Irradiation and non-lethal hypoxia promote attraction of hematopoietic stem cells towards glioma cells by HIF1-mediated induction of CXCL12

We have previously demonstrated that adult hematopoietic stem and progenitor cells (PC) migrate towards glioma cells in vitro and home to experimental gliomas in vivo, stressing the potential of PC as vectors for a cell-based therapy. We defined stromal cell-derived factor-1 (SDF-1/ CXCL12) that is released by glioma cells as the essential chemokine in this process. Because hypoxia is a critical aspect of the microenvironment of gliomas and irradiation is an essential part of the standard therapy, we aimed to investigate the impact of both on the attraction of PC by glioma cells in vitro. Supernatants of irradiated or hypoxic LNT229 glioma cells lead to enhanced migration of PC. Reporter-assays reveal that the CXCL12-promoter is induced in glioma cells 24h after irradiation at 8 Gy or after culturing at 1% oxygen for 12h. The irradiation- and hypoxia-induced release of CXCL12 depend on the transcription factor hypoxia inducible factor 1-alpha (HIF-1) but not on p53.

As a future perspective, these data suggest that the use of hematopoietic PC as cellular vectors in the treatment of glioblastomas may well be combined with irradiation or other anti-angiogenic therapies leading to tumor-hypoxia.