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- Title
Human stem cells expressing novel TSP-1 variant have anti-angiogenic effect on brain tumors.
- Authors
van Eekelen, M.; Sasportas, L. S.; Kasmieh, R.; Yip, S.; Figueiredo, J.-L.; Louis, D. N.; Weissleder, R.; Shah, K.
- 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.
- Subjects
MEDICAL research; STEM cells; VASCULAR endothelial growth factors; BRAIN tumors; PHARMACOKINETICS; DRUG delivery systems
- Publication
Oncogene, 2010, Vol 29, Issue 22, p3185
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2010.75