Abstract
Cancer stem cells (CSCs), known also as tumor-initiating cells, are quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic tumors and soon after in solid malignancies. CSCs have attracted remarkable research interest due to their role in tumor resistance to chemotherapy and radiation treatment as well as recurrence. Extensive research has been devoted to the role of CSCs in glioblastoma multiforme (GBM), the most common primary brain tumor in adults, which is characterized by a dismal prognosis because of its aggressive course and poor response to treatment. The aim of the current paper is to provide an overview of current knowledge on the role of cancer stem cells in the pathogenesis and treatment resistance of glioblastoma. The six regulatory mechanisms of glioma stem cells (GSCs)—tumor microenvironment, niche concept, metabolism, immunity, genetics, and epigenetics—are reviewed. The molecular markers used to identify GSCs are described. The role of GSCs in the treatment resistance of glioblastoma is reviewed, along with future treatment options targeting GSCs. Stem cells of glioblastoma thus represent both a driving mechanism of major treatment difficulties and a possible target for more effective future approaches.
Highlights
The aim of the current article is to review the current knowledge on glioma stem cells (GSCs), including their historical background, definition, the six main regulatory mechanisms, and their role in glioblastoma multiforme (GBM) resistance to chemotherapy and radiation treatment, as well as future treatment options targeting GSCs
Reactive gemistocytes in glioblastoma might suggest a secondary nature of the tumor, while astrocytes at the invasive front of low-grade glioma had to be distinguished from the neoplastic cells themselves in order to confirm the diagnosis of a glioma
The Sonic hedgehog (Shh) cascade leads to activation of the glioma-associated oncogene gliomaassociated oncogene 1 (GLI1) and GLI2 products, which bind to the Nanog promoter and upregulate this stem cell marker
Summary
Primary CNS tumors account only for 4% of all newly diagnosed cancer cases in the United States of America [2] Some of these neoplasms represent a major challenge for healthcare because of their dismal prognosis and poor response to treatment. The gold standard of glioblastoma care includes surgical resection, followed by radiotherapy combined with concomitant or adjuvant chemotherapy with an alkylating agent, temozolomide, which induce single- and double-strand DNA breaks [7,8,9] This protocol results in a median survival time of 14–18 months, with few reports on longer overall survival periods reaching 20.9 months [4,9,10]. The aim of the current article is to review the current knowledge on glioma stem cells (GSCs), including their historical background, definition, the six main regulatory mechanisms, and their role in glioblastoma multiforme (GBM) resistance to chemotherapy and radiation treatment, as well as future treatment options targeting GSCs
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