Abstract: Current therapies for glioblastoma multiforme (GBM) are directed against the tumor mass: the part of the tumor that elicits clinical manifestations. Insights into the biology of this tumor (such as the over-expression of growth factor receptor tyrosine kinases and angiogenesis) have led to novel therapies, which are now in clinical trials. However, to date there are no therapies directed against the invasive GBM population, which is causative of the inevitable recurrence of the tumor. To specifically impact these motile cells, it is necessary to understand not only the mechanisms of GBM invasion, but also how their interaction with the microenvironment may influence invasion. Gene expression profiling was used to define transcriptional differences between invasive glioma cells and the tumor core from which they originated. Genes up-regulated with invasion showed a heightened cellular commitment to motility and invasion, they also contained genes that encode proteins involved in CNS development, such as axonal guidance molecules (ephrin ligand B3, netrin 4) and oligodendrocyte differentiation (autotaxin). Autotaxin (ATX) is an autocrine motility factor that is expressed in various invasive cancers including invasive glioma cells in vivo. GBM secreted ATX promotes glioma invasion in vitro and results in increased cellular adhesion, these effects vary with the level of LPA receptors expressed in the cell. The catalytic activity of GBM derived ATX has a weak pro-adhesive effect on normal human astrocytes, whereas it is disadhesive to oligodendrocytes. Furthermore, GBM cells secreting ATX either constitutively or from a transgene, are able to permeate an oligodendrocyte monolayer, suggesting that ATX may be a factor that facilitates glioma invasion by acting on cells in the brain parenchyma. The expression of ATX can be seen as an example of dual signaling by the invading tumor cell: the first, an autocrine motility stimulation; the second, a paracrine signal to the cells in the path of invasion. The study of proteins capable of signaling to both invading cells and the invaded cellular parenchyma may lead to insights helpful in the management of invasive tumors.