Spatiotemporal differences in CXCL12 expression and cyclic AMP underlie the unique pattern of optic glioma growth in neurofibromatosis type 1.

Astrocytoma (glioma) formation in neurofibromatosis type 1 (NF1) occurs preferentially along the optic pathway during the first decade of life. The molecular basis for this unique pattern of gliomagenesis is unknown. Previous studies in mouse Nf1 optic glioma models suggest that this patterning results from cooperative effects of Nf1 loss in glial cells and the action of factors derived from the surrounding Nf1+/- brain. Because CXCL12 is a stroma-derived growth factor for malignant brain tumors, we tested the hypothesis that CXCL12 functions in concert with Nf1 loss to facilitate NF1-associated glioma growth. Whereas CXCL12 promoted cell death in wild-type astrocytes, it increased Nf1-/- astrocyte survival. This increase in Nf1-/- astrocyte survival in response to CXCL12 was due to sustained suppression of intracellular cyclic AMP (cAMP) levels. Moreover, the ability of CXCL12 to suppress cAMP and increase Nf1-/- astrocyte survival was a consequence of mitogen-activated protein/extracellular signal-regulated kinase kinase-dependent inhibition of CXCL12 receptor (CXCR4) desensitization. In support of an instructive role for CXCL12 in facilitating optic glioma growth, we also show that CXCL12 expression along the optic pathway is higher in infant children and young mice and is associated with low levels of cAMP. CXCL12 expression declines in multiple brain regions with increasing age, correlating with the age-dependent decline in glioma growth in children with NF1. Collectively, these studies provide a mechanism for the unique pattern of NF1-associated glioma growth.

[1]  D. Gutmann,et al.  Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth. , 2007, Human molecular genetics.

[2]  D. Piwnica-Worms,et al.  Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo. , 2007, Cancer research.

[3]  D. Gutmann,et al.  Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation , 2005, Development.

[4]  N. Warrington,et al.  Widespread CXCR4 activation in astrocytomas revealed by phospho-CXCR4-specific antibodies. , 2005, Cancer research.

[5]  D. Gutmann,et al.  Neurofibromatosis type 1 — a model for nervous system tumour formation? , 2005, Nature Reviews Cancer.

[6]  D. Gutmann,et al.  Natural history of neurofibromatosis 1–associated optic nerve glioma in mice , 2005, Annals of neurology.

[7]  D. Gutmann,et al.  Glioma formation in neurofibromatosis 1 reflects preferential activation of K-RAS in astrocytes. , 2005, Cancer research.

[8]  Marc G Caron,et al.  Desensitization of G protein-coupled receptors and neuronal functions. , 2004, Annual review of neuroscience.

[9]  R. Klein,et al.  Immune and nervous system CXCL12 and CXCR4: parallel roles in patterning and plasticity. , 2004, Trends in immunology.

[10]  K. Black,et al.  Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. , 2004, Neoplasia.

[11]  David A. Davis,et al.  Differential processing of stromal-derived factor-1α and stromal-derived factor-1β explains functional diversity , 2004 .

[12]  Jialin C. Zheng,et al.  Stromal cell‐derived factor 1‐mediated CXCR4 signaling in rat and human cortical neural progenitor cells , 2004, Journal of neuroscience research.

[13]  Toshio Matsuda,et al.  Astrocyte apoptosis: implications for neuroprotection , 2004, Progress in Neurobiology.

[14]  D. Gutmann,et al.  Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. , 2003, Cancer research.

[15]  David A. Williams,et al.  Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/– mast cells , 2003 .

[16]  J. Serratosa,et al.  High‐yield isolation of murine microglia by mild trypsinization , 2003, Glia.

[17]  C. James,et al.  Molecular analysis of astrocytomas presenting after age 10 in individuals with NF1 , 2003, Neurology.

[18]  Andrew L Kung,et al.  A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  D. Gutmann,et al.  The Neurofibromatosis 1 Gene Product Neurofibromin Regulates Pituitary Adenylate Cyclase-Activating Polypeptide-Mediated Signaling in Astrocytes , 2003, The Journal of Neuroscience.

[20]  J. Eccleston,et al.  The mechanism of Ras GTPase activation by neurofibromin. , 2003, Biochemistry.

[21]  David A. Williams,et al.  Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells. , 2003, The Journal of clinical investigation.

[22]  M. Rao,et al.  Microarray analysis of selected genes in neural stem and progenitor cells , 2002, Journal of neurochemistry.

[23]  M. L. de Ceballos,et al.  Cannabinoids Protect Astrocytes from Ceramide-induced Apoptosis through the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway* , 2002, The Journal of Biological Chemistry.

[24]  D. Gutmann,et al.  Astrocyte-Specific Inactivation of the Neurofibromatosis 1 Gene (NF1) Is Insufficient for Astrocytoma Formation , 2002, Molecular and Cellular Biology.

[25]  M. Tatagiba,et al.  Loss of NF1 Alleles Distinguish Sporadic from NF1‐Associated Pilocytic Astrocytomas , 2001, Journal of neuropathology and experimental neurology.

[26]  R. Klein,et al.  SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. , 2001, Development.

[27]  Karlyne M. Reilly,et al.  Neurofibromatosis 1 (NF1) heterozygosity results in a cell‐autonomous growth advantage for astrocytes , 2001, Glia.

[28]  R. Klein,et al.  SDF-1 α induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells , 2001 .

[29]  D. Gutmann,et al.  Loss of neurofibromatosis 1 (NF1) gene expression in NF1‐associated pilocytic astrocytomas , 2000, Neuropathology and applied neurobiology.

[30]  M. Pešić,et al.  Inhibition of Cell Growth and Proliferation in Human Glioma Cells and Normal Human Astrocytes Induced by 8-Cl-cAMP and Tiazofurin , 2000, Nucleosides, nucleotides & nucleic acids.

[31]  J L Benovic,et al.  Regulation of G protein-coupled receptor kinases. , 2000, Trends in cardiovascular medicine.

[32]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[33]  Julie A. Pitcher,et al.  Feedback Inhibition of G Protein-coupled Receptor Kinase 2 (GRK2) Activity by Extracellular Signal-regulated Kinases* , 1999, The Journal of Biological Chemistry.

[34]  S. Mundell,et al.  Trafficking of the HIV Coreceptor CXCR4 , 1999, The Journal of Biological Chemistry.

[35]  D. Holtzman,et al.  Differential Effects of cAMP in Neurons and Astrocytes , 1999, The Journal of Biological Chemistry.

[36]  A. Guha,et al.  Neurofibromatosis type 1 peripheral nerve tumors: aberrant activation of the Ras pathway. , 1999, Surgical neurology.

[37]  A. Guha.  Ras Activation in Astrocytomas and Neurofibromas , 1998, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[38]  S. Burchill,et al.  Contrasting levels of p21 ras activation and expression of neurofibromin in peripheral primitive neuroectodermal tumour and neuroblastoma cells, and their response to retinoic acid , 1998, Journal of the Neurological Sciences.

[39]  J. Benovic,et al.  The role of receptor kinases and arrestins in G protein-coupled receptor regulation. , 1998, Annual review of pharmacology and toxicology.

[40]  J. Gusella,et al.  Rescue of a Drosophila NF1 mutant phenotype by protein kinase A. , 1997, Science.

[41]  Y. Zhong,et al.  Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuropeptides. , 1997, Science.

[42]  D. Louis,et al.  Optic pathway gliomas in children with neurofibromatosis 1: Consensus statement from the nf1 optic pathway glioma task force , 1997 .

[43]  M. Caron,et al.  G-protein-coupled receptor regulation: role of G-protein-coupled receptor kinases and arrestins , 1996 .

[44]  T. Jacks,et al.  Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells , 1996, Nature Genetics.

[45]  M. Caron,et al.  G-protein-coupled receptor regulation: role of G-protein-coupled receptor kinases and arrestins. , 1996, Canadian journal of physiology and pharmacology.

[46]  M. Wigler,et al.  A conserved alternative splice in the von Recklinghausen neurofibromatosis (NF1) gene produces two neurofibromin isoforms, both of which have GTPase-activating protein activity , 1993, Molecular and cellular biology.

[47]  A. Paller.  Neurofibromatosis: Phenotype, Natural History, and Pathogenesis , 1993 .

[48]  V. Riccardi,et al.  Neurofibromatosis: Phenotype, Natural History and Pathogenesis , 1992 .

[49]  D. Lowy,et al.  Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis , 1992, Cell.

[50]  M. Boguski,et al.  cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. , 1991, Genomics.

[51]  F. Collins,et al.  Identification of the neurofibromatosis type 1 gene product. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[52]  M. Wigler,et al.  The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins , 1990, Cell.

[53]  P. O’Connell,et al.  The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21 , 1990, Cell.

[54]  Margaret Robertson,et al.  The neurofibromatosis type 1 gene encodes a protein related to GAP , 1990, Cell.