEGFR2 significantly reduced VEGF expression and impaired cancer cell migration. Importantly, besides blocking VEGF-induced Erk and SAPK phosphorylation in endothelial cells, the Raf inhibitor diminished STAT3 phosphorylation, independent of a VEGFR2 blockade, and reduced the expression of survivin. In addition, cell proliferation and migration of both endothelial cells and vascular smooth muscle cells were significantly reduced. In vivo, blocking Raf/VEGFR2 significantly inhibited orthotopic tumor growth and vascularization and reduced cancer metastasis. In conclusion, blocking Raf exerts growth-inhibitory effects on pancreatic tumor cells, endothelial cells, and pericytes and elicits antiangiogenic properties. Dual targeting of Raf and VEGFR2 appears to be a valid strategy for therapy of pancreatic cancer. [Mol Cancer Ther 2008;7(11):3509–18] |
| Databáze: | OpenAIRE |
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