Modeling meningioma growth orthotopically in the nude mouse

描述（由申请人提供）：脑膜瘤是第二常见的脑肿瘤，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受到阻碍。脑膜瘤肿瘤细胞在培养中生长不好，通常在几代后衰老。虽然有几个已建立的脑膜瘤细胞系，有没有很好的特点描述其生长为原位异种移植。脑膜瘤的生长特别是在含有脑脊液的硬膜下腔。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罕见生长模式。虽然原位建模具有挑战性，但为了提高我们对这些肿瘤的认识，创建相关模型至关重要。现有的遗传性脑膜瘤小鼠模型，即敲除蛛网膜细胞中的NF 2基因，具有有限的实用性，因为这些小鼠中只有20%在一年多后发生脑膜瘤。该R 03申请提出在无胸腺小鼠中开发和表征荧光原位脑膜瘤异种移植模型。我们的目的是确定一个可靠的和可重复的技术生产颅内脑膜瘤，以确定在三个不同的原位位置脑膜瘤生长的模式，并表征异种移植物的生物学。我们推测硬膜下腔的独特环境对脑膜瘤的生长至关重要。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瘤肿块，这是以前没有实现的。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明确地观察肿瘤的行为和体内生长。荧光标记也将有助于我们在组织学检查时评估播散。我们预计该模型系统将适用于解剖脑膜瘤肿瘤发生的功能遗传学，并作为临床前模型，用于测试传统和新型治疗方案的毒性和疗效。该系统还将作为一种工具，专门研究生长在大脑或颅底表面的脑膜瘤的局部药物递送技术，并研究脑膜瘤独特的肿瘤-宿主相互作用。该模型系统的开发是脑膜瘤研究领域急需的资源。

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.