Abstract
Hypoxia is a critical aspect of the microenvironment in glioma and generally signifies unfavorable clinical outcome. Effective targeting of hypoxic areas in gliomas remains a significant therapeutic challenge. New therapeutic platforms using neural stem cells (NSC) for tumor-targeted drug delivery show promise in treatment of cancers that are refractory to traditional therapies. However, the molecular mechanisms of NSC targeting to hypoxic tumor areas are not well understood. Therefore, we investigated the role of hypoxia in directed migration of NSCs to glioma and identified the specific signaling molecules involved. Our data showed that hypoxia caused increased migration of human HB1.F3 NSCs to U251 human glioma-conditioned medium in vitro. In HB1.F3 NSCs, hypoxia led to up-regulation of CXCR4, urokinase-type plasminogen activator receptor (uPAR), vascular endothelial growth factor receptor 2 (VEGFR2), and c-Met receptors. Function-inhibiting antibodies to these receptors inhibited the migration of HB1.F3 cells to glioma-conditioned medium. Small interfering RNA knockdown of hypoxia-inducible factor-1alpha in glioma cells blocked the hypoxia-induced migration of NSCs, which was due to decreased expression of stromal cell-derived factor-1 (SDF-1), uPA, and VEGF in glioma cells. Our in vivo data provided direct evidence that NSCs preferentially distributed to hypoxic areas inside intracranial glioma xenografts, as detected by pimonidazole hypoxia probe, as well as to the tumor edge, and that both areas displayed high SDF-1 expression. These observations indicate that hypoxia is a key factor in determining NSC tropism to glioma and that SDF-1/CXCR4, uPA/uPAR, VEGF/VEGFR2, and hepatocyte growth factor/c-Met signaling pathways mediate increased NSC-to-glioma tropism under hypoxia. These results have significant implications for development of stem cell-mediated tumor-selective gene therapies.
Highlights
Malignant gliomas are the most common subtype of primary brain tumors, and glioblastoma multiforme is uniformly fatal with a mean survival of less than 1 year from diagnosis [1]
These data indicate that hypoxia leads to increased migration of neural stem cells (NSC) to glioma cells when U251 target cells only, or NSCs only, or both cell types are exposed to hypoxia, with the latter condition showing the highest NSC migration
We investigated whether HB1.F3 NSCs can target such ‘‘hard-to-reach’’ hypoxic areas in glioma, and if so, which cytokines are responsible for the NSC targeting
Summary
Malignant gliomas (e.g., glioblastoma multiforme) are the most common subtype of primary brain tumors, and glioblastoma multiforme is uniformly fatal with a mean survival of less than 1 year from diagnosis [1]. Radiation, and chemotherapy treatments do not alleviate the poor prognosis of this highly aggressive form of brain cancer, and effective targeting of hypoxic areas in gliomas remains a significant therapeutic challenge [2]. Recent research indicates that neural stem cells (NSC) can target invasive solid tumors, including glioma, and provide a novel platform for targeted delivery of therapeutic agents to tumors, resulting in significant antitumor effect [3, 4]. It is unknown whether NSCs are able to target the hypoxic areas in glioma and which factors induced by hypoxia may be involved in NSC-glioma tropism. We investigate the role of hypoxia and identify the cytokines responsible for directed migration of NSCs to gliomas
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