Brain Metastasis Microenvironment and Mechanisms

脑转移是癌症和黑色素瘤复发的最不祥的形式。每年发病率 在美国有近20万例，几乎都是致命的。然而，脑转移缺乏 实验模型，机械见解，治疗目标和一般研究。大脑生物学 转移性细胞与脑微环境的独特特征深深交织在一起，特别是， 血管周围的壁龛在通过血脑屏障（BBB）外渗后，这需要一套 癌细胞粘附并伸展到毛细血管内皮的基底侧， 在一些实施方案中，星形胶质细胞与血管周围的小生境（“血管共选择”）结合，吸引星形胶质细胞并与星形胶质细胞相互作用，并在血管周围的小生境内生长。大脑 内皮细胞和星形胶质细胞通过释放癌细胞可以利用的因子来反应。为 当肿瘤生长时，它重塑现存的脉管系统，形成嵌入生长结节中的毛细血管环。 放射治疗之前或不手术，是治疗明显脑转移患者的标准。 然而，RT后复发是典型的，这引起了许多关于支持RT可行性的机制的问题。 照射组织中的残留疾病。在项目2中，Massagu 6实验室正在进行一项多学科的 基于人体组织和数据集、小鼠模型和分子遗传解剖的方法， 脑转移的问题。脑转移的两个主要来源是肺腺癌和 乳腺癌，因此这两种模式是我们研究的主题。我们将利用 最近鉴定的一组候选脑转移基因（Bos等Nature 2009; Nguyen等Cell 2009）， 和实验方法，我们已经开发出的机制描绘转移到大脑， 骨（Kang等Cancer Cell 2003; Zhang等Cancer Cell 2009）和肺（Minn等Nature 2005; Gupta等 等人Nature 2007; Tavazoie Nature 2008; Padua等人Celt 2008）。在目标1中，我们将研究 我们最近发现的候选脑转移基因的表达与促转移有关， 癌细胞与血脑屏障、近腔内皮表面和星形胶质细胞的相互作用， 在Aim 2和Aim 3中，在血管周围龛中的小胶质细胞和神经元中， 在脑内皮细胞、星形胶质细胞和其他细胞类型中原位激活，作为对浸润性癌症的反应 细胞，或癌细胞暴露于脑微环境中;在目标4中，这些细胞的作用 微环境信号作为促转移介质，如通过遗传手段以及临床前评估的那样。 在目标5中，确定在癌细胞中特异性激活的基因和途径 抵抗放射治疗我们的具体目标2至5之间存在着多层次的相互依存关系， 项目1（荷兰），以及目标3-4和项目3（Rafii）之间。病理学核心将是人类 组织获取和组织病理学分析，这是我们致力于提供临床 验证实验鉴定的转移介质。

Brain metastasis is the most ominous form of relapse from carcinomas and melanoma. Its annual incidence nears 200,000 cases in the U.S, and is almost invariably lethal. Yet, brain metastasis suffers from a dearth of experimental models, mechanistic insights, therapeutic targets, and research in general. The biology of brain metastatic cells is deeply intertwined with the singular features of the brain microenvironment and, in particular, the perivascular niche. After extravasation through the blood-brain barrier (BBB), which requires a set of specialized functions, cancer cells adhere to and stretch over the basal side of the capillary endothelium ("vascular cooption"), attract and interact with astrocytes, and grow within the perivascular niche. Brain endothelia and astrocytes react by releasing factors that cancer cells may employ to their advantage. As the tumor grows it remodels the extant vasculature, forming capillary loops embedded in the growing nodule. Radiation therapy preceded or not by surgery, is the standard of care for overt brain metastasis in patients. Relapse after RT is typical, however, raising many questions about the mechanisms that support the viability of residual disease in the irradiated tissue. In Project 2, the Massagu6 lab is undertaking a multidisciplinary approach based on human tissue and data sets, mouse models, and molecular genetic dissection to address the problem of brain metastasis. The two main sources of cerebral metastasis are lung adenocarcinoma and breast adenocarcinoma, and as such these two modalities are the subject of our study. We will leverage a recently identified set of candidate brain metastasis genes (Bos et al Nature 2009; Nguyen et al Cell 2009), and experimental approaches that we have developed for the mechanistic delineation of metastasis to brain, bone (Kang et al Cancer Cell 2003; Zhang et al Cancer Cell 2009) and lung (Minn et al Nature 2005; Gupta et al Nature 2007; Tavazoie Nature 2008; Padua et al Celt 2008). We will investigate, in Aim 1, the functional role of candidate brain metastasis genes that we recently identified whose expression is linked to pro-metastatic interactions of cancer cells with the blood-brain barrier, the abluminal endothelial surface, and astrocytes, microglia and neurons in the perivascular niche; in Aim 2 and Aim 3, the genes and pathways that become activated in situ, in brain endothelial cells, astrocytes and other cell types as a reaction to infiltrating cancer cells, or in cancer cells on exposure to the brain microenvironment; in Aim 4, the role of these microenvironment signals as pro-metastatic mediators, as assessed by genetic means as well as with preclinical agents; and, in Aim 5, the identity of genes and pathways that are specifically activated in cancer cells that resist radiation therapy . Multiple levels of interdependency exist between our specific Aims 2 to 5 and Project 1 (Holland), and between Aims 3-4 and Project 3 (Rafii). A Pathology Core will be pivotal for human tissue procurement and histopathological analysis, a trademark of our commitment to providing clinical validation of experimentally identified mediators of metastasis.