Role of SerpinA3 in the response of glioblastoma to cerebrospinal fluid

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ROLE OF SERPINA3 IN THE RESPONSE OF GLIOBLASTOMA TO CEREBROSPINAL FLUID Project Summary Glioblastoma (GBM) is the most common, aggressive and proliferative primary brain tumor in adults despite current therapeutic strategies that combine surgery, radio, and chemotherapy. The high invasive capacity of GBM makes total surgical resection virtually impossible, resulting in an extremely high recurrence rate. The ability to form a new tumor resides in a subpopulation of cells within the GBM called brain tumor initiating cells (BTICs). BTICs are undifferentiated cells with self-renewing and pluripotential capacity, similar to neural stem cells (NSCs), but with the added ability of forming tumors in vivo. Our group and others have reported that among primary GBMs, those that are located in close proximity to the lateral ventricles (LV) present multiple factors, including increased recurrence at distant locations, that negatively affect patients' survival. The cause for a worse outcome in patients suffering LV-proximal GBMs is not known. Possible explanations may involve the proximity of these tumors to the cerebrospinal fluid (CSF) and neurogenic niche in the sub-ventricular zone (SVZ). In preliminary studies we have demonstrated that CSF stimulation increases the invasive capacity of GBM cells. Furthermore CSF stimulation induces the overexpression of the serine protease inhibitor SerpinA3. Here we propose to study the role of SerpinA3 in the response of GBM cells to CSF. Upon completion of this study we will have gained a better understanding of the effects of CSF on GBM cells through SerpinA3. Ultimately, we hope to reveal specific targets for therapeutic intervention to lead to increased survival in patients with GBM.