Abstract
Many in vivo and in vitro studies have demonstrated the targeted migration of neural stem cells (NSC) to infiltrating brain tumors, including malignant glioma, highlighting a potential therapeutic approach. However, there is not enough information to apply this approach to clinical therapy. The most important things in stem cell therapy for brain tumors involve selecting the appropriate neural progenitor type and optimizing the efficiency of the cell engraftment. By histological analysis using two different live-dyes, human NSCs were shown to migrate away from the transplanted site in the direction of the expanding C6 glioma and to intermix with the tumor bed, especially with the tumor core. This intermixing occurred within 7 days when NSCs were implanted into glioma model. The time course of migratory HB1.F5 with the greatest mobility of three NSC lines was as follows. As early as 3 days after transplantation, several NSCs were found leaving the implant site, primarily approaching microsatellites and frontier cells located near the site of NSC implantation. Through 7 days post-transplantation, massive numbers of NSCs continued to be attracted to and interspersed with C6 glioma, and were finally distributed extensively throughout the whole tumor bed, including the core and penumbra of the tumor mass. However, NSCs appeared to penetrate into the tumor mass very well, whereas normal fibroblast cells could not migrate. These findings strengthen the potential for human NSCs as attractive vehicles to improve therapeutic gene delivery to cancer or glioma if they are optimized to selectively kill neoplastic cells.
Highlights
Some malignant brain tumors, such as glioma and glioblastoma, are virtually resistant to current treatments and frequently recur, with a mean survival period of less than a year despite extensive surgical excision, radiation and chemo-therapy (Cho and Klemke, 2000; Mariani et al, 2001)
Many in vivo and in vitro studies have demonstrated that neural stem cells (NSCs) have the unique capacity to migrate throughout the brain and to aggressively target invading tumor cells, such as glioma, highlighting their therapeutic potential (Zhenggang et al, 2004; Khalid et al, 2005)
Consistent with previous reports that showed tumor tropism of murine or human NSCs (Aboody et al, 2000; Kim et al, 2005), these findings suggest that soluble chemotactic factors produced by glioma cells, from the tumor core and from solitary tumor cells infiltrating normal brain tissues, are in part responsible for inducing and guiding NSC migration
Summary
Some malignant brain tumors, such as glioma and glioblastoma, are virtually resistant to current treatments and frequently recur, with a mean survival period of less than a year despite extensive surgical excision, radiation and chemo-therapy (Cho and Klemke, 2000; Mariani et al, 2001). One impediment to eliminating glioma cells by conventional therapy is their exceptional infiltration into surrounding neural tissues, often distinct from primary tumor localization. These microsatellites act as seeds for recurrent tumor growth (Giese et al, 2003). Many in vivo and in vitro studies have demonstrated that neural stem cells (NSCs) have the unique capacity to migrate throughout the brain and to aggressively target invading tumor cells, such as glioma, highlighting their therapeutic potential (Zhenggang et al, 2004; Khalid et al, 2005). The ability of NSC to target glioma cells for delivery of desired product(s) makes NSC a very promising delivery system in gene therapy for brain tumors. NSC- based gene therapy may be stably engrafted in the brain and chase tumor cells that are expanding out while expressing (a) therapeutic transgene product(s) (Kim et al, 2005, 2006)
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