Spatiotemporal Differences in CXCL12 Expression and Cyclic AMP Underlie the Unique Pattern of Optic Glioma Growth in Neurofibromatosis Type 1

Abstract

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+/À 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 Nf1À/À astrocyte survival. This increase in Nf1À/À 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 Nf1À/À astrocyte survival was a consequence of mitogen-activated protein/extracellular signalregulated 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. [Cancer Res 2007;67(18):8588-95]

In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

“…Activation of MEK/MAPK was also observed in the peripheral nerve sheath in one mouse model (36). Conversely, Nf1 +/− heterozygous mice showed decreased cAMP levels in astrocytes (37,38) and central nervous system neurons (39). Recently, Anastasaki and Gutmann (40) analyzed neurons derived from induced pluripotent stem cells from patients with NF1 and proposed a way to reconcile those conflicting results by showing that in neurons, decreased neurofibromin expression led to lower rather than higher cAMP levels.…”

The ecology of brain tumors: lessons learned from neurofibromatosis-1

“…In contrast, ectopic expression of phosphodiesterase-4 to lower cAMP levels in the forebrain of Nf1 optic glioma mice did lead to glioma formation (Warrington et al, 2010). Interestingly, there are significant variations in the levels of cAMP in different brain regions, with high levels of cAMP in the forebrain compared with the optic nerve (Warrington et al, 2007(Warrington et al, , 2010. Collectively, these findings support the hypothesis that a combination of Nf1 þ /À stromal cell types, permissive cell types and basal signaling levels contribute to the pattern of gliomagenesis in NF1.…”

“…The regulation of both Ras and cAMP is one of the properties of G-protein-coupled receptors, which suggests that chemokines present in the tumor microenvironment might increase Nf1 À/À astrocyte growth. One of these chemokines, CXCL12, is developmentally and spatially regulated, such that high levels of CXCL12 is found in young mammals along the optic pathway (Warrington et al, 2007). Moreover, Nf1 þ /À microglia express three times more CXCL12 than their wild-type counterparts.…”

“…CXCL12 acts on its receptor, CXCR4, to regulate both cAMP levels and Ras activity (Klein and Rubin, 2004), and CXCL12 treatment of wild-type astrocytes causes increased cell death through apoptosis (Warrington et al, 2007). In striking contrast, CXCL12 treatment of Nf1 À/À astrocytes resulted in increased cell survival.…”

Eliminating barriers to personalized medicine

“…Studies are currently under way in several laboratories to identify these glioma-associated microglial factors. 44,45 The key role of the microenvironment in tumor development and growth is further underscored by analogous observations involving mast cells and macrophages in Nf1 GEM plexiform neurofibromas. 46 Similar to Nf1 murine optic gliomas, Nf1 plexiform neurofibroma formation requires that Nf1 loss in Schwann cell precursors occur in mice with a germline inactivating Nf1 gene mutation (Nf11/2mice).…”