Malignant gliomas are diffuse and highly invasive tumors arising from glial cells in the central nervous system. Persons with malignant gliomas have a poor prognosis, with an average patient survival rate of less than 1 year. The p75 neurotrophin receptor (p75NTR) is one crucial regulator of glioma invasiveness. Here, Wang et al. investigate the mechanism underlying neurotrophin-mediated tumor invasiveness. Glioma cells expressing either wild-type or cleavage-resistant p75NTR were implanted into mouse brains and, in contrast to typical glioma infiltration, cleavage-resistant p75NTR cells formed well-defined tumors. Furthermore, inhibition of the cleavage enzyme γ-secretase prevented tumor cell invasion and prolonged survival in the mice implanted with wild-type p75NTR cells. In combination with in vitro experiments using patient tumor samples, these studies demonstrate that proteolytic processing of p75NTR is a major mechanism underlying glioma invasiveness and that targeting γ-secretase might be key in preventing the spread of these tumors.
Wang L, Rahn J.J., Lun X., Sun B., Kelly J.J.P., Weiss S., Robbins S.M., Forsyth P.A., Senger D.L. (2008). Gamma-secretase represents a therapeutic target for the treatment of invasive glioma mediated by the p75 neurotrophin receptor. PLoS Biol. 6, e289.
