P50. Role of glioma produced CM1 in the brain tumor tropism of human neural stem cells

Stem cells from various lineages have well known for its migration tendency toward glioma and become attractive vehicles to deliver therapeutic genes to brain tumors. However, which factors and mechanisms work in these functions is not yet known. To identify those factors and mechanisms, we analyzed the brain tumor-specific gene expression profile using microarray analysis. We choose 14 candidate genes, reported to play roles in tumor metastasis, angiogenesis, and cell motility to further experiments. Chemoattract molecule 1 (CM1) is one of them, and highly expressed in malignancy tumors. Real time polymerase chain reaction and Immuno-histochemistry assay results support that. To check possibility of NSC motility reinforcement by CM1, in vitro boyden chamber assay was performed. CM1 dramatically induced the migration of human neural stem cells (NSC) two times as VEGF, previously known chemoattract molecule, did. Interestingly, when CM1 over-expressing cells were transplanted in rat brain, it attracted NSCs, which were transplanted in the same or contra-lateral hemisphere. These migrations were mediated by FAK downstream signaling pathway controlling actin and tubulin dynamics. We prepared cytosine deaminase gene encoding NSC (CD-NSC) line by retrovirus transduction. We explored their therapeutic potential on brain tumor model in the presence of prodrug 5-fluorocytosine (5-FC). CD-NSCs injected to animal that transplanted CM1 over expressing cells mixed with C6 rat glioma cell followed by 5-FC administration for 2 weeks. In more CM1 over-expressing cells were transplanted to the animal, tumor volume was significantly decreased compare less transplanted it. Additionally, many stem cells showed dramatic migratory capacity in much more CM1 over-expressing cell transplanted groups. These results suggest that malignant tumor derived CM1, induce FAK downstream signal pathway, could play an important role in NSC tropism for glioma cells for tumor growth inhibition gene deliver and may provide valuable information for establishment of a new stem cell base cancer therapeutic strategy.