Turning cancer stem cells inside out: an exploration of glioma stem cell signaling pathways

Abstract

Tumors are complex collections of heterogeneous cells with recruited vasculature, inflammatory cells, and stromal elements. Neoplastic cells frequently display a hierarchy in differentiation status. Recent studies suggest that brain tumors have a limited population of neoplastic cells called cancer stem cells with the capacity for sustained self-renewal and tumor propagation. Brain tumor stem cells contribute to therapeutic resistance and tumor angiogenesis. In this minireview, we summarize recent data regarding critical signaling pathways involved in brain tumor stem cell biology and discuss how targeting these molecules may contribute to the development of novel anti-glioma therapies.

FIGURE 1.

Complex signaling pathways and cellular factors regulate glioma CSCs. Glioma CSCs are controlled at multiple levels by complicated regulatory networks. Signals initiated by RTKs, BMPRs, Hedgehog, and Notch result in complicated intracellular events to help balance self-renewal and differentiation of CSCs as well as the promotion of cell survival and proliferation. Intracellular regulators, including transcriptional factors (Olig2, Myc, Oct4, etc.), epigenetic modifiers (Bmi1), and miRNAs, are also highly potent in maintaining CSC population due to their ability to regulate massive downstream targets simultaneously. FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; IGF, insulin-like growth factor; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 1,4,5-trisphosphate; PI3K, phosphoinositide 3-hydroxykinase; GSK, glycogen synthase kinase; PKA, protein kinase A; NICD, Notch intracellular domain.

FIGURE 2.

Glioma stem cells reside within a perivascular niche. Regulated by oncogene activation or microenvironment conditions such as hypoxia, CSCs are strongly capable of stimulating the growth of the neovasculature by expressing high levels of pro-angiogenic factors such as VEGF. On the other hand, blood vessels create a vascular niche to help maintain CSC population. Such reciprocal relationships between glioma CSCs and blood vessels enable rapid and sustained tumorigenesis.