STROMAL CONTRIBUTIONS TO NF1 GLIOMA FORMATION AND GROWTH

描述（由申请人提供）：肿瘤微环境在肿瘤的形成和进展中发挥重要作用，提供影响肿瘤生长的消极和积极信号。与正常的大脑发育类似，儿童脑肿瘤的形成和生长也可能在一定程度上受到来自周围基质的空间和发育调节信号的影响。患有遗传性肿瘤易感性综合征，1型神经纤维瘤病（NF1）的个体，通常在儿童早期沿着视神经通路发展低级别胶质瘤（星形细胞肿瘤）。使用NF1作为模型系统来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，除非与NF1微环境相结合，否则胶质细胞中NF1的损失不足以形成胶质瘤，并且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-1a； SDF-1a），分别刺激NF1 -/-星形胶质细胞的增殖和存活。基于这些观察结果，我们假设Nf1小胶质细胞是致瘤微环境的关键细胞成分，MGEA5和CXCL12是促进Nf1-/-星形胶质细胞和胶质瘤体外和体内生长的关键基质源旁分泌因子。本课题的总体目标是确定Nf1小胶质细胞异常细胞表型的分子基础，确定Nf1胶质瘤的形成和持续生长是否需要Nf1小胶质细胞，并确定MGEA5和CXCL12这两个基质源性旁分泌因子如何在体外控制Nf1缺陷星形胶质细胞生长和体内Nf1胶质瘤的形成。公共卫生相关性：与正常的大脑发育类似，儿童脑肿瘤的形成和生长可能部分由周围基质中产生的空间和发育调节信号的存在所决定。使用1型神经纤维瘤病（NF1）作为模型系统来了解肿瘤微环境对胶质瘤生长的贡献，我们建议确定NF1胶质瘤生长是否需要NF1小胶质细胞，并定义最近发现的两种基质来源的旁分泌因子如何在体外控制NF1缺陷星形胶质细胞生长和体内NF1胶质瘤形成。这些研究提供了一个很好的机会来定义肿瘤微环境产生的生长调节信号，并开发未来针对脑肿瘤及其间质之间营养关系的儿科脑肿瘤治疗方法。

DESCRIPTION (provided by applicant): 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-1a; SDF-1a), 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.