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Increased VEGF levels induced by anti-VEGF treatment are independent of tumor burden in colorectal carcinomas in mice

Gene Therapy volume 13, pages 1198–1205 (2006)Cite this article

Abstract

Inhibition of vascular endothelial growth factor (VEGF) by gene transfer techniques was effectively applied to control experimental tumor growth, whereas effects on systemic VEGF levels had not been investigated. Therefore, we evaluated the effect of VEGF inhibition by adenoviral-mediated gene delivery of a dominant-negative soluble fragment of FLK-1 (sFlk-1) on systemic VEGF levels, organ-specific VEGF-RNA expression and antitumor efficacy in a murine colorectal cancer (CRC) tumor model. Vector function of AdsFlk-1 was shown by Western blot analysis and transgene expression was documented over a time period of 42 days in the serum of treated mice. Although cell supernatant of CT26 cells contained considerable levels of VEGF, systemic VEGF levels in the serum of tumor-bearing mice remained unaffected. Interestingly, mice that were systemically treated with AdsFlk-1 showed a strong upraise of circulating VEGF, whereas VEGF remained at background levels in the control. Vascular endothelial growth factor was increased not only in tumor bearing but also in healthy, tumor-free mice. Vascular endothelial growth factor determination in liver tissue homogenates showed a 16.5-fold upraise in AdsFlk-1-treated animals as compared to the AdLacZ control. Consecutively, systemic small interfering RNA injection targeted against VEGF reverted elevated VEGF levels almost back to normal levels. In spite of elevated VEGF levels, AdsFlk-1 administration showed significant antitumor effects in a subcutaneous metastatic CRC tumor model. There was no significant correlation between antitumour treatment response and VEGF levels in this model. Collectively, we conclude that the systemic administration of AdsFlk-1 had significant inhibitory effects on metastatic CRC tumor growth in spite of elevated systemic VEGF levels and that VEGF serum concentrations did not correlate to tumor burden and antitumor treatment response in this model.

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Acknowledgements

This study was partly supported by BONFOR and Deutsche Krebshilfe grants to VS. AdsFlk-1 construct was generously provided by R Mulligan, Boston, USA.

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Author notes

  1. W H Caselmann

    Present address: Bavarian State Ministry of the Environment, Public Health and Consumer Protection, Munich, Germany

  2. V Schmitz and H Vilanueva: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine I, University Hospital, Bonn, Germany

    V Schmitz, E Raskopf, T Hilbert, C Dzienisowicz, M Gorschlüter, J Strehl, C Rabe, T Sauerbruch & W H Caselmann

  2. Gene Therapy Unit, University Hospital, Universidad de Navarra, Pamplona, Spain

    H Vilanueva, M Barajas, J Prieto & C Qian

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  1. V Schmitz
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Correspondence to V Schmitz or C Qian.

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Schmitz, V., Vilanueva, H., Raskopf, E. et al. Increased VEGF levels induced by anti-VEGF treatment are independent of tumor burden in colorectal carcinomas in mice. Gene Ther 13, 1198–1205 (2006). https://doi.org/10.1038/sj.gt.3302772

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