Brain injury drives optic glioma formation through neuron-glia signaling.

Tissue injury and tumorigenesis share many cellular and molecular features, including immune cell (T cells, monocytes) infiltration and inflammatory factor (cytokines, chemokines) elaboration. Their common pathobiology raises the intriguing possibility that brain injury could create a tissue microenvironment permissive for tumor formation. Leveraging several murine models of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome and two experimental methods of brain injury, we demonstrate that both optic nerve crush and diffuse traumatic brain injury induce optic glioma (OPG) formation in mice harboring Nf1-deficient preneoplastic progenitors. We further elucidate the underlying molecular and cellular mechanisms, whereby glutamate released from damaged neurons stimulates IL-1ß release by oligodendrocytes to induce microglia expression of Ccl5, a growth factor critical for Nf1-OPG formation. Interruption of this cellular circuit using glutamate receptor, IL-1ß or Ccl5 inhibitors abrogates injury-induced glioma progression, thus establishing a causative relationship between injury and tumorigenesis.

Estrogen-induced glial IL-1ß mediates extrinsic retinal ganglion cell vulnerability in murine Nf1 optic glioma.

Optic pathway gliomas (OPGs) arising in children with neurofibromatosis type 1 (NF1) can cause retinal ganglion cell (RGC) dysfunction and vision loss, which occurs more frequently in girls. While our previous studies demonstrated that estrogen was partly responsible for this sexually dimorphic visual impairment, herein we elucidate the underlying mechanism. In contrast to their male counterparts, female Nf1OPG mice have increased expression of glial interleukin-1ß (IL-1ß), which is neurotoxic to RGCs in vitro. Importantly, both IL-1ß neutralization and leuprolide-mediated estrogen suppression decrease IL-1ß expression and ameliorate RGC dysfunction, providing preclinical proof-of-concept evidence supporting novel neuroprotective strategies for NF1-OPG-induced vision loss.

Treatment during a developmental window prevents NF1-associated optic pathway gliomas by targeting Erk-dependent migrating glial progenitors.

The mechanism of vulnerability to pediatric low-grade gliomas (pLGGs)-the most common brain tumor in children-during development remains largely unknown. Using mouse models of neurofibromatosis type 1 (NF1)-associated pLGGs in the optic pathway (NF1-OPG), we demonstrate that NF1-OPG arose from the vulnerability to the dependency of Mek-Erk/MAPK signaling during gliogenesis of one of the two developmentally transient precursor populations in the optic nerve, brain-derived migrating glial progenitors (GPs), but not local progenitors. Hyperactive Erk/MAPK signaling by Nf1 loss overproduced GPs by disrupting the balance between stem-cell maintenance and gliogenesis of hypothalamic ventricular zone radial glia (RG). Persistence of RG-like GPs initiated NF1-OPG, causing Bax-dependent apoptosis in retinal ganglion cells. Removal of three Mek1/Mek2 alleles or transient post-natal treatment with a low-dose MEK inhibitor normalized differentiation of Nf1-/- RG-like GPs, preventing NF1-OPG formation and neuronal degeneration. We provide the proof-of-concept evidence for preventing pLGGs before tumor-associated neurological damage enters an irreversible phase.

Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability. RESULTS: Here we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment. CONCLUSIONS: The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1.

Non-Coding RNA and Tumor Development in Neurofibromatosis Type 1: ANRIL Rs2151280 Is Associated with Optic Glioma Development and a Mild Phenotype in Neurofibromatosis Type 1 Patients.

Non-coding RNAs (ncRNAs) are known to regulate gene expression at the transcriptional and post-transcriptional levels, chromatin remodeling, and signal transduction. The identification of different species of ncRNAs, microRNAs (miRNAs), circular RNAs (circRNAs), and long ncRNAs (lncRNAs)-and in some cases, their combined regulatory function on specific target genes-may help to elucidate their role in biological processes. NcRNAs' deregulation has an impact on the impairment of physiological programs, driving cells in cancer development. We here carried out a review of literature concerning the implication of ncRNAs on tumor development in neurofibromatosis type 1 (NF1), an inherited tumor predisposition syndrome. A number of miRNAs and a lncRNA has been implicated in NF1-associated tumors, such as malignant peripheral nerve sheath tumors (MPNSTs) and astrocytoma, as well as in the pathognomonic neurofibromas. Some authors reported that the lncRNA ANRIL was deregulated in the blood of NF1 patients with plexiform neurofibromas (PNFs), even if its role should be further elucidated. We here provided original data concerning the association of a specific genotype about ANRIL rs2151280 with the presence of optic gliomas and a mild expression of the NF1 phenotype. We also detected the LOH of ANRIL in different tumors from NF1 patients, supporting the involvement of ANRIL in some NF1-associated tumors. Our results suggest that ANRIL rs2151280 may be a potential diagnostic and prognostic marker, addressing early diagnosis of optic glioma and predicting the phenotype severity in NF1 patients.

Optic Pathway Gliomas Secondary to Neurofibromatosis Type 1.

Children with neurofibromatosis type 1 frequently manifest optic pathway gliomas-low-grade gliomas intrinsic to the visual pathway. This review describes the molecular and genetic mechanisms driving optic pathway gliomas as well as the clinical symptoms of this relatively common genetic condition. Recommendations for clinical management and descriptions of the newest imaging techniques are discussed.

Defining the temporal course of murine neurofibromatosis-1 optic gliomagenesis reveals a therapeutic window to attenuate retinal dysfunction.

Background: Optic gliomas arising in the neurofibromatosis type 1 (NF1) cancer predisposition syndrome cause reduced visual acuity in 30%-50% of affected children. Since human specimens are rare, genetically engineered mouse (GEM) models have been successfully employed for preclinical therapeutic discovery and validation. However, the sequence of cellular and molecular events that culminate in retinal dysfunction and vision loss has not been fully defined relevant to potential neuroprotective treatment strategies. Methods: Nf1flox/mut GFAP-Cre (FMC) mice and age-matched Nf1flox/flox (FF) controls were euthanized at defined intervals from 2 weeks to 24 weeks of age. Optic nerve volumes were measured, and optic nerves/retinae analyzed by immunohistochemistry. Optical coherence tomography (OCT) was performed on anesthetized mice. FMC mice were treated with lovastatin from 12 to 16 weeks of age. Results: The earliest event in tumorigenesis was a persistent elevation in proliferation (4 wk), which preceded sustained microglia numbers and incremental increases in S100+ glial cells. Microglia activation, as evidenced by increased interleukin (IL)-1ß expression and morphologic changes, coincided with axonal injury and retinal ganglion cell (RGC) apoptosis (6 wk). RGC loss and retinal nerve fiber layer (RNFL) thinning then ensued (9 wk), as revealed by direct measurements and live-animal OCT. Lovastatin administration at 12 weeks prevented further RGC loss and RNFL thinning both immediately and 8 weeks after treatment completion. Conclusion: By defining the chronology of the cellular and molecular events associated with optic glioma pathogenesis, we demonstrate critical periods for neuroprotective intervention and visual preservation, as well as establish OCT as an accurate biomarker of RGC loss.

3-D imaging mass spectrometry of protein distributions in mouse Neurofibromatosis 1 (NF1)-associated optic glioma.

Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder, in which affected individuals develop tumors of the nervous system. Children with NF1 are particularly prone to brain tumors (gliomas) involving the optic pathway that can result in impaired vision. Since tumor formation and expansion requires a cooperative tumor microenvironment, it is important to identify the cellular and acellular components associated with glioma development and growth. In this study, we used 3-D matrix assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) to measure the distributions of multiple molecular species throughout optic nerve tissue in mice with and without glioma, and to explore their spatial relationships within the 3-D volume of the optic nerve and chiasm. 3-D IMS studies often involve extensive workflows due to the high volume of sections required to generate high quality 3-D images. Herein, we present a workflow for 3-D data acquisition and volume reconstruction using mouse optic nerve tissue. The resulting 3-D IMS data yield both molecular similarities and differences between glioma-bearing and wild-type (WT) tissues, including protein distributions localizing to different anatomical subregions. BIOLOGICAL SIGNIFICANCE: The current work addresses a number of challenges in 3-D MALDI IMS, driven by the small size of the mouse optic nerve and the need to maintain consistency across multiple 2-D IMS experiments. The 3-D IMS data yield both molecular similarities and differences between glioma-bearing and wild-type (WT) tissues, including protein distributions localizing to different anatomical subregions, which could then be targeted for identification and related back to the biology observed in gliomas of the optic nerve.

RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth.

Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies.

The impact of coexisting genetic mutations on murine optic glioma biology.

BACKGROUND: Children with the neurofibromatosis type 1 (NF1) tumor predisposition syndrome are prone to the development of optic pathway gliomas resulting from biallelic inactivation of the NF1 gene. Recent studies have revealed the presence of other molecular alterations in a small portion of these NF1-associated brain tumors. The purpose of this study was to leverage Nf1 genetically engineered mouse strains to define the functional significance of these changes to optic glioma biology. METHODS: Nf1+/- mice were intercrossed with Nf1(flox/flox) mice, which were then crossed with Nf1(flox/flox); GFAP-Cre mice, to generate Nf1(flox/mut); GFAP-Cre (FMC) mice. These mice were additionally mated with conditional KIAA1549:BRAF knock-in or Pten(flox/wt) mice to generate Nf1(flox/mut); f-BRAF; GFAP-Cre (FMBC) mice or Nf1(flox/mut); Pten(flox/wt); GFAP-Cre (FMPC) mice, respectively. The resulting optic gliomas were analyzed for changes in tumor volume, proliferation, and retinal ganglion cell loss. RESULTS: While KIAA1549:BRAF conferred no additional biological properties on Nf1 optic glioma, FMPC mice had larger optic gliomas with greater proliferative indices and microglial infiltration. In addition, all 3 Nf1 murine optic glioma strains exhibited reduced retinal ganglion cell survival and numbers; however, FMPC mice had greater retinal nerve fiber layer thinning near the optic head relative to FMC and FMBC mice. CONCLUSIONS: Collectively, these experiments demonstrate genetic cooperativity between Nf1 loss and Pten heterozygosity relevant to optic glioma biology and further underscore the value of employing genetically engineered mouse strains to define the contribution of discovered molecular alterations to brain tumor pathogenesis.

Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth.

BACKGROUND: Children with neurofibromatosis type 1 (NF1) develop optic pathway gliomas, which result from impaired NF1 protein regulation of Ras activity. One obstacle to the implementation of biologically targeted therapies is an incomplete understanding of the individual contributions of the downstream Ras effectors (mitogen-activated protein kinase kinase [MEK], Akt) to optic glioma maintenance. This study was designed to address the importance of MEK and Akt signaling to Nf1 optic glioma growth. METHODS: Primary neonatal mouse astrocyte cultures were employed to determine the consequence of phosphatidylinositol-3 kinase (PI3K)/Akt and MEK inhibition on Nf1-deficient astrocyte growth. Nf1 optic glioma-bearing mice were used to assess the effect of Akt and MEK inhibition on tumor volume, proliferation, and retinal ganglion cell dysfunction. RESULTS: Both MEK and Akt were hyperactivated in Nf1-deficient astrocytes in vitro and in Nf1 murine optic gliomas in vivo. Pharmacologic PI3K or Akt inhibition reduced Nf1-deficient astrocyte proliferation to wild-type levels, while PI3K inhibition decreased Nf1 optic glioma volume and proliferation. Akt inhibition of Nf1-deficient astrocyte and optic glioma growth reflected Akt-dependent activation of mammalian target of rapamycin (mTOR). Sustained MEK pharmacologic blockade also attenuated Nf1-deficient astrocytes as well as Nf1 optic glioma volume and proliferation. Importantly, these MEK inhibitory effects resulted from p90RSK-mediated, Akt-independent mTOR activation. Finally, both PI3K and MEK inhibition reduced optic glioma-associated retinal ganglion cell loss and nerve fiber layer thinning. CONCLUSION: These findings establish that the convergence of 2 distinct Ras effector pathways on mTOR signaling maintains Nf1 mouse optic glioma growth, supporting the evaluation of pharmacologic inhibitors that target mTOR function in future human NF1-optic pathway glioma clinical trials.

Intraocular astrocytoma and its differential diagnosis.

Astrocytomas arising within the eye display 2 distinct histologies: one comprises interlacing bundles of spindle-shaped cells mixed with a minority of polygonal cells, and the other consists of large cells with abundant glassy cytoplasm (gemistocytic astrocytes) indistinguishable from cells found in subependymal giant cell astrocytoma. Both histologic patterns express glial fibrillary acid protein diffusely, are biologically benign, and are frequently associated with dysgenic syndromes, particularly tuberous sclerosis complex. Tumors with gemistocytes, however, demonstrate a greater propensity for invasive growth. The clinical history may provide information to guide the pathologist in distinguishing intraocular astrocytoma from reactive astrocytosis, conditions that are histologically similar. It remains to be determined if other types of primary intraocular glioma exist or whether some degree of ependymal or oligodendroglial differentiation can accompany reactive astrocytosis.

Optic nerve glioma: case series with review of clinical, radiologic, molecular, and histopathologic characteristics.

PURPOSE: This study was designed to better understand the biologic nature of optic nerve gliomas (ONGs) and to investigate staining techniques that might improve the pathologic interpretation of surgical margins. METHODS: In this retrospective case series, clinical data on patient presentation, MRI, surgical visualization, and initial pathologic interpretation were gathered. Specimens were then reexamined using analysis of p53, isocitrate dehydrogenase 1 (IDH1), MIB-1, and B-rapidly accelerated fibrosarcoma (BRAF) duplication. RESULTS: Six patients were studied. All were diagnosed with World Health Organization grade 1 ONGs on original pathology. On reexamination, BRAF tandem duplication was found in 2 patients with neurofibromatosis Type 1 association. P53 immunoreactivity was noted in a third case. No cases had IDH1 immunoreactivity. Focal elevations of MIB-1 up to 7.5% were noted in 2 cases. CONCLUSIONS: ONGs are neoplasms with variable degrees of aggressiveness. As more is understood regarding their varied genetic underpinnings, improved pathologic classification and individualized treatment regimens may be achieved. The authors hope that this study helps guide the oculoplastic community toward a multi-institutional, prospective study of ONG genomic sequencing.

NG2-cells are not the cell of origin for murine neurofibromatosis-1 (Nf1) optic glioma.

Low-grade glial neoplasms (astrocytomas) represent one of the most common brain tumors in the pediatric population. These tumors frequently form in the optic pathway (optic pathway gliomas, OPGs), especially in children with the neurofibromatosis type 1 (NF1)-inherited tumor predisposition syndrome. To model these tumors in mice, we have previously developed several Nf1 genetically-engineered mouse strains that form optic gliomas. However, there are three distinct macroglial cell populations in the optic nerve (astrocytes, NG2+ (nerve/glial antigen 2) cells and oligodendrocytes). The presence of NG2+ cells in the optic nerve raises the intriguing possibility that these cells could be the tumor-initiating cells, as has been suggested for adult glioma. In this report, we used a combination of complementary in vitro and novel genetically-engineered mouse strains in vivo to determine whether NG2+ cells could give rise to Nf1 optic glioma. First, we show that Nf1 inactivation results in a cell-autonomous increase in glial fibrillary acidic protein+ (GFAP+), but not in NG2+, cell proliferation in vitro. Second, similar to the GFAP-Cre transgenic strain that drives Nf1 optic gliomagenesis, NG2-expressing cells also give rise to all three macroglial lineages in vivo. Third, in contrast to the GFAP-Cre strain, Nf1 gene inactivation in NG2+ cells is not sufficient for optic gliomagenesis in vivo. Collectively, these data demonstrate that NG2+ cells are not the cell of origin for mouse optic glioma, and support a model in which gliomagenesis requires Nf1 loss in specific neuroglial progenitors during embryogenesis.

BRAF duplications and MAPK pathway activation are frequent in gliomas of the optic nerve proper.

Optic pathway gliomas represent a specific subtype of astrocytoma with unique clinicopathologic and biologic properties, but studies of tumors in the optic nerve proper have been hampered by limited tissue availability. We analyzed optic nerve gliomas of 59 patients (median age, 9 years; range, 3 months-66 years; 33 female, 26 male) using formalin-fixed paraffin-embedded material in tissue microarrays. Seven patients had the clinical diagnosis of neurofibromatosis type 1 (NF1). Fluorescence in situ hybridization studies were performed for BRAF, PTEN, CDKN2A (p16), and NF1. Immunohistochemistry was performed for glial fibrillary acidic protein, phospho-ERK, and mutant IDH1 protein. The BRAF duplication was present in 11 (73%) of 15 evaluable tumors, including 1 NF1 patient (1 of 4 tested; 25%). The single tumor lacking BRAF duplication or NF1 association had histologic features of a ganglioglioma. Conversely, heterozygous PTEN deletions were present in 2 (8%) of 25 evaluable cases, one of which was BRAF duplicated and the other was NF1 associated. CDKN2A and NF1 deletions were absent in all tumors tested. Phospho-ERK immunoreactivity was present in 55 (96%) of 57 tumors and was mostly strong and diffuse (80%). Only 1 case of 53 expressed IDH1. Thus, optic nerve gliomas demonstrated molecular alterations typical of pilocytic astrocytomas, including the universal presence of either BRAF duplication or NF1 association and common mitogen-activated protein kinase pathway activation but very rare mutant IDH1 expression.

Reduced striatal dopamine underlies the attention system dysfunction in neurofibromatosis-1 mutant mice.

Learning and behavioral abnormalities are among the most common clinical problems in children with the neurofibromatosis-1 (NF1) inherited cancer syndrome. Recent studies using Nf1 genetically engineered mice (GEM) have been instructive for partly elucidating the cellular and molecular defects underlying these cognitive deficits; however, no current model has shed light on the more frequently encountered attention system abnormalities seen in children with NF1. Using an Nf1 optic glioma (OPG) GEM model, we report novel defects in non-selective and selective attention without an accompanying hyperactivity phenotype. Specifically, Nf1 OPG mice exhibit reduced rearing in response to novel objects and environmental stimuli. Similar to children with NF1, the attention system dysfunction in these mice is reversed by treatment with methylphenidate (MPH), suggesting a defect in brain catecholamine homeostasis. We further demonstrate that this attention system abnormality is the consequence of reduced dopamine (DA) levels in the striatum, which is normalized following either MPH or l-dopa administration. The reduction in striatal DA levels in Nf1 OPG mice is associated with reduced striatal expression of tyrosine hydroxylase, the rate-limited enzyme in DA synthesis, without any associated dopaminergic cell loss in the substantia nigra. Moreover, we demonstrate a cell-autonomous defect in Nf1+/- dopaminergic neuron growth cone areas and neurite extension in vitro, which results in decreased dopaminergic cell projections to the striatum in Nf1 OPG mice in vivo. Collectively, these data establish abnormal DA homeostasis as the primary biochemical defect underlying the attention system dysfunction in Nf1 GEM relevant to children with NF1.

Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1.

Current models of oncogenesis incorporate the contributions of chronic inflammation and aging to the patterns of tumor formation. These oncogenic pathways, involving leukocytes and fibroblasts, are not readily applicable to brain tumors (glioma), and other mechanisms must account for microenvironmental influences on central nervous system tumorigenesis. Previous studies from our laboratories have used neurofibromatosis-1 (NF1) genetically engineered mouse (GEM) models to understand the spatial restriction of glioma formation to the optic pathway of young children. Based on our initial findings, we hypothesize that brain region-specific differences in cAMP levels account for the pattern of NF1 gliomagenesis. To provide evidence that low levels of cAMP promote glioma formation in NF1, we generated foci of decreased cAMP in brain regions where gliomas rarely form in children with NF1. Focal cAMP reduction was achieved by forced expression of phosphodiesterase 4A1 (PDE4A1) in the cortex of Nf1 GEM strains. Ectopic PDE4A1 expression produced hypercellular lesions with features of human NF1-associated glioma. Conversely, pharmacologic elevation of cAMP with the PDE4 inhibitor rolipram dramatically inhibited optic glioma growth and tumor size in Nf1 GEM in vivo. Together, these results indicate that low levels of cAMP in a susceptible Nf1 mouse strain are sufficient to promote gliomagenesis, and justify the implementation of cAMP-based stroma-targeted therapies for glioma.

CXCL12 alone is insufficient for gliomagenesis in Nf1 mutant mice.

Tumorigenesis requires interactions between tumor progenitors and their microenvironment. We found that low cAMP levels were sufficient for tumorigenesis in a mouse model of Neurofibromatosis-1 (NF1)-associated optic pathway glioma (OPG). We hypothesized that the distinct pattern of glioma in NF1 reflected spatiotemporal differences in CXCL12 effects on cAMP levels. Thus, we sought to alter the pattern of gliomagenesis through manipulation of CXCL12-CXCR4 pathway activation in Nf1 OPG mice. Forced CXCL12 expression induced glioma at a low frequency. Further, treatment of Nf1 OPG mice with AMD3100, a CXCR4 antagonist, did not attenuate glioma growth. Thus, it appears, CXCL12 alone cannot promote gliomagenesis in NF1 mice.

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.