Targeting Brain Cancer Stem Cells in the Clinic

Abstract

Malignant gliomas (MG) include glioblastoma multiforme (GBM), the most frequent and aggressive of primary brain tumors (Holland, Proc Natl Acad Sci USA 97:6242–6244, 2000). The standard of care for GBM, including surgery followed by radiotherapy and chemotherapy with temozolomide, is associated with a median overall survival of 14.6 months following diagnosis (Reardon et al., J Clin Oncol 24:1253–1265, 2006). The identification of brain cancer stem cells has led to a great opportunity to exploit stem cell mechanisms to inhibit brain tumor initiation, progression, and invasion. Brain cancer stem cells – also called tumor initiating cells or tumor propagating cells - share features with normal neural stem cells but do not necessarily originate from stem cells. Although most cancers have only a small fraction of cancer stem cells, these tumor cells have been shown in laboratory studies to contribute to therapeutic resistance, formation of new blood vessels to supply the tumor and tumor invasion. The presence of this population of cells can explain the recurrence of some brain tumors after chemotherapy, radiation therapy, and other current treatments. In fact, a few of these cells is enough to give rise to a new recurrent tumor. Viewing cancer through the prism of the cancer stem cell hypothesis may fundamentally transform brain cancer therapeutics and translate into improved prognosis of brain tumor patients through a novel means for testing of new strategies for treating brain tumors that focus on the eradication of the cancer stem cells. In animal models, dendritic cell immunotherapy and novel drugs that target stem cell pathways active in brain tumors have been efficacious against cancer stem cells suggesting that anti-cancer stem cell therapies may improve brain tumor therapy. In this chapter, we will discuss the approaches to isolate cancer stem cells and test the therapeutic resistance of cancer stem cells. We will then focus on the implications of cancer stem cells in the clinic, such as the effect of cancer stem cells in prognosis. Finally, we will explore several new strategies to target cancer stem cells.Key WordsGliomaBrain tumor-initiating cellsBrain tumor propagating cellsNeurospheresTumorospheresGlioblastomaDendritic cell vaccineSide populationCD133