Abstract
Glioblastoma (World Health Organization/WHO grade IV) is the most common and most aggressive adult glial tumor. Patients with glioblastoma, despite being treated with gross total resection and post-operative radiation/chemotherapy, will almost always develop tumor recurrence. Glioblastoma stem cells (GSC), a minor subpopulation within the tumor mass, have been recently characterized as tumor-initiating cells and hypothesized to be responsible for post-treatment recurrence because of their enhanced radio-/chemo-resistant phenotype and ability to reconstitute tumors in mouse brains. Genome-wide expression profile analysis uncovered molecular properties of GSC distinct from their differentiated, proliferative progeny that comprise the majority of the tumor mass. In contrast to the hyperproliferative and hyperangiogenic phenotype of glioblastoma tumors, GSC possess neuroectodermal properties and express genes associated with neural stem cells, radial glial cells, and neural crest cells, as well as portray a migratory, quiescent, and undifferentiated phenotype. Thus, cell cycle-targeted radio-chemotherapy, which aims to kill fast-growing tumor cells, may not completely eliminate glioblastoma tumors. To prevent tumor recurrence, a strategy targeting essential gene pathways of GSC must be identified and incorporated into the standard treatment regimen. Identifying intrinsic and extrinsic cues by which GSC maintain stemness properties and sustain both tumorigenesis and anti-apoptotic features may provide new insights into potentially curative strategies for treating brain cancers.
Highlights
Cancer remains the third biggest killer worldwide
Glioblastoma stem cells (GSC) isolated from recurrent glioblastoma tumors express molecular properties of a quiescent stem cell phenotype distinct from their proliferative progeny which make up the majority of tumor mass [1]
In our recent study of GSC, we performed the first genome-wide expression profile analysis of purified, tumorigenic CD133+ GSC derived from treatment-refractory recurrent brain tumors [1]. We found that these tumorigenic CD133+ GSC possess characteristics of neuro ectoderm-like cells and express multiple markers for adult stem cells, including radial glial cells (RGC), neural stem cells (NSC) (e.g., Sry-Related HMG-box 2 (SOX2), nestin), mesenchymal stem cells (MSC) (e.g., CD44, CD105), neural crest cells (NCC) (e.g., Distal-less homeo box 5/6, v-myc myelocytomatosis viral-related oncogene), and stem cells in the small intestine and colon (e.g., Leucine-rich repeat-containing G protein-coupled receptor 5)
Summary
Cancer remains the third biggest killer worldwide. its survival rates are improving, it is still responsible for 13 percent of all deaths (according to the World Health Organization/WHO, 2010). GSC isolated from recurrent glioblastoma tumors express molecular properties of a quiescent stem cell phenotype distinct from their proliferative progeny which make up the majority of tumor mass [1]. This suggests that they may evade standard cell cycle target-based therapy and continue seeding the new tumor, despite local treatment to the bulk tumor mass (Figure 1). This review summarizes signaling pathways that have been relatively well-studied in GSC and are essential for maintaining GSC stemness, tumorigenic potential, and anti-apoptotic features Based on these reported signaling pathways relevant for maintaining GSC, we discuss and propose potential targeting strategies for future therapeutic developments in the treatment of brain cancer. Slow-cycling tumor initiation active non-CSC proliferative differentiation angiogenic fast-growing radio-chemoresistant dormant CSC early activated CSC active CSC progenitors differentiated tumor cells differentiated tumor cells apoptotic cells necrotic cells radio-chemosensitive
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