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
.