Glioma Stem Cells: Cell Culture, Markers and Targets for New Combination Therapies

Abstract

Gliomas are brain tumors with glial cell characteristics, and are composed of a heterogeneous mix of cells, which includes glioma stem cells. Gliomas include astrocytomas, oligodendrogliomas, ependymoma, and mixed gliomas. Gliomas account for 32% of all brain and central nervous system tumors (CNS) and 80% of all malignant brain and CNS tumors (CBTRUS, 2010). The WHO grade III anaplastic astrocytomas (AAs) and grade IV glioblastoma multiforme (GBMs) are highly invasive tumors and make up approximately three-quarters of all gliomas (CBTRUS, 2010). GBM is the most common and malignant form of brain tumor. GBMs make up 17% of all primary brain tumors in the United States, with an incidence of 3.17 cases per 100,000 persons per year (CBTRUS, 2010). Although both the knowledge of glioma biology and the available resources for treatment have greatly increased over the past decade, the expected survival of malignant glioma patients remains dismal. For AA patients, the current five-year and ten-year survival rates are 27.4% and 21.3%, respectively (CBTRUS, 2010). GBM patients have a much lower survival. The current five-year and ten-year survival rates for GBM patients are 4.5% and 2.7%, respectively (CBTRUS, 2010). Clinical treatment for gliomas consists of a combination of surgical resection, radiotherapy and chemotherapy. Due to the infiltrative nature of GBMs, complete removal of the tumor by surgery is not possible. Following surgery, the conventional radiation dosage of up to 60 Gy is given daily in 2 Gy fractions (Buatti et al 2008). The commonly used chemotherapy drug, temozolomide (Temodar®), is an alkylating agent that is taken orally and readily penetrates the blood-brain barrier (Ostermann et al., 2004). 1,3bis(2-chloroethyl)-1-nitrosourea (BCNU) is an older drug that surgeons deposit in the tumor bed as dissolvable wafers (Grossman et al., 1992). Both of these drugs alkylate DNA at multiple sites, including the O6 position of guanine, which can result in futile cycles of DNA repair and, ultimately, cell death (Sarkaria et al., 2008). These alkylating agents can also induce senescence (Gunther et al., 2003). Temozolomide is administered as both concomitant and adjuvant treatments to radiotherapy. This aggressive treatment increases the two-year survival rate for GBM patients from 10.4%, with radiotherapy alone, to 26.5% (Stupp et al., 2005). Cells that escape radiotherapyand chemotherapy-induced cell death eventually reenter the cell cycle and contribute to local tumor recurrence. Despite advances in chemotherapy regimens, the median progression free survival in AA and GBM patients is, 15.2 months (Chamberlain et al., 2008) and 6.9 months (Stupp et al., 2005), respectively. The median overall survival time for GBMs is 14.6 months (Stupp et al., 2005).