A significant proportion of benign meningiomas progress into atypical and malignant tumors that are surgically intractable and incurable. There are no markers that will predict which benign tumors will progress. In addition, there are no markers to distinguish the histomorphologically benign, recurrent tumors from the histomorphologically benign, but biologically aggressive, invasive tumors. Furthermore, there are no invasive-specific markers. This phenotype may be missed if the tumor/brain interface is not present on the specimen used for diagnosis. These complications may lead to misdiagnosis and misgrading of the tumor. Consequently, menigioma patients may be either over-or under treated. They have identified SPARC (secreted protein acidic and rich in cysteine) as a gene over-expressed in astrocytic tumors and have observed its expression in abnormal cells at the infiltrating edge of the tumor/brain interface in primary tumor specimens. In addition, using a xenograft model, the expression of SPARC was observed in human tumor cells invading adjacent rat brain, suggesting that SPARC is a marker of invasive tumor cells. To further address this correlation in other invasive brain tumors, they have examined SPARC expression in a subset of recurrent and non-recurrent meningiomas of all grades. Their preliminary data suggest that SPARC expression is associated with the invasive phenotype in meningioma, regardless of tumor grade. This proposal aims to determine whether SPARC over expression serves as an indicator of meningioma invasiveness (in vivo and in vitro), thereby providing an objective diagnostic marker for identifying those patients with histologically benign but biologically aggressive, invasive tumors and consequently identifying those individuals in need of adjuvant therapy and close follow-up.
Specific Aim 1 : To determine whether SPARC over expression serves as a diagnostic marker for invasion in meningiomas, using immunohistomorphological and histopathological analyses of primary tumor specimens.
Specific Aim 2 : To determine whether the level of SPARC overexpression in vivo correlates with tumor cell migration in vitro, using demsitometric northern blot analyses, western blot analyses, and cell migration assays of the corresponding primary tumor cell lines.
