Anti-GSC monoclonal antibody, clone 5I8

Due to the nature of enhanced resistance to conventional chemo/radiotherapies and metastasis, highly tumorigenic cancer stem cells (CSCs) have been proposed as a promising target for cancer eradication. To tackle the therapeutic difficulties of cancers involving CSCs, extensive research efforts have been directed toward understanding the extracellular microenvironments of CSCs, i.e., CSC niche, which plays important roles in CSC maintenance and expansion. Here we review recently identified mechanisms of maintenance and expansion of glioma CSCs (GSCs) leading to glioma progression and recurrence, with particular emphasis on the reports made by studies with a unique approach using polymer microarrays screening and with a unique viewpoint of necrotic particles. The polymer-based approach identified two groups of niche components, extracellular matrices (ECMs) and iron, and uncovered that co-expression of ECM-, iron-, and macrophage-related genes is predictive of glioma patients' outcome. The study in view of a unique fraction of GSC-derived necrotic particles proposed that such particles develop GSC-supportive tumor-associated macrophages (TAMs). Taken together, these studies provide new insights into the mechanisms underlying GSC-driven niche development, i.e., organization of the self-advantageous niche microenvironments for GSC maintenance and expansion leading to glioma progression and recurrence. A series of such studies can redefine the current concept of anti-GSC niche therapy that targets ligands/receptors supporting GSCs, and have potential to accelerate cancer therapy development.

Recently, the finding of cancer stem cells in brain tumors has increased the possibilities for advancing new therapeutic approaches with the aim to overcome the limits of current available treatments. In addition, a role for ion channels, particularly of TRP channels, in developing neurons as well as in brain cancer development and progression have been demonstrated. Herein, we focus on the latest advancements in understanding the role of TRPV2, a Ca2+ permeable channel belonging to the TRPV subfamily in neurogenesis and gliomagenesis. TRPV2 has been found to be expressed in both neural progenitor cells and glioblastoma stem/progenitor-like cells (GSCs). In developing neurons, post-translational modifications of TRPV2 (e.g., phosphorylation by ERK2) are required to stimulate Ca2+ signaling and nerve growth factor-mediated neurite outgrowth. TRPV2 overexpression also promotes GSC differentiation and reduces gliomagenesis in vitro and in vivo. In glioblastoma, TRPV2 inhibits survival and proliferation, and induces Fas/CD95-dependent apoptosis. Furthermore, by proteomic analysis, the identification of a TRPV2 interactome-based signature and its relation to glioblastoma progression/recurrence, high or low overall survival and drug resistance strongly suggest an important role of the TRPV2 channel as a potential biomarker in glioblastoma prognosis and therapy.