Modeling meningioma growth orthotopically in the nude mouse

描述(申请人提供)：脑膜瘤是第二种最常见的脑肿瘤，是发病率和死亡率的重要原因，但由于缺乏适当的模型系统，对其生物学的实验研究一直受到阻碍。脑膜瘤细胞在培养中生长不好，通常在传代几代后衰老。虽然有一些已建立的脑膜瘤细胞系，但没有很好地描述它们作为原位异种移植的生长特征。脑膜瘤生长在含有脑脊液的硬膜下间隙是特殊的。在这种微环境中模拟肿瘤生长与广泛传播有关，这是人类脑膜瘤的一种不常见的生长模式。虽然建立原位模型具有挑战性，但为了提高我们对这些肿瘤的认识，建立相关的模型是必不可少的。现有的遗传性脑膜瘤小鼠模型，即蛛网膜细胞中NF2基因的敲除，用途有限，因为这些小鼠中只有20%在一年多后发展为脑膜瘤。此R03应用程序建议开发和鉴定无菌小鼠原位荧光脑膜瘤移植模型。我们的目的是定义一种可靠和可重复的技术来制造颅内脑膜瘤，确定脑膜瘤在三个不同原位位置的生长模式，并对异种移植物的生物学特性进行表征。我们推测，硬膜下间隙的独特环境对脑膜瘤的生长是必不可少的。此外，我们的方案将局部限制脑膜瘤的生长，并允许我们可视化实体肿瘤肿块，这是以前没有达到的。用绿色荧光蛋白标记肿瘤细胞将使我们能够使用荧光体扫描来明确观察肿瘤在体内的行为和生长。荧光标记也将有助于我们评估组织学检查后的扩散情况。我们期望这个模型系统将适用于解剖脑膜瘤发生的功能遗传学，并作为一个临床前模型来测试传统和新的治疗方案的毒性和有效性。该系统还将作为一种工具，专门用于研究局部给药技术，特别是针对生长在大脑表面或颅底的脑膜瘤，以及研究脑膜瘤独特的肿瘤-宿主相互作用。这一模型系统的开发是推动脑膜瘤研究领域向前发展的迫切需要的资源。

DESCRIPTION (provided by applicant): Meningiomas are the second most common brain tumor and are a considerable cause of morbidity and mortality, yet experimental investigations into their biology have been hampered by the lack of appropriate model systems. Meningioma tumor cells do not grow well in culture, usually senescing after a few passages. Although there are a few established meningioma cell lines, there is no well-characterized description of their growth as orthotopic xenografts. Meningioma tumor growth is particular to the subdural space that contains the cerebrospinal fluid. Modeling tumor growth in this microenvironment is associated with widespread dissemination, an uncommon growth pattern for human meningiomas. Although challenging to model orthotopically, it is essential to create a relevant model in order to advance our knowledge about these tumors. The available genetic meningioma mouse model, a knockout of the NF2 gene in arachnoidal cells, has limited utility because only 20% of these mice develop meningiomas after over a year. This R03 application proposes to develop and characterize a fluorescent orthotopic meningioma xenograft model in athymic mice. It is our intention to define a reliable and reproducible technique for producing intracranial meningiomas, to define the pattern of meningioma growth at three different orthotopic locations and to characterize the biology of the xenografts. We hypothetize that the unique environment of the subdural space is essential for meningioma growth. In addition, our protocol will locally constrain meningioma growth and allow us to visualize solid tumor masses, which have not previously been attained. Labeling tumor cells with green fluorescent protein will allow us to definitively observe tumor behavior and growth in vivo using fluorescent body scanning. The fluorescent label will also facilitate our assessment of dissemination upon histological examination. We anticipate this model system will be applicable to dissect the functional genetics of meningioma tumorigenesis and to serve as a preclinical model for testing the toxicity and efficacy of conventional and novel therapeutic protocols. This system will also serve as a tool to investigate techniques of local drug delivery specifically to meningiomas which grow on the surface of the brain or the skull base, and for investigations into the unique tumor-host interactions of meningiomas. The development of this model system is a resource badly needed to move the field of meningioma research forward.