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Blood outgrowth endothelial cell-based systemic delivery of antiangiogenic gene therapy for solid tumors

Cancer Gene Therapy volume 17, pages 855–863 (2010)Cite this article

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Abstract

Endothelial cells and endothelial cell precursors encoding a therapeutic gene have induced antitumor responses in preclinical models. Culture of peripheral blood provides a rich supply of autologous, highly proliferative endothelial cells, also referred to as blood outgrowth endothelial cells (BOECs). The aim of this study was to evaluate a novel antiangiogenic strategy using BOECs expressing fms-like tyrosine kinase-1 (sFlt1) and/or angiostatin–endostatin (AE) fusion protein. Conditioned medium from BOECs expressing sFlt1 or AE suppressed in vitro growth of pulmonary vein endothelial cells by 70% compared with conditioned medium from non-transduced BOEC controls. Reverse transcriptase-PCR analysis indicated that systemically administered BOECs proliferated in tumor tissue relative to other organs in C3(1)SV40 TAG transgenic (C3TAG) mice with spontaneous mammary tumors. Tumor volume was reduced by half in C3TAG mice and in mice bearing established lung or pancreatic tumors in response to the treatment with sFlt1-BOECs, AE-BOECs or their combination. Studies of tumor vascular density confirmed that angiogenic inhibition contributed to slowed tumor growth. In an orthotopic model of glioma, the median survival of mice treated with sFlt1-BOECs was double that of mice receiving no BOEC treatment (P=0.0130). These results indicate that further research is warranted to develop BOECs for clinical application.

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Acknowledgements

We thank The Susan G Komen Breast Cancer Foundation (Grant no. BCTR86006) (AZD) for supporting this research. This work was also supported by grants from the NIH; HL-55552 (RPH), CA109582 (KG), NS055738-01A2 (JRO) and the Dana Foundation (JRO). We thank Julia Nguyen from the Department of Medicine, University of Minnesota for culture and immunophenotyping of blood outgrowth endothelial cells, and Michael J Franklin from the University of Minnesota for editorial review.

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Authors and Affiliations

  1. Division of Hematology, Vascular Biology Center and Department of Medicine, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA

    V Bodempudi, K Terai, K Gupta, R P Hebbel & A Z Dudek

  2. Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA

    J R Ohlfest & E A Zamora

  3. Department of Biostatistics and Bioinformatics, University of Minnesota Masonic Cancer Center, Minneapolis, MN, USA

    R I Vogel

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  1. V Bodempudi
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  2. J R Ohlfest
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  6. K Gupta
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  7. R P Hebbel
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Correspondence to A Z Dudek.

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Competing interests

The University of Minnesota and RPH own a patent on the BOEC culture technology used in this research, but there is no current financial interest.

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Bodempudi, V., Ohlfest, J., Terai, K. et al. Blood outgrowth endothelial cell-based systemic delivery of antiangiogenic gene therapy for solid tumors. Cancer Gene Ther 17, 855–863 (2010). https://doi.org/10.1038/cgt.2010.42

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