PTPμ suppresses glioma cell migration and dispersal

The cell-surface receptor protein tyrosine phosphatase mu (PTP mu) is a homophilic cell adhesion molecule expressed in CNS neurons and glia. Glioblastomas (GBMs) are the highest grade of primary brain tumors with astrocytic similarity and are characterized by marked dispersal of tumor cells. PTP mu expression was examined in human GBM, low-grade astrocytoma, and normal brain tissue. These studies revealed a striking loss of PTP mu protein expression in highly dispersive GBMs compared to less dispersive low-grade astrocytomas and normal brain. We hypothesized that PTP mu contributes to contact inhibition of glial cell migration by transducing signals in response to cell adhesion. Therefore, loss of PTP mu may contribute to the extensive dispersal of GBMs. The migration of brain tumor cells was assessed in vitro using a scratch wound assay. Parental U-87 MG cells express PTP mu and exhibited limited migration. However, short-hairpin RNA (shRNA)-mediated knockdown of PTP mu induced a morphological change and increased migration. Next, a brain slice assay replicating the three-dimensional environment of the brain was used. To assess migration, labeled U-87 MG glioma cells were injected into adult rat brain slices, and their movement was followed over time. Parental U-87 MG cells demonstrated limited dispersal in this assay. However, PTP mu shRNA Induced migration and dispersal of U-87 MG cells in the brain slice. Finally, in a mouse xenograft model of intracranially injected U-87 MG cells, PTP mu shRNA induced morphological heterogeneity in these xenografts. Together, these data suggest that loss of PTP mu in human GBMs contributes to tumor cell migration and dispersal, implicating loss of PTP mu in glioma progression. Neuro-Oncology 11, 767778, 2009 (Posted to Neuro-Oncology [serial online], Doc. D08-00201, March 20, 2009. URL http://neuro-oncology.dukejournals.org; DOI: 10.1215/152285172009-019)