CXCL12 alone is insufficient for gliomagenesis in Nf1 mutant mice

Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Journal of neuroimmunology (Impact Factor: 2.47). 07/2010; 224(1-2):108-13. DOI: 10.1016/j.jneuroim.2010.05.002
Source: PubMed


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.

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Available from: Tao Sun, Feb 18, 2015
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    • "Using several Nf1 genetically-engineered mouse strains, pharmacologic and genetic silencing of microglia function impairs optic glioma growth (Daginakatte and Gutmann, 2007 Daginakatte et al., 2008; Simmons et al., 2011). One of the stromal factors that facilitates gliomagenesis and continued growth is the chemokine CXCL12 (stroma-derived factor-1α) (Warrington et al., 2007), such that forced expression of CXCL12 in the brains of Nf1 optic glioma mice results in ectopic glioma-like formation (Sun et al., 2010). CXCL12 acting through its receptor, CXCR4, regulates glial cell survival in a cAMP-dependent manner: Restoring cAMP levels in Nf1 optic glioma strains reduces tumor growth (Warrington et al., 2010). "
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    • "Given that TNFR2-deficient mice exhibit lack of CXCL12 up-regulation within astrocytes of the demyelinated CC (Fig. 2f), we wondered whether reinstating CXCL12 expression at this site might rescue the delayed remyelination observed in TNFR2−/− mice. Two lentiviral constructs were used to test this hypothesis, one encoding-CXCL12 and mCherry and another encoding mCherry alone [50]. In vitro infection of astrocytes with lentivirus encoding both CXCL12 and mCherry confirmed transduction and CXCL12 expression as assessed by immunocytochemistry (Fig. 4a–d). "
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    • "Knockdown of CXCR4 was confirmed by western blot. For over-expression experiments, HUVECs were infected with lentivirus containing CXCL12 gene as described previously [38]. CXCL12 overexpression was confirmed by ELISA. "
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