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作用，因为它提供了 影响肿瘤生长的正负信号。类似于正常的大脑发育，脑瘤 儿童的形成和成长也可能在一定程度上受到空间-和 从周围基质发出的发育调节的线索。具有遗传性的个体 肿瘤易感综合征，1型神经纤维瘤病(NF1)，发展为低级别胶质瘤(星形细胞瘤 肿瘤)沿着视路，通常在儿童早期。使用NF1作为模型系统 了解肿瘤微环境对胶质瘤形成和生长的贡献，我们已经展示了 胶质细胞中NF1的丢失不足以形成胶质瘤，除非与NF1+/-微环境相结合 而NF1+/-小胶质细胞产生两种生长因子，MGEA5(透明质酸酶)和CXCL12(基质细胞 衍生因子-1；SDF-1)，分别刺激NF1-/-星形胶质细胞的增殖和存活。 基于这些观察，我们假设NF1+/-小胶质细胞是 致瘤微环境和MGEA5和CXCL12是基质来源旁分泌关键 促进NF1-/-星形胶质细胞和胶质瘤生长的体内外因素。总的目标是 本研究旨在探讨NF1+/-小胶质细胞异常细胞表型的分子基础。 确定NF1+/-小胶质细胞是否是NF1胶质瘤形成和持续生长所必需的，并确定 这两种基质来源的旁分泌因子MGEA5和CXCL12是如何控制NF1缺乏的星形胶质细胞生长的 在体外和体内形成NF1胶质瘤。

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.