The p75 neurotrophin receptor is a central regulator of glioma invasion

The invasive nature of cancers in general, and malignant gliomas in particular, is a major clinical problem rendering tumors incurable by conventional therapies. Using a novel invasive glioma mouse model established by serial in vivo selection, we identified the p75 neurotrophin receptor (p75^NTR) as a critical regulator of glioma invasion. Through a series of functional, biochemical, and clinical studies, we found that p75^NTR dramatically enhanced migration and invasion of genetically distinct glioma and frequently exhibited robust expression in highly invasive glioblastoma patient specimens. Moreover, we found that p75^NTR-mediated invasion was neurotrophin dependent, resulting in the activation of downstream pathways and producing striking cytoskeletal changes of the invading cells. These results provide the first evidence for p75^NTR as a major contributor to the highly invasive nature of malignant gliomas and identify a novel therapeutic target.