Presenting Author:
Shivani Baisiwala, B.S.
Principal Investigator:
Department:
Neurological Surgery
Keywords:
vascular co-option, endothelial cells, glioma stem cells, cancer stem cells, recurrence, GBM
Location:
Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital
B89 - Basic Science
The Role of Vascular Co-Option in Glioblastoma Recurrence
Glioblastoma Multiforme (GBM) is a highly invasive, heterogeneous brain tumor that affects 22,850 adults in the US. Patients have an average survival time of 15 months after diagnosis, making GBM the most lethal form of human cancer. GBM is usually treated with surgery to resect as much of the tumor as possible, followed by radiation and temozolomide (TMZ)-based chemotherapy. Unfortunately, GBM recurs in close to 100% of patients. This recurrence is due to the inherent therapy resistance of glioma stem cells (GSCs). However, there remains some uncertainty around the exact mechanisms governing this process. Our data suggests that vascular mimicry plays a critical role in recurrence. Our goal is therefore to elucidate the role and mechanism of vascular mimicry in glioma resistance and recurrence. Here, we show that there is an enrichment of GSCs and a transdifferentiation from GSCs to tumor-derived endothelial cells occurring in response to therapeutic stress. After treatment with TMZ, CD133+ GSC populations are increased at least three-fold compared to untreated cells (p < .001). In addition, there was at least a two-fold increase in CD105+ endothelial cells after treatment with TMZ compared to untreated cells (p < .001). The functionality of these tumor-derived endothelial cells was assessed using a tube forming assay. Cells treated with TMZ showed a three-fold increase in tube-forming capability compared to cells that were not treated (p < .01). These results were further confirmed in vivo. Mice treated with TMZ with recurrent tumors showed a six-fold increase in populations of CD105+ and CD34+ endothelial cells compared to those mice with primary tumors that were not treated (p < .001). These results suggest that CD133+ GSC can transdifferentiate in vitro and in vivo into functional endothelial cells (ECs) upon treatment with TMZ. These ECs are functional and can organize into vessel-like structures, suggesting that therapeutic stress induces a vascular mimicry response in GBM. Our next step is to demonstrate the role of tumor-derived endothelial cells in GBM recurrence, using an endothelial cell-specific negative selection system that can be virally transduced into GBM cell lines. This will allow us to assess the impact of selective depletion on tumor growth and animal survival and to investigate the role of therapy-induced vascular mimicry in GBM recurrence. Even with aggressive treatment, GBM recurrence is inevitable and fatal. This study will provide us with insight into the role of vascular co-option in tumor recurrence and allow us to formulate novel therapeutic interventions for a disease that desperately needs them.
