Abstract 5021: Temozolomide-induced conversion of glioma cells into glioma “stem-like” cells with enhanced invasion properties.

Abstract

Abstract Glioblastoma multiforme patients present a poor prognosis due to therapeutic resistance and tumor recurrence after surgical resection. It has been suggested that gliomas are driven by a rare subset of tumor cells, known as cancer stem cells (CSCs). These tumor-initiating cells are considered to be responsible for sustaining long-term tumor growth and disease recurrence. Today, two popular hypotheses try to explain the origin of CSCs: one postulates that CSCs represent an adult stem cell population with tumorigenic alterations, while the second argues that CSCs were once differentiated tumor cells that have re-initiated a self-renewal program. In this study, we first show that exposure to the therapeutic dose of 5 μM (the peak concentration in patient's cerebral spinal fluid) or 50 μM (the concentration in patient's blood) of temozolamide (TMZ), the most commonly used alkylating agent to treat GBM patients, consistently increase the CSC pool over time both in vitro and in vivo. Second, lineage-tracing analysis of genetically tagged glioma cells suggests that TMZ induces a phenotypic shift in the non-CSC population to mimic that of CSCs. These newly formed CSC-like cells co-express markers of pluripotency and stemness (CD133, CD15, Sox-2, Oct-4 and Nestin), a classical characteristic of CSCs. We further show that intracranial implantation of TMZ-treated non-CSC cells in athymic nude mice result in more efficient grafting (100% grafting as compared to 60% for DMSO treated control group). Moreover, these TMZ-treated non-CSC xenografts demonstrate extremely invasive characteristics, which is similar to the CSC enriched xenografts. In addition, they express elevated levels of HIF2α, a critical factor for maintaining the CSC pool. These findings strongly corroborate that chemotherapy-induced selection pressure can facilitate a CSC specific ‘niche’, which may provide the necessary signals to induce an interconversion between differentiated tumor cells and cancer “stem like” cells, leading to a more infiltrative glioma phenotype thereby resulting in therapeutic relapse and may frustrate our attempts to develop effective anti-glioma therapy. Citation Format: Atique U. Ahmed, Brenda Auffinger, Alex Tobias, Bart Thaci, Yu Han, Maciej S. Lesniak. Temozolomide-induced conversion of glioma cells into glioma “stem-like” cells with enhanced invasion properties. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5021. doi:10.1158/1538-7445.AM2013-5021