Glioblastoma Multiforme Stem Cells

Abstract

Glioblastoma multiforme (GBM) is an aggressive, malignant, and lethal brain tumor, resistant to all current forms of treatment. The rapidly emerging focus on cancer stem cells embodies a paradigm shift in our understanding of tumor pathogenesis, while the development of powerful genome-wide screening techniques has provided cause for optimism related to the development of more reliable therapies primarily targeting GBM stem cells (GBMSCs). There are promising mounting data on providing new molecular targets and predictive markers of response, leading to more effective therapies of GBM, guided by patient-specific genetic and epigenetic profiling. However, the achievement of efficient GBMSC targeting also requires an adequate understanding of the unique microenvironment, and the relationship with the immune system in the central nervous system (CNS) and CNS tumors. The endogenous immune regulation is likely to limit or abrogate the efficacy of the host's immune response, as well as the developed immunotherapeutic strategies at present. Therefore, a comprehensive understanding of the mechanisms underlying the GBM-induced immunosuppression is indispensable. This review presents a summary of the present knowledge both on GBMSCs and the GBM, and/or GBMSC-related mechanisms of developing both local and systemic immunosuppression, of which an understanding may lead to the development of the novel and effective therapeutic strategies.

Characteristics of the expression of KAI1/CD82 and PDGFRβ and their impact on glioma progression

“…Some authors suggest that the autocrine and paracrine stimulation of PDGFRβ could play an essential role in glial tumorigenesis [4,31]. It was revealed that during glioma progression the PDGFRβ stimulation can induce the activation of different signaling receptors like EGFR, Notch which lead to dedifferentiation of glioma cells, and increase cell motility and malignancy of the tumor [8,31].…”

“…Grade I/II astrocytomas are slow-growing tumors without aggressive features, whereas grade III and IV glio mas possess a malignant phenotype associated with high proliferative activity and vascular formation [18,19]. Glioblastoma (grade IV) is one of the most aggressive and deadly malignant brain tumors with an average survival time of 15 months after diagnosis [8,13,18,20]. Most primary glioblastomas develop de novo but some parts of diffuse astrocytomas grade II and III may progress to grade IV as secon dary glioblastomas [12,25].…”

“…According to some authors, the migratory behavior of glioma cells observed during the tumor progression might be a result of the activa-tion of surface receptors and signaling pathways [19]. A number of alternations in different genes have been identified in human gliomas and some of them are involved in glioma progression [8]. Among the growth factors, the platelet-derived growth factor (PDGF) has been well described in glioblastomas [19,20].…”

“…This process involves a molecular mechanism which requires the contribution of a multiple gene alteration [15,30]. The role of metastasis suppressor genes has been discussed very rarely in gliomas [8,19]. The most interesting is the KAI1/CD82 gene originally identified as a putative metastasis suppressor gene for prostate cancer [9].…”

Identification of OLIG2 as the most specific glioblastoma stem cell marker starting from comparative analysis of data from similar DNA chip microarray platforms

“…Many markers potentially specific for GSCs have been proposed such as A2B5 cell surface ganglioside epitope (A2B5) [26,27], aldehyde dehydrogenase (ALDH) [28], BMI1 polycomb ring finger oncogene (BMI1) [29,30], fucosyltransferase 4 (FUT4) (CD15) [31], Thy-1 cell surface antigen (Thy-1) (CD90) [32], prominin-1 (PROM1) (CD133) [5,6], chemokine (C-X-C motif) receptor 4 (CXCR4) [33], inhibitor of DNA binding 1 (ID1) [34], integrin α6 (ITGA6) [35], L1 cell adhesion molecule (L1CAM) [36], maternal embryonic leucine zipper kinase (MELK) [37], musashi-1 (msi1) [38], nestin (NES) [38][39][40], octamer-binding transcription factor 4 (OCT4) [41], OLIG2 [42] and SOX2 [38,[43][44][45]. Among these, much attention has been given to CD133, which is currently used to identify and isolate GSCs [40,43,[46][47][48][49][50].…”