PTPmu suppresses glioma cell migration and dispersal

¹ Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, Cleveland, OH
² Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, OH
³ Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH
⁴ Department of Neurosurgery, School of Medicine, Case Western Reserve University, Cleveland, OH
⁵ Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, Cleveland, OH; Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH

^* To whom correspondence should be addressed. E-mail: susann.brady-kalnay{at}case.edu.

	Abstract

The cell surface receptor protein tyrosine phosphatase mu (PTPµ) is a homophilic cell adhesion molecule expressed in CNS neurons and glia. Glioblastomas (GBMs) are the highest grade primary brain tumors with astrocytic similarity and are characterized by marked dispersal of tumor cells. PTPµ expression was examined in human GBM, low-grade astrocytoma, and normal brain tissue. These studies revealed a striking loss of PTPµ protein expression in highly dispersive GBMs compared to less dispersive low-grade astrocytomas and normal brain. We hypothesized that PTPµ contributes to contact inhibition of glial cell migration by transducing signals in response to cell adhesion. Therefore, loss of PTPµ 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 PTPµ and exhibited limited migration. However, shRNA-mediated knockdown of PTPµ 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, PTPµ shRNA induced migration and dispersal of U-87 MG cells in the brain slice. Finally, a mouse xenograft model of intracranially injected U-87 MG cells was used. PTPµ shRNA induced morphological heterogeneity in these xenografts. Together, these data suggest that loss of PTPµ in human glioblastomas contributes to tumor cell migration and dispersal, implicating loss of PTPµ in glioma progression.

Key Words: protein tyrosine phosphatase, , PTP-µ, glioblastoma, cell migration, dispersal

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?