Possible future issues in the treatment of glioblastomas: Special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis

Purpose The present review aims to emphasize that malignant gliomas are characterized by the diffuse invasion of distant brain tissue by a myriad of single migrating cells that exhibit decreased levels of apoptosis (programmed cell death type I), thus a resistance to cytotoxic insult. Methods The present review surveys the molecular mechanisms of migration in malignant gliomas and potential issues arising from treatments, in addition to relationships between glioma cell migration and resistance to apoptosis in terms of the molecular signaling pathways. Results Clinical and experimental data demonstrate that glionna cell migration is a complex combination of multiple molecular processes, including the alteration of tumor cell adhesion to a modified extracellular matrix, the secretion of proteases by the cells, and modifications to the actin cytoskeleton. Intracellular signaling pathways involved in the acquisition of resistance to apoptosis by migrating glionna cells concern PI3K, Akt, mTOR, NF-KB, and autophagy (programmed cell death type II). Conclusion A number of signaling pathways can be constitutively activated in migrating glionna cells, thus rendering these cells resistant to cytotoxic insults. However, these pathways are not all constitutively activated at the same time in any one glioma. Particular inhibitors should therefore only be chosen if the target is present in the tumor tissue, but this is only possible if individual patients are submitted to the molecular profiling of their tumors before undergoing any treatment to combat their migratory glioma cells. Specific antimigratory compounds should be added to conventional radio- and/or chemotherapy. J Clin Oncol 23:2411-2422. (c) 2005 by American Society of Clinical Oncology.