Signaling in malignant astrocytomas: role of neural stem cells and its therapeutic implications

Abstract

Malignant astrocytomas are infiltrative and aggressive brain tumors. Conventional forms of therapy have not been effective in controlling this incurable disease. Recent advances in understanding the molecular biology of these tumors have revealed potential mechanisms by which astrocytoma cells undergo tumor initiation, progression, and maintenance, as well as possible avenues for targeted therapeutics. Studies on the role of neural stem cells as cells of origin and tumor-propagating cells have also greatly increased our understanding of the biology and clinical behavior of these tumors. An integrated view of the genetics, signal transduction, and cell biology of astrocytomas, as well as clinical data from patients, will provide a more useful approach in designing novel therapies for this devastating disease.

Figure 1. Stem Cell-Related Signaling Pathways in Malignant Astrocytomas

Simplified schematic of genetic alterations and perturbed developmental pathways found in astrocytomas. Mutations in astrocytomas frequently involve cell cycle and apoptosis regulation and growth factor receptor signaling. Receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) are frequently overactivated in malignant astrocytomas, stimulating its downstream effectors, such as Ras and phosphatidylinositide-3-kinase (PI3K). Nf1 and Pten are tumor suppressors that negatively regulate Ras and PI3K signaling, respectively. Other tumor suppressors such as p53, retinoblastoma (Rb) and Ink4A have also been implicated. These pathways have been shown to regulate neural stem cell function. Bone morphogenetic proteins (BMP), Notch, Sonic hedgehog (Shh) and Wnt are developmentally-regulated signaling pathways that are also active in normal neural stem cells but are dysregulated in malignant astrocytomas.

Figure 2. Neural Stem/Progenitor Origin and Stem-Like Cancer Cells in Malignant Astrocytomas and Potential Therapeutic Approaches

Model of neural stem/progenitor origin posits that targeting of known tumor-initiating mutations in these self-renewing cells give rise to malignant astrocytomas. Activation of developmental signaling pathways may be secondary events during tumorigenesis. Stem-like cancer cells in astrocytomas may represent the more malignant subpopulation of cancer cells and provide a mechanism for therapeutic resistance. Potential avenues for therapeutic intervention may require combinations of targeted therapies against both stem-like and less tumorigenic cancer cells as well as inhibition of resistance mechanisms by targeting cancer stem cells. The stem/progenitor origin and the presence of stem-like cancer cells also paves the way for therapeutic avenues such as differentiation therapy in retarding the growth of malignant astrocytomas.