Modeling meningioma growth orthotopically in the nude mouse

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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.