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Human stem cells expressing novel TSP-1 variant have anti-angiogenic effect on brain tumors

Oncogene volume 29, pages 3185–3195 (2010)Cite this article

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Abstract

Novel therapeutic agents combined with innovative modes of delivery and non-invasive imaging of drug delivery, pharmacokinetics and efficacy are crucial in developing effective clinical anticancer therapies. In this study, we have created and characterized multiple novel variants of anti-angiogenic protein thrombospondin (aaTSP-1) that comprises unique regions of three type-I-repeats of TSP-1 and used engineered human neural stem cells (hNSC) to provide sustained on-site delivery of secretable aaTSP-1 to tumor-vasculature. We show that hNSC-aaTSP-1 has anti-angiogenic effect on human brain and dermal microvascular endothelial cells co-cultured with established glioma cells and CD133+ glioma-initiating cells. Using human glioma cells and hNSC engineered with different combinations of fluorescent and bioluminescent marker proteins and employing multi-modality imaging techniques, we show that aaTSP-1 targets the vascular-component of gliomas and a single administration of hNSC-aaTSP-1 markedly reduces tumor vessel-density that results in inhibition of tumor-progression and increased survival in mice bearing highly malignant human gliomas. We also show that therapeutic hNSC do not proliferate and remain in an un-differentiated state in the brains of glioma-bearing mice. This study provides a platform for accelerated development of future cell-based therapies for cancer.

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Acknowledgements

This work was supported by American Cancer Society (KS), Goldhirsh foundation (KS), Alliance for Cancer Gene Therapy (KS), P50 CA86355 (KS, RW), R21CA131980 (KS). We thank Dr Rainer Koehler for his help with intravital microscopy and Dr Claudio Vinegoni for his help with processing images. We also thank Dr Jack Lawler (Beth Israel Deaconess Hospital, Boston) for providing us with TSP-1 cDNA construct and Dr Paul van Bergen en Henegouwen (Utrecht University, The Netherlands) for his constructive comments.

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Author notes

  1. M van Eekelen and L S Sasportas: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    M van Eekelen, L S Sasportas, R Kasmieh & K Shah

  2. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    M van Eekelen, L S Sasportas, R Kasmieh, J-L Figueiredo, R Weissleder & K Shah

  3. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    D N Louis & K Shah

  4. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    S Yip & D N Louis

  5. MGH-Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    S Yip & D N Louis

  6. Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    J-L Figueiredo & R Weissleder

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  1. M van Eekelen
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Correspondence to K Shah.

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van Eekelen, M., Sasportas, L., Kasmieh, R. et al. Human stem cells expressing novel TSP-1 variant have anti-angiogenic effect on brain tumors. Oncogene 29, 3185–3195 (2010). https://doi.org/10.1038/onc.2010.75

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