The tumor microenvironment plays an important role in tumor formation and progression by providing both negative and positive signals that influence tumor growth. Similar to normal brain development, brain tumor formation and growth in children may also be dictated in part by the presence of spatially- and developmentally-regulated cues that emanate from the surrounding stroma. Individuals with the inherited tumor predisposition syndrome, neurofibromatosis type 1 (NF1), develop low-grade gliomas (astrocytic neoplasms) along the optic pathway typically during early childhood. Using NF1 as a model system to understand the contribution of the tumor microenvironment to glioma formation and growth, we have shown that Nf1 loss in glial cells is insufficient for glioma formation unless coupled with an Nf1+/- microenvironment and that Nf1+/- microglia produce two growth factors, MGEA5 (hyaluronidase) and CXCL12 (stromal cell derived factor-1?;SDF-1?), that stimulate the proliferation and survival of Nf1-/- astrocytes, respectively. Based on these observations, we hypothesize that Nf1+/- microglia are a critical cellular component of the tumorigenic microenvironment and that MGEA5 and CXCL12 are key stroma-derived paracrine factors which promote Nf1-/- astrocyte and glioma growth in vitro and in vivo. The overall objective of this proposal is to identify the molecular basis for the abnormal cellular phenotypes of Nf1+/- microglia, to determine whether Nf1+/- microglia are required for Nf1 glioma formation and continued growth, and to define how these two stroma-derived paracrine factors, MGEA5 and CXCL12, control Nf1-deficient astrocyte growth in vitro and Nf1 glioma formation in vivo.

Public Health Relevance

Similar to normal brain development, brain tumor formation and growth in children may be dictated in part by the presence of spatially- and developmentally-regulated cues that emanate from the surrounding stroma. Using neurofibromatosis type 1 (NF1) as a model system to understand the contribution of the tumor microenvironment to glioma growth, we propose to determine whether Nf1+/- microglia are required for Nf1 glioma growth and to define how two recently identified stroma-derived paracrine factors control Nf1-deficient astrocyte growth in vitro and Nf1 glioma formation in vivo. These studies provide an excellent opportunity to define the growth regulatory signals produced by the tumor microenvironment, and to develop future therapies that target the trophic relationship between brain tumors and their stroma for pediatric brain tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136573-05
Application #
8458133
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2009-07-13
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$287,582
Indirect Cost
$98,383
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Warrington, Nicole M; Sun, Tao; Luo, Jingqin et al. (2015) The cyclic AMP pathway is a sex-specific modifier of glioma risk in type I neurofibromatosis patients. Cancer Res 75:16-21
Sun, Tao; Warrington, Nicole M; Luo, Jingqin et al. (2014) Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males. J Clin Invest 124:4123-33
Brooks, Michael D; Sengupta, Rajarshi; Snyder, Steven C et al. (2013) Hitting Them Where They Live: Targeting the Glioblastoma Perivascular Stem Cell Niche. Curr Pathobiol Rep 1:101-110
Fisher, Michael J; Avery, Robert A; Allen, Jeffrey C et al. (2013) Functional outcome measures for NF1-associated optic pathway glioma clinical trials. Neurology 81:S15-24
Pong, Winnie W; Higer, Samantha B; Gianino, Scott M et al. (2013) Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation. Ann Neurol 73:303-8
Sun, Tao; Warrington, Nicole M; Rubin, Joshua B (2012) Why does Jack, and not Jill, break his crown? Sex disparity in brain tumors. Biol Sex Differ 3:3
Sun, Tao; Gianino, Scott M; Jackson, Erin et al. (2010) CXCL12 alone is insufficient for gliomagenesis in Nf1 mutant mice. J Neuroimmunol 224:108-13