The role of cancer stem cells in glioblastoma

Abstract

G lioblastoma (GBM) is the most common primary malignant brain tumor. It is extremely aggressive, with a median overall survival (OS) of less than 15 months after diagnosis even with maximal therapy. 95 Survival rates are dismal, ranging from 26% to 33% for 2-year survival and less than 5% for 5-year survival. 49,53,96 The standard first-line treatment includes resection, if possible, followed by concurrent radio-and chemotherapy, typically temozolomide (TMZ), and then 6-12 months of adjuvant TMZ. 38,68 Despite treatment, recurrence is nearly universal. 96 Glioblastoma demonstrates a great deal of phenotypic, morphological, and cellular heterogeneity and is thought to contain a population of self-renewing cancer stem cells (CSCs) that contributes to tumorigenesis and treatment resistance. Both intratumoral heterogeneity and the presence of these CSCs may contribute to the treatment-resistant nature of GBM and its propensity to recur in patients. 15,70 History and DefinitionThe concept of CSCs originated in 1994 with the observation that a fraction of cells in human acute myeloid leukemia can self-renew and reconstitute both the leukemic cell hierarchy and the clinical disease state in vivo after xenotransplantation. 1,11,49,99 These self-renewing cells were later discovered to exist in various solid tumors as well, including those of the breast, colon, lung, brain, and liver. 1,20,71,81,92 The CSC hypothesis proposes that individual tumors comprise a cellular hierarchy. Cancer stem cells reside at the apex of the hierarchy and possess the ability to self-renew and to divide to give rise to the variety of cells that populate a tumor. As tumor cells differentiate, their ability to self-renew is reduced and they lose their "stemness." The hierarchy is dynamic with respect to cell type (CSCs, non-CSCs) and is maintained by the balance between self-renewal and differentiation. 43,107 Viewed in this light, tumors can be thought of as aberrant organs comprising heterogeneous cell types derived from CSCs rather than simply an accumulation of diverse neoplastic clones.Researchers who made the initial attempts to define CSCs described a qualitatively distinct population of pathological cells that was able to self-renew and ir- Recurrence in glioblastoma is nearly universal, and its prognosis remains dismal despite significant advances in treatment over the past decade. Glioblastoma demonstrates considerable intratumoral phenotypic and molecular heterogeneity and contains a population of cancer stem cells that contributes to tumor propagation, maintenance, and treatment resistance. Cancer stem cells are functionally defined by their ability to self-renew and to differentiate, and they constitute the diverse hierarchy of cells composing a tumor. When xenografted into an appropriate host, they are capable of tumorigenesis. Given the critical role of cancer stem cells in the pathogenesis of glioblastoma, research into their molecular and phenotypic characteristics is a therapeutic priority. In this review, the authors discuss...

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