Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy. Proc Natl Acad Sci USA

Molecular Neurotherapy and Imaging Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School Boston, MA 02114, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2009; 106(12):4822-7. DOI: 10.1073/pnas.0806647106
Source: PubMed


The poor prognosis of patients with aggressive and invasive cancers combined with toxic effects and short half-life of currently available treatments necessitate development of more effective tumor selective therapies. Mesenchymal stem cells (MSCs) are emerging as novel cell-based delivery agents; however, a thorough investigation addressing their therapeutic potential and fate in different cancer models is lacking. In this study, we explored the engineering potential, fate, and therapeutic efficacy of human MSCs in a highly malignant and invasive model of glioblastoma. We show that engineered MSC retain their "stem-like" properties, survive longer in mice with gliomas than in the normal brain, and migrate extensively toward gliomas. We also show that MSCs are resistant to the cytokine tumor necrosis factor apoptosis ligand (TRAIL) and, when engineered to express secreted recombinant TRAIL, induce caspase-mediated apoptosis in established glioma cell lines as well as CD133-positive primary glioma cells in vitro. Using highly malignant and invasive human glioma models and employing real-time imaging with correlative neuropathology, we demonstrate that MSC-delivered recombinant TRAIL has profound anti-tumor effects in vivo. This study demonstrates the efficacy of diagnostic and therapeutic MSC in preclinical glioma models and forms the basis for developing stem cell-based therapies for different cancers.

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    • "Accordingly, each composite image was subjected to ImageJ particle analysis and the number of mCherry-positive particles per section was plotted. Caspase 3 staining was performed as described (Sasportas et al., 2009) using cleaved caspase-3 antibody (Cell Signaling). The number of caspase 3-positive puncta per tumour foci area was counted in multiple sections using ImageJ measurement tools. "
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    • "These combinations were implanted stereotactically into nude mice brains (3×105 tumor cells/mouse and 6×104 MSCs/mouse) in the following co-ordinates: 2.2 mm lateral from bregma, 2.5 mm ventral from dura on the cranial suture. Mice were imaged for Fluc activity on 1, 3 and 7 days after implantations as previously described [18]. All in vivo procedures were approved by the Subcommittee on Research Animal Care at Massachusetts General Hospital. "
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    • "Tumor-directed migration and incorporation of MSCs have been demonstrated by a number of preclinical studies using both transwell migration assays (in vitro) and animal tumor models (in vivo). The homing capacity of MSCs has been demonstrated with almost all tested human cancer cell lines, including lung cancer,8 malignant glioma,9 breast cancer,10 colon carcinoma,11 pancreatic cancer,12,13 melanoma,14 and ovarian cancer.10 The high frequency of MSC migration and incorporation was observed during in vitro coculture and in vivo xenograft tumors, respectively; these findings were found to be consistent, and were independent of tumor type, immunocompetence, and delivery route of MSCs. "
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