ABSTRACT
Glioblastoma (GBM) remains the most common and lethal intracranial tumor. In a comparison of gene expression by A2B5-defined tumor-initiating progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain, we found that the F2R gene encoding PAR1 was differentially overexpressed by A2B5-sorted TPCs isolated from gliomas at all stages of malignant development. In this study, we asked if PAR1 is causally associated with glioma progression. Lentiviral knockdown of PAR1 inhibited the expansion and self-renewal of human GBM-derived A2B5(+) TPCs in vitro, while pharmacological inhibition of PAR 1 similarly slowed both the growth and migration of A2B5(+) TPCs in culture. In addition, PAR1 silencing potently suppressed tumor expansion in vivo, and significantly prolonged the survival of mice following intracranial transplantation of human TPCs. These data strongly suggest the importance of PAR1 to the self-renewal and tumorigenicity of A2B5-defined glioma TPCs; as such, the abrogation of PAR1-dependent signaling pathways may prove a promising strategy for gliomas.
Subject(s)
Brain Neoplasms/genetics , Cell Self Renewal , Glioma/genetics , Neoplastic Stem Cells/metabolism , Receptor, PAR-1/genetics , Adult , Animals , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Cell Survival/genetics , Gangliosides/metabolism , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Glioma/metabolism , Glioma/pathology , Humans , Mice , Neoplastic Stem Cells/pathology , RNA Interference , Receptor, PAR-1/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/genetics , Transplantation, HeterologousABSTRACT
In the central nervous system, neuron generation continues throughout adulthood. This neurogenesis is involved in a continual adaptative process in relation with the environmental complexity. It decreases with age and is reduced in several types of experimental conditions mimicking stress, depression, addiction and neurodegenerative diseases. It may be enhanced after excitotoxic, ischemic or traumatic injuries suggesting a compensatory adaptative response. Available data on this new concept in the field of neurosciences and possible therapeutic relevance are reported.
Subject(s)
Brain/pathology , Brain/physiology , Neurons/pathology , Neurons/physiology , Adolescent , Adult , Brain/anatomy & histology , Brain-Derived Neurotrophic Factor/pharmacology , Cell Movement , Child , Humans , Nervous System Diseases/pathology , Nervous System Diseases/physiopathology , Stem Cell Transplantation , Stem Cells/drug effects , Stem Cells/physiologyABSTRACT
Prior epileptic episodes have been shown to decrease markedly the neuronal damage induced by a second epileptic episode, similar to the tolerance following an episode of mild ischemia. Endogenous neuroprotective effects mediated by various mechanisms have been put forward. This study investigated whether neuroprotection against the excitotoxic damage induced by re-exposure to an epileptic challenge can reflect a change in epileptic susceptibility. Tolerance was elicited in rats by a preconditioning session using intrahippocampal kainic acid (KA) administration followed at 1, 7 and 15-day intervals by a subsequent intraventricular KA injection. The degree of pyramidal cell loss in the vulnerable CA3 subfield contralateral to the KA-injected hippocampus was extensively reduced in animals experiencing KA ventricular administration. This neuroprotection was highly significant 1 and 7 days after injection, but not 15 days after injection. In preconditioned animals, the after-discharge threshold was assessed as an index of epileptic susceptibility. It increased significantly from 1 to 15 days after intrahippocampal KA administration. Finally, an enhancement of neuropeptide Y expression in both non-principal cells and mossy fibers was detected, occurring at the same time as the decrease in epileptic susceptibility. These results provide further evidence of an 'epileptic tolerance' as shown by the substantial neuroprotective effect of a prior episode of epileptic activity upon subsequent epileptic insult and suggest that the prevention of excitotoxic damage after preconditioning results from an endogenous neuroprotective mechanism against hyperexcitability and seizures.
