Lang, Sven Arke and Brecht, Isabel and Moser, Christian and Obed, Aiman and Batt, David and Schlitt, Hans Juergen and Geissler, Edward Kenneth and Stoeltzing, Oliver (2008) Dual inhibition of Raf and VEGFR2 reduces growth and vascularization of hepatocellular carcinoma in an experimental model. LANGENBECKS ARCHIVES OF SURGERY, 393 (3). pp. 333-341. ISSN 1435-2443,
Full text not available from this repository. (Request a copy)Abstract
Background and aims Activation of the mitogen-activated protein kinase-extracellular-signal-regulated kinase (ERK) pathways plays an important role in the progression of hepatocellular carcinoma (HCC). Importantly, Raf kinases are principal effectors within this oncogenic signaling cascade. We hypothesized that concomitant inhibition of Raf and vascular endothelial growth factor receptor 2 (VEGFR2) will affect tumor growth and angiogenesis of HCC. Materials and methods Human HCC cell lines, endothelial cells (EC), and vascular smooth muscle cells (VSMC) were used. For blocking Raf kinase and VEGFR2, the small molecule inhibitor NVP-AAL881 (Novartis, USA) was used. Activation of signaling intermediates was assessed by Western blotting, and changes in cell motility were evaluated in migration assays. Effects of NVP-AAL881 on HCC growth were determined in a subcutaneous tumor model. Results NVP-AAL881 disrupted activation of ERK and STAT3 in HCC cells and reduced cancer cell motility. In addition, the migration of ECs and VSMC was also significantly impaired. In ECs, HCC-conditioned media-induced activation of STAT3 was diminished by NVP-AAL881 treatment. In vivo, NVP-AAL881 significantly reduced tumor growth, CD31-vessel area, and numbers of BrdU-positive proliferating tumor cells. Conclusions Combined inhibition of Raf and VEGFR2 disrupts oncogenic signaling and efficiently reduces tumor growth and vascularization of HCC. Hence, this strategy could prove valuable for therapy of HCC.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ORTHOTOPIC TUMOR-GROWTH; CANCER; RECEPTOR; CELLS; ANGIOGENESIS; EXPRESSION; ACTIVATOR; ERK; PATHWAYS; BLOCKS; Raf; HCC; STAT3; angiogenesis; tumor growth |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Nov 2020 10:26 |
| Last Modified: | 03 Nov 2020 10:26 |
| URI: | https://pred.uni-regensburg.de/id/eprint/30971 |
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