Stem cells from various lineages have been well known for their migration tendency toward glioma and become attractive vehicles to deliver therapeutic genes to brain tumors. However, which factors and mechanisms in these processes are not yet known. In the present study, I aimed at identifying the chemoattractant molecules which induce the tropism of human neural stem cell (hNSC) for brain tumor and characterizing their mode of mechanisms. For this, I performed microarray analyses of different type of brain tumors and identified 14 secretory proteins that were highly and specifically expressed in brain tumors. Real-time PCR assay and immunohistochemistry with various brain tumor samples showed that periostin (POSTN) among these factors, known for its role in angiogenesis and invasion during tumor development, was specifically expressed only in glioblastoma multiforms, malignancty tumors. We are also found that a recombinant human POSTN promoted migration of hNSCs in vitro with 3 times higher potency than VEGF. Transplantation of NIH3T3 cells in a rat brain expressing a secretable POSTN in one cerebral hemisphere induced migration of NSCs that were inoculated in the contralateral of hemisphere. We found that POSTN bound to integrin alphaV beta5 complex in NSCs promoted phosphorylation of focal adhesion kinase (FAK) and protein kinase B (AKT) through activation of the phosphorinositide 3-kinase (PI3K) pathway. Inhibition of CDK5 but not ERK suppress that signaling dramatically impaired the migration of hNSCs toward POSTN. NSC use similar signaling pathway during CNS development and glioma invasion
Previous study demonstrated that hNSCs (F3.CD) that were retrovirally transduced with cytosine deaminase (CD) gene showed remarkable bystander effects on the glioma cells after application of the prodrug, 5-fluorocytosine (5-FC). To harness the chemotactic ability of POSTN as a tool to induce a strong bystander killer effect of brain tumors, we established the brain tumor animal model which was implanted with C6 cells and the increasing number of POSTN-overexpressing cells, and F3.CD cells were injected into the contralateral hemisphere followed by systemic 5-FC administration. Interestingly, increasing number of POSTN-overexpressing cells resulted in significant reduced tumor volumes, but not tumor cell numbers. While many tumor cells scattered around the original transplantation site in control tumor group, scattered cells became disappeared with increasing number of POSTN-releasing cells. This result demonstrated that the more POSTN was released, the faster hNSC migrated, which resulted in much NSCs at tumor site and more clearance of tumor cells. Taken together, POSTN treatment combined with bystander killer effect of NSCs might have strong therapeutic potential against aggressively invasive gliomas.
