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Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

Cancer Gene Therapy volume 18, pages 100–109 (2011)Cite this article

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Abstract

Despite optimal surgery and chemotherapy, the prognosis of ovarian cancer patients remains poor and new treatments are urgently needed. Solid tumors require the formation of new vessels for growth and metastasis. In the present study, we have used soluble vascular endothelial growth factor (sVEGF) receptors sVEGFR-1 and -3, soluble receptors Tie1 and Tie2 and their combinations in an ovarian cancer xenograft model. Human ovarian cancer cells were injected intraperitoneally into nude mice (n=42) and magnetic resonance imaging (MRI) was used for confirming tumors before gene delivery. Treatment with combined AdsVEGFR-1, AdsVEGFR-3 and AdsTie2 significantly decreased the size of the intraperitoneal tumors compared with the controls (AdLacZ; P=0.038) with significantly less microvessels and vascular area. Unexpectedly, treatment with combined AdsTie1 and AdsTie2 led to a dramatic shortening of the survival which was not observed in the groups receiving either of the soluble receptors alone (P=0.031). The only difference to other treatments was liver toxicity observed after the combined Tie receptor treatment. In conclusion, combined inhibition of VEGFR-1, VEGFR-3 and Tie2 pathways was safe and provided efficient therapy for ovarian cancer in mice.

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Acknowledgements

We thank Ms Seija Sahrio, Ms Sari Järveläinen, Ms Tiina Koponen, Ms Anneli Miettinen and Ms Helena Kemiläinen for skilful technical assistance. This study was supported by the Finnish Academy, EU Lymphangiogenomics network (LSHG-CT-2004-503573), Kuopio University Hospital (EVO grant 5185), the Finnish Medical Foundation, the Foundation of Finnish Cancer Institute, the Cancer Foundation of Northern Savo, the Finnish Cultural Foundation of Northern Savo, the Research Foundation of Orion Corporation and the Emil Aaltonen Foundation.

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Authors and Affiliations

  1. Department of Molecular Medicine, AI Virtanen Institute, University of Eastern Finland, Kuopio, Finland

    H Sallinen, M Anttila, J Koponen, I Kholova & S Ylä-Herttuala

  2. Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland

    H Sallinen, M Anttila, K Hämäläinen, I Kholova, V-M Kosma & S Heinonen

  3. Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland

    H Sallinen, M Anttila & S Heinonen

  4. National BIO-NMR Facility, AI Virtanen Institute, University of Eastern Finland, Kuopio, Finland

    O Gröhn

  5. Department of Pathology, Kuopio University Hospital, Kuopio, Finland

    K Hämäläinen, I Kholova & V-M Kosma

  6. Molecular/Cancer Biology Laboratory Biomedicum Helsinki and Haartman Institute, University of Helsinki, Helsinki, Finland

    K Alitalo

  7. Gene Therapy Unit and University Hospital Research Unit, Kuopio, Finland

    S Ylä-Herttuala

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  1. H Sallinen
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Correspondence to S Ylä-Herttuala.

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Sallinen, H., Anttila, M., Gröhn, O. et al. Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice. Cancer Gene Ther 18, 100–109 (2011). https://doi.org/10.1038/cgt.2010.56

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