ABSTRACT
High-grade gliomas in patients with neurofibromatosis type 1 are rare and may therefore not be considered in the differential of brain lesions. Here, we describe 5 children with neurofibromatosis type 1; four of them developed various types of high-grade gliomas. The fifth patient had imaging features concerning for a high-grade lesion, but tissue diagnosis showed a low-grade glioma. The cases and literature summary provided here are to raise awareness for the occurrence of high-grade gliomas in children with neurofibromatosis type 1 and the limited ability of imaging features alone to predict a high-grade malignancy.
Subject(s)
Brain Neoplasms/etiology , Brain Neoplasms/pathology , Glioma/etiology , Glioma/pathology , Neurofibromatosis 1/complications , Child , Child, Preschool , Female , Humans , MaleABSTRACT
Recent studies suggest that medulloblastoma, the most common malignant brain tumor of childhood, is comprised of four disease variants. The WIP1 oncogene is overexpressed in Group 3 and 4 tumors, which contain medulloblastomas with the most aggressive clinical behavior. Our data demonstrate increased WIP1 expression in metastatic medulloblastomas, and inferior progression-free and overall survival of patients with WIP1 high-expressing medulloblastoma. Microarray analysis identified upregulation of genes involved in tumor metastasis, including the G protein-coupled receptor CXCR4, in medulloblastoma cells with high WIP1 expression. Stimulation with the CXCR4 ligand SDF1α activated PI-3 kinase signaling, and promoted growth and invasion of WIP1 high-expressing medulloblastoma cells in a p53-dependent manner. When xenografted into the cerebellum of immunodeficient mice, medulloblastoma cells with stable or endogenous high WIP1 expression exhibited strong expression of CXCR4 and activated AKT in primary and invasive tumor cells. WIP1 or CXCR4 knockdown inhibited medulloblastoma growth and invasion. WIP1 knockdown also improved the survival of mice xenografted with WIP1 high-expressing medulloblastoma cells. WIP1 knockdown inhibited cell surface localization of CXCR4 by suppressing expression of the G protein receptor kinase 5, GRK5. Restoration of wild-type GRK5 promoted Ser339 phosphorylation of CXCR4 and inhibited the growth of WIP1-stable medulloblastoma cells. Conversely, GRK5 knockdown inhibited Ser339 phosphorylation of CXCR4, increased cell surface localization of CXCR4 and promoted the growth of medulloblastoma cells with low WIP1 expression. These results demonstrate crosstalk among WIP1, CXCR4 and GRK5, which may be important for the aggressive phenotype of a subclass of medulloblastomas in children.
