STROMAL CONTRIBUTIONS TO NF1 GLIOMA FORMATION AND GROWTH

项目摘要 肿瘤微环境在肿瘤的形成和发展中起着重要的作用， 影响肿瘤生长的积极和消极信号。与正常大脑发育相似，脑肿瘤 儿童的形成和成长也可能部分取决于空间上的存在， 来自周围基质的发育调节线索。有遗传病的人 肿瘤易感综合征，神经纤维瘤病1型（NF 1），发展为低级别胶质瘤（星形细胞瘤）， 肿瘤）沿着通常在儿童早期。使用NF 1作为模型系统， 为了了解肿瘤微环境对胶质瘤形成和生长的贡献，我们已经表明， 神经胶质细胞中的Nf 1缺失不足以形成神经胶质瘤，除非与Nf 1 +/-微环境结合 Nf 1 +/-小胶质细胞产生两种生长因子，MGEA 5（透明质酸酶）和CXCL 12（基质细胞 衍生因子-1 <$; SDF-1 <$），其分别刺激NF 1-/-星形胶质细胞的增殖和存活。 基于这些观察结果，我们假设Nf 1 +/-小胶质细胞是一个关键的细胞成分， 致瘤微环境和MGEA 5和CXCL 12是关键基质衍生旁分泌 在体外和体内促进Nf 1-/-星形胶质细胞和胶质瘤生长的因子。的总体目标 该建议旨在确定Nf 1 +/-小胶质细胞异常细胞表型的分子基础， 确定Nf 1 +/-小胶质细胞是否是Nf 1胶质瘤形成和持续生长所必需的，并确定 这两种基质衍生的旁分泌因子MGEA 5和CXCL 12如何控制Nf 1缺陷型星形胶质细胞生长 体外和体内Nf 1胶质瘤形成。

Project Summary 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.