Lang, Sven A. and Schachtschneider, Philipp and Moser, Christian and Mori, Akira and Hackl, Christina and Gaumann, Andreas and Batt, David and Schlitt, Hans J. and Geissler, Edward K. and Stoeltzing, Oliver (2008) 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. MOLECULAR CANCER THERAPEUTICS, 7 (11). pp. 3509-3518. ISSN 1535-7163, 1538-8514
Full text not available from this repository. (Request a copy)Abstract
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-yi)-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 block-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]
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SMOOTH-MUSCLE-CELLS; ACTIVATED PROTEIN-KINASE; FACTOR-I; K-RAS; PHOSPHATIDYLINOSITOL 3-KINASE; THERAPEUTIC TARGET; SIGNALING PATHWAY; TYROSINE KINASES; CARCINOMA CELLS; AUTOCRINE LOOP; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 21 Oct 2020 07:16 |
| Last Modified: | 21 Oct 2020 07:16 |
| URI: | https://pred.uni-regensburg.de/id/eprint/30128 |
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