Mesenchymal stem cells (MSCs) have been expected to become useful gene delivery vehicles against human malignant gliomas when coupled with an appropriate vector system, because they migrate towards the lesion. Human artificial chromosomes (HACs) are non-integrating vectors with several advantages for gene therapy, namely, no limitations on the size and number of genes that can be inserted. We investigated the migration of human immortalized MSCs bearing a HAC vector containing the herpes simplex virus thymidine kinase gene (HAC-tk-hiMSCs) towards malignant gliomas in vivo. Red fluorescence protein-labeled human glioblastoma HTB14 cells were implanted into a subcortical region in nude mice. Four days later, green fluorescence protein-labeled HAC-tk-hiMSCs were injected into a contralateral subcortical region (the HTB14/HAC-tk-hiMSC injection model). Tropism to the glioma mass and the route of migration were visualized by fluorescence microscopy and immunohistochemical staining. HAC-tk-hiMSCs began to migrate toward the HTB14 glioma area via the corpus callosum on day 4, and gathered around the HTB14 glioma mass on day 7. To test whether the delivered gene could effectively treat glioblastoma in vivo, HTB14/HAC-tk-hiMSC injected mice were treated with ganciclovir (GCV) or PBS. The HTB14 glioma mass was significantly reduced by GCV treatment in mice injected with HAC-tk-hiMSCs. It was confirmed that gene delivery by our HAC-hiMSC system was effective after migration of MSCs to the glioma mass in vivo. Therefore, MSCs containing HACs carrying an anticancer gene or genes may provide a new tool for the treatment of malignant gliomas and possibly of other tumor types.
The effect of hypoxia on glioma growth including pathological changes was investigated in an experimental model of brain ischemia in the rat C6 glioma model. C6 glioma cells were inoculated into the subcortex of adult Wistar rats. Focal cerebral ischemia near the implanted glioma area was induced by permanent middle cerebral artery occlusion (PMCAO). Ten days later, the rats were sacrificed to compare tumor volume of C6 glioma without PMCAO (control group) versus C6 glioma with PMCAO (hypoxia group). The histological features were also observed. The mean tumor volume in the hypoxia group was significantly larger than that in the control group. The most prominent histological finding in the hypoxia group was abundant formation of pseudopalisading around the necrotic areas. Immunohistological examinations showed intensive staining for vascular endothelial growth factor and hypoxia-inducible factor in these pseudopalisading cells. These findings suggest that cerebral ischemia positively modulates glioma mass growth by the formation of pseudopalisading necrosis, a characteristic histological finding of glioblastoma.
The advantage of the intracarotid injection route is the absence of an operative scar in the cranium. This established animal model is a novel model of primary diffuse leptomeningeal gliomatosis. This model probably can be used for pre-clinical testing in the progression of glioblastoma.
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