Identification of Gliotropic Factors That Induce Human Stem Cell Migration to Malignant Tumor

Abstract

Neural stem cells are mobile, are attracted to regions of brain damage, and can migrate a considerable distance to reach a glioma site. However, the molecular basis of the progression of gliotropism to malignant gliomas remains poorly understood. With the use of clinically and histologically assessed glioma cells, we have assessed their protein and gene profiles via proteomics and microarray approaches, and have identified candidate genes from human glioma tissues. This research is expected to provide clues to the molecular mechanisms underlying the migration of neural stem cells (F3 cell) to glioma sites. The expression of 16 proteins was shown to have increased commonly in human glioma tissues. Among them, the expression of annexin A2, TIMP-1, COL11A1, bax, CD74, TNFSF8, and SPTLC2 were all increased in human glioma cells, as confirmed by Western blotting and immunohistochemical staining. In particular, annexin A2 effects an increase in migration toward F3 and glioblastoma cells (U87 cell) in a Boyden chamber migration assay. An ERK inhibitor (PD98057) and a CDK5 inhibitor (rescovitine) inhibited 50% and 90% of annexin A2-induced migration in F3 cells, respectively. A similar chemotactic migration was noted in F3 and U87 cells. These results demonstrated that 7 candidate proteins may harbor a potential glioma tropism factor relevant to the pathology of malignant glioma. These results reveal that this novel molecular approach to the monitoring of glioma may provide clinically relevant information regarding tumor malignancy, and should also prove appropriate for high-throughput clinical screening applications.

p39, the Primary Activator for Cyclin-dependent Kinase 5 (Cdk5) in Oligodendroglia, Is Essential for Oligodendroglia Differentiation and Myelin Repair

“…Further delineating molecular mechanisms that control p35 and p39 expression may allow differential and independent manipulation of Cdk5 function in neuronal and glial lineages during normal development as well as in the pathogenesis of brain disorders involving cell type-specific Cdk5 dysregulation, such as neuronal degeneration in Alzheimer disease and glioma tumorigenesis (38,54,55). In particular, identification of OLspecific mechanisms that control p39 expression may ultimately help to develop novel strategies to advance CNS myelinogenesis in numerous disorders for which the pathogenic impacts of myelin impairment have become increasingly recognized, represented by multiple sclerosis and schizophrenia (1).…”

Therapeutic cell carriers: a potential road to cure glioma

“…This ability of NSCs to migrate to brain tumors has been demonstrated in primary brain tumors, such as gliomas, medulloblastomas and neuroblastomas, as well as brain metastases from breast cancer and melanoma. Although the exact mechanism governing the migration of NSCs is not completely understood, cytokines and other factors produced in the tumor microenvironment, such hypoxia-inducible factor-1a, HGF/c-MET and VEGF/VEGFR, have been shown to act as chemoattractants for NSCs [17].…”

Neural Stem Cells as Therapeutic Delivery Vehicles for Malignant Brain Tumors

“…A large-scale screen to examine the factors expressed by tumor cells with a role in inducing NSC migration would be very benefi cial to identify novel mechanisms involved in NSC tumor-tropism. An et al utilized such a strategy assessing protein and gene expression profi les of a panel of tumor cells and identifi ed tumor-derived Annexin A2 as a potential inducer of NSC migration [ 40 ].…”