In addition, CXCL12 may promote the survival of NSPCs

as an alternative explanation for why more of these cells were detected in the combined treatment group [45]. No therapeutic effect of NSPC transplantation alone BIBW2992 concentration on brain tumors was observed in the present study. This may be due to only a few NSPCs migrating toward sites of ENU-induced brain tumors with low or undetectable CXCL12 levels to exert tumor-inhibitory functions (Figure 3). Stronger CXCL12 and CXCR4 expressions were detected in the CXCL12-NSPC group than in the CXCL12-only group (Figure 3, CXCL12 and CXCR4), which may have resulted from the interaction between NSPCs and CXCL12. When the level of CXCL12 is high, it has been shown to act synergistically with NSPCs [46] and [47] to upregulate CXCL12/CXCR4 signaling of astrocytes [48], endothelial cells [49] and [50], and tumor cells [51]. The scarce CXCR4 expression in the CXCL12-only group is probably attributable to CXCL12 alone at the given dose not forming a gradient that was sufficiently strong to attract CXCR4-expressing cells toward tumor sites. In contrast, the combination of CXCL12 and NSPC exerted significant effects in recruiting CXCR4-expressing cells into the tumor, thereby elevating CXCR4 levels at the tumor site. Furthermore, CXCL12 not only elicits migratory responses but also increases the proliferation

buy Crizotinib [10] and CXCR4 expression [46] of grafted NSPCs. The grafted NSPCs would be activated by CXCL12, and the NSPCs may tend to be closely associated Tryptophan synthase with endothelial cells and astrocytes (which express CXCR4), which would support their survival and growth [10], [52] and [53]. This is another possible source of the CXCR4 expression seen in the CXCL12-NSPC group. The chemokine CXCL12 and its cell surface receptor CXCR4 are vital mediators of NSPC migration toward brain tumors. Murine NSPCs inoculated into established intracranial GL26 tumors

have demonstrated significant tumor-specific migration away from the site of inoculation to the proximity of the disseminating tumor cells [54]. Cells that had demonstrated tumor-tracking behavior showed significant staining for CXCR4. In the same study, both murine and human fetal NSPC migration toward tumor-conditioned medium could be impaired by using anti-CXCL12 and anti-CXCR4 neutralizing antibodies. Intravascularly injected murine NSPCs have been shown to migrate to and infiltrate subcutaneous and intracranial glioma tumors in nude mice [55]. CXCL12 expressed by a tumor-derived endothelium may attract NSPCs to migrate to the site of the tumor [53] and [56]. Furthermore, NSPC-to-glioma tropism was increased through up-regulation of CXCR4 on NSPCs and CXCL12 on glioma cells under a hypoxic condition [57]. All of these findings indicate the importance of CXCL12 and CXCR4 in the tumor-specific migration of NSPCs.