Targeting glioblastoma cancer stem cells: the next great hope?

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain tumor and is notorious for its poor prognosis. The highly invasive nature of GBM and its inherent resistance to therapy lead to very high rates of recurrence. Recently, a small cohort of tumor cells, called cancer stem cells (CSCs), has been recognized as a subset of tumor cells with self-renewal ability and multilineage capacity. These properties, along with the remarkable tumorigenicity of CSCs, are thought to account for the high rates of tumor recurrence after treatment. Recent research has been geared toward understanding the unique biological characteristics of CSCs to enable development of targeted therapy. Strategies include inhibition of CSC-specific pathways and receptors; agents that increase sensitivity of CSCs to chemotherapy and radiotherapy; CSC differentiation agents; and CSC-specific immunotherapy, virotherapy, and gene therapy. These approaches could inform the development of newer therapeutics for GBM. Key WordS • glioblastoma multiforme • cancer stem cells • treatment • tumor-initiating cells • glioma stem cellsAbbreviations used in this paper: Akt = protein kinase B; BCNU = 1,3-bis(2-chloroethyl)-1-nitrosourea; CSC = cancer stem cell; EGFR = epidermal growth factor receptor; GBM = glioblastoma multiforme; MGMT = methylguanine-DNA methyltransferase; STAT3 = signal transducer and activator of transcription 3; TGFb = transforming growth factor-b.

HEB silencing induces anti-proliferative effects on U87MG cells cultured as neurospheres and monolayers

“…Promoting the differentiation of CSCs, thus reducing tumor growth, is a novel approach to cancer therapy (43). Previous studies have described how CG500354 (44), a short hairpin RNA for ubiquitin ligases (45) and all-trans retinoic acid (46), may induce stem cell differentiation in GBM.…”

Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway

“…10–12 Eradication of GSCs is critical for the development of efficient therapeutic strategies, 13 and several strategies of targeting GSCs are currently being developed. 14 A potential therapeutic strategy for GBM would be to use forced differentiation and apoptosis of GSCs. 15 …”

Targeting Glioblastoma Stem Cells: A Review on Biomarkers, Signal Pathways and Targeted Therapy

“…The neuroepithelial stem cell protein commonly known as nestin, first described as an antigen of rat-401 against embryonic spinal cord and later identified as a class VI intermediate filament protein (80), has been shown to be expressed in neuroepithelial stem cells, and is highly expressed in several types of human malignancies, including higher grade GBM. Nestin has been shown to be strongly correlated with lower cancer patient survival, while some researchers hold the opposing view that there is no connection between Nestin expression and poor prognosis in GBM (78,(81)(82)(83)(84)(85). Nestin, as another putative marker for the GSC phenotype, probably plays a significant role in aggressive growth metastasis and selfrenewal capacity of CSCs, organizing the cytoskeleton, cell signaling, organogenesis, and cell metabolism, and represents the proliferation, migration, and multi-differentiated characteristics of multi-lineage progenitor cells, and it is thus a more suitable target molecule to identify GSCs in GBM than CD133 (86,87).…”