PEX-producing Human Neural Stem Cells Inhibit Tumor Growth in a Mouse Glioma Model

Kim, Seung-Ki; Black, Peter McL.; Kim, Seung Up; Cargioli, Theresa; Sun, Yanping; Al-Hashem, Ruqayyah; Machluf, Marcelle; Carroll, Rona S.

doi:10.1093/neurosurgery/57.2.411

Cited by 43 publications

(55 citation statements)

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“…Injection of NSCs transfected with the PEX gene significantly inhibits proliferation and growth of gliomas by inhibiting angiogenesis in the tumor. 62 Although none of these target proteins have been used in combination, it would be useful to learn whether NSCs that can secrete more than one target protein have additive effects of inhibiting tumor growth.…”

Section: Figmentioning

confidence: 99%

Novel Treatment Strategies for Malignant Gliomas Using Neural Stem Cells

Lim

2009

Neurotherapeutics

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Summary:Recent studies in stem cell biology have refined our understanding of the origin and progression of cancer. Identification and characterization of endogenous neural stem cells (NSCs), especially those in the adult human brain, have inspired new ideas for selectively targeting and destroying malignant gliomas. Gliomas consist of a heterogeneous population of cells, and some of these cells have characteristics of cancer stem cells. These brain tumor stem cells (BTSCs) share certain characteristics with normal NSCs. It is still unclear, however, whether malignant gliomas in human patients originate from these aberrant BTSCs. Nonetheless, the cellular and molecular similarities between BTSCs and normal NSCs suggest a common research landscape underlying both normal and cancer stem cell biology, wherein findings of one field are relevant to the other. Furthermore, the natural tropism of NSCs to gliomas has generated the idea that modified NSCs can deliver modified genes to selectively destroy malignant brain tumor cells, and even BTSCs, while leaving healthy surrounding neurons intact. These studies and others on the basic biology of both BTSCs and NSCs will be crucial to expanding our treatment strategies for malignant gliomas.

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Section: Figmentioning

confidence: 99%

Novel Treatment Strategies for Malignant Gliomas Using Neural Stem Cells

Lim

2009

Neurotherapeutics

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“…These cells showed migration to the tumor boundary and reduced tumor volume by 90% showing decreased angiogenesis. 94 …”

Section: Cellular Vectors Targeting Tumor Vasculaturementioning

confidence: 99%

Gene therapy targeting to tumor endothelium

2006

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Tumor-associated vasculature is a relatively accessible component of solid cancers that is essential for tumor survival and growth, providing a vulnerable target for cancer gene therapy administered by intravenous injection. Several features of tumor-associated vasculature are different from normal vasculature, including overexpression of receptors for angiogenic growth factors, markers of vasculogenesis, upregulation of coagulation cascades, aberrant expression of adhesion molecules and molecular consequences of hypoxia. Many of these differences provide candidate targets for tumor-selective 'transductional targeting' of genetically-or chemically modified vectors and upregulated gene expression can also enable 'transcriptional targeting', regulating tumor endothelia-selective expression of transgenes following nonspecific gene delivery. Tumor vasculature also represents an important site of therapeutic action by the secreted products of antiangiogenic gene therapies that are expressed in non-endothelial cells. In this review we assess the challenges faced and the vectors that may be suitable for gene delivery to exploit these targets. We also overview some of the strategies that have been developed to date and highlight the most promising areas of research.

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“…[7][8][9] In addition, NSCs can target brain metastasis in leptomeningeal medulloblastoma, breast cancer, melanoma and disseminated neuroblastoma. 8,[10][11][12] Therefore, we adopted NSCs as a targeting delivery system for subdural medulloblastomas, which serves as a disseminated tumor model.…”

Section: Introductionmentioning

confidence: 99%

“…13 NSCs that are engineered to express a prodrug-activating enzyme are a particularly safe way to administer gene therapy, because they can kill tumor cells and nearby NSCs in the circumstance of NSCs, should they not cease dividing in vivo. 9 CPT-11 (irinotecan-7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) is a chemotherapeutic agent that is used to treat a wide range of pediatric malignant tumors including medulloblastoma. 14 CPT-11 is activated by carboxylesterases (CE) leading to conversion to SN-38 (7-ethyl-10-hydroxycamptothecin), a topoisomerase I inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic targeting of subdural medulloblastomas using human neural stem cells expressing carboxylesterase

Lim

et al. 2011

Cancer Gene Ther

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The prognosis of medulloblastoma has improved significantly because of advances in multi-modal treatments; however, metastasis remains one of the prognostic factors for a poor outcome and is usually associated with tumor recurrence. We evaluated the migratory potential and therapeutic efficacy of genetically engineered human neural stem cells (NSCs) that encode a prodrug enzyme in the subdural medulloblastoma model. We genetically modified HB1.F3 (F3) immortalized human NSCs to express rabbit carboxylesterase (rCE) enzyme, which efficiently converts the prodrug CPT-11 (Irinotecan) into an active anti-cancer agent (SN-38). To simulate clinical metastatic medulloblastomas, we implanted human medulloblastoma cells into the subdural spaces of nude mice. rCE expressing NSCs (F3.rCE) were labeled with fluorescence magnetic nanoparticle for in vivo imaging. The therapeutic potential of F3.rCE was confirmed using a mouse subdural medulloblastoma model. The majority of intravenously (i.v.) injected, F3.rCE cells migrated to the subdural medulloblastoma site and a small number of F3.rCE cells were found in the lungs, pancreas, kidney and liver. Animals that received F3.rCE cells in combination with prodrug CPT-11 survived significantly longer (median survival: 142 days) than control mice that received F3.rCE cells only (median survival: 80 days, Po0.001) or CPT-11 only (median survival: 118 days, Po0.001). In conclusion, i.v. injected F3.rCE NSCs were able to target subdural medulloblastomas and demonstrate therapeutic efficacy. Our study provides data that supports further investigation of stem-cell-based gene therapy against metastatic medulloblastomas.

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PEX-producing Human Neural Stem Cells Inhibit Tumor Growth in a Mouse Glioma Model

Cited by 43 publications

References 0 publications

Novel Treatment Strategies for Malignant Gliomas Using Neural Stem Cells

Novel Treatment Strategies for Malignant Gliomas Using Neural Stem Cells

Gene therapy targeting to tumor endothelium

Therapeutic targeting of subdural medulloblastomas using human neural stem cells expressing carboxylesterase

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