Neurotrophin receptor p75 regulates the invasiveness of malignant gliomas

Johnston ALM et al. (2007) The p75 neurotrophin receptor is a central regulator of glioma invasion. PLoS Biol 5: e212

The highly invasive nature of malignant gliomas makes them very difficult to treat. To elucidate the underlying mechanism of glioma invasiveness, Johnston et al. used serial in vivo selection to establish a mouse model of the disease. These authors subsequently identified the p75 neurotrophin receptor (p75^NTR) to be a major regulator of glioma invasion and migration. They suggest that this receptor could be targeted to prevent recurrence of malignant gliomas.

The authors isolated a population of invasive cells from a noninvasive human glioma cell line following implantation in immunocompromised mice. After reinjection into a new group of immunocompromised mice, these invasive cells migrated far from the original tumor site and formed tumors with highly infiltrative edges; by contrast, reinjected noninvasive cells resulted in large tumors with well-defined borders. Microarray analyses revealed that p75^NTR was upregulated in the invasive cells and not expressed in tumor cells, and reverse-transcriptase polymerase chain reaction and western blot analysis confirmed that ectopic expression of p75^NTR induced migration and invasion in vitro. Furthermore, upregulation of p75^NTR in glioblastoma cells from various cell lines dramatically increased their invasiveness in vivo. Disruption of the ability of p75^NTR to bind neurotrophin resulted in tumors similar to those derived from noninvasive cells, indicating that p75^NTR-induced invasiveness was neurotrophin-dependent. The authors observed that p75^NTR results in striking actin cytoskeletal rearrangements in invading cells. Analyses of resected human tumors demonstrated that p75^NTR is commonly expressed in glioblastoma multiforme, and that p75^NTR-positive cells migrate at a greater rate than do p75^NTR-negative cells.