Non-coding RNAs and glioma: Focus on cancer stem cells

Glioblastoma and gliomas can have a wide range of histopathologic subtypes. These heterogeneous histologic phenotypes originate from tumor cells with the distinct functions of tumorigenesis and self-renewal, called glioma stem cells (GSCs). GSCs are characterized based on multi-layered epigenetic mechanisms, which control the expression of many genes. This epigenetic regulatory mechanism is often based on functional non-coding RNAs (ncRNAs). ncRNAs have become increasingly important in the pathogenesis of human cancer and work as oncogenes or tumor suppressors to regulate carcinogenesis and progression. These RNAs by being involved in chromatin remodeling and modification, transcriptional regulation, and alternative splicing of pre-mRNA, as well as mRNA stability and protein translation, play a key role in tumor development and progression. Numerous studies have been performed to try to understand the dysregulation pattern of these ncRNAs in tumors and cancer stem cells (CSCs), which show robust differentiation and self-regeneration capacity. This review provides recent findings on the role of ncRNAs in glioma development and progression, particularly their effects on CSCs, thus accelerating the clinical implementation of ncRNAs as promising tumor biomarkers and therapeutic targets. Glioblastoma and gliomas can have a wide range of histopathologic subtypes. These heterogeneous histologic phenotypes originate from tumor cells with the distinct functions of tumorigenesis and self-renewal, called glioma stem cells (GSCs). GSCs are characterized based on multi-layered epigenetic mechanisms, which control the expression of many genes. This epigenetic regulatory mechanism is often based on functional non-coding RNAs (ncRNAs). ncRNAs have become increasingly important in the pathogenesis of human cancer and work as oncogenes or tumor suppressors to regulate carcinogenesis and progression. These RNAs by being involved in chromatin remodeling and modification, transcriptional regulation, and alternative splicing of pre-mRNA, as well as mRNA stability and protein translation, play a key role in tumor development and progression. Numerous studies have been performed to try to understand the dysregulation pattern of these ncRNAs in tumors and cancer stem cells (CSCs), which show robust differentiation and self-regeneration capacity. This review provides recent findings on the role of ncRNAs in glioma development and progression, particularly their effects on CSCs, thus accelerating the clinical implementation of ncRNAs as promising tumor biomarkers and therapeutic targets. 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Oncol. 2013; 6: 37Crossref PubMed Scopus (355) Google Scholar Here, we review the current information on the role of ncRNAs in glioma, particularly their effects on cancer stem cells (CSCs). The cellular heterogeneity in CNS tumors has long been appreciated15Bonavia R. Inda M.d.M. Cavenee W.K. Furnari F.B. Heterogeneity maintenance in glioblastoma: a social network.Cancer Res. 2011; 71: 4055-4060Crossref PubMed Scopus (337) Google Scholar,16Meacham C.E. Morrison S.J. Tumour heterogeneity and cancer cell plasticity.Nature. 2013; 501: 328-337Crossref PubMed Scopus (1535) Google Scholar; however, the role of self-regenerating tumor cells with increased tumorigenesis has been poorly recognized. Up to now, different terms have been used to denote these cells, including tumor/cancer/brain stem cells, stem-like tumor cells, tumor/cancer/glioma/brain tumor-propagating cells, and glioma/cancer/brain tumor-initiating cells. Because of these inconsistencies, attention has shifted away from their biology and their role in tumorigenesis, toward the discovery of new markers expressed on these cells, and determining if these cells can replicate as floating (non-adherent) spheroids. Moreover, these tumor cells are not necessarily produced from transformed stem cells, and other cell types, including normal stem cells and well-differentiated progenitor cells, could undergo oncogenic transformation. Therefore, precise functional assays must be performed, and an accepted definition should be used in all experimental studies. Any population of CSCs must have the capacity for self-regeneration, and also be able to produce well-differentiated progeny (Figure 1). In the case of brain tumors, these cells can form a tumor following intracranial transplantation, recapitulating the heterogeneity of parental tumor cells. Tumor-initiating cells in animal models can be used for investigation, but CSCs are more infiltrative capability than their progeny, and also their progeny lose tumorigenic potential during differentiation. The presence of a cellular hierarchy can be demonstrated by prospective enrichment and depletion of tumorigenic and non-tumorigenic cells. Cancer cells that contain a cellular hierarchy and are tumorigenic, are considered glioma stem cells or glioma CSCs. Cell culture spheroids can be derived from brain cells (normal or neoplastic), and their progenitors have limited self-renewal potential. However, the mere ability to form spheroids does not define CSCs, without showing a self-renewing population.18Pastrana E. Silva-Vargas V. Doetsch F. 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