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+/- 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.
Highlights
Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that affects f1:3,000 people worldwide [1]
Antibodies and suppliers were as follows: phosphoErk1/2, Erk1/2, phospho-Akt, and Akt were from Cell Signaling; CXCR4 monoclonal antibody was from R&D Systems; CXCR4 polyclonal antibody was from Leinco; CXCL12 was from Peprotech; neurofilament 160 (NF160) was from Sigma; CD68 was from DakoCytomation; phospho-GRK2 was from Abcam; GRK2 was from Epitomics; and immunoglobulin G (IgG) isotype controls were from Jackson ImmunoResearch
These results show that the proximity of these multiple sources of CXCL12 to tumor cell CXCR4 comprises a functional paracrine relationship for CXCR4 activation
Summary
Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that affects f1:3,000 people worldwide [1]. Individuals with NF1 are susceptible to a variety of neoplasms but are especially prone to the development of benign and malignant tumors of the peripheral and central nervous systems [2]. Loss of the second (wild-type functional) NF1 allele presumably occurs randomly in tumor progenitors, the natural history of NF1-associated gliomas indicates that a non-random process influences where and when tumors grow. OPGs typically grow in young children and rarely progress after 10 years of age, regardless of treatment. These observations suggest that the growth of OPG in NF1 is developmentally regulated, and that regulatory signals from the surrounding brain microenvironment dictate when tumors are most likely to form and grow
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