Biological and clinical implications of cancer stem cells in primary brain tumors

Abstract

Despite therapeutic advances, glioblastoma multiforme (GBM) remains a lethal disease. The infiltrative nature of this disease and the presence of a cellular population resistant to current medical treatments account for the poor prognosis of these patients. Growing evidence indicates the existence of a fraction of cancer cells sharing the functional properties of adult stem cells, including self-renewal and a greater ability to escape chemo-radiotherapy-induced death stimuli. Therefore, these cells are commonly defined as cancer stem cells (GBM-SCs). The initial GBM-SC concept has been challenged, and refined according to the emerging molecular taxonomy of GBM. This allowed to postulate the existence of multiple CSC types, each one driving a given molecular entity. Furthermore, it is becoming increasingly clear that GBM-SCs thrive through a dynamic and bidirectional interaction with the surrounding microenvironment. In this article, we discuss recent advances in GBM-SC biology, mechanisms through which these cells adapt to hostile conditions, pharmacological strategies for selectively killing GBM-SCs, and how novel CSC-associated endpoints have been investigated in the clinical setting.

Keywords: cancer stem cells; canonical pathway inhibitors; chemo-radioresistance; differentiation-inducing agents; glioblastoma multiforme; hypoxia; self-renewal pathway inhibitors; stem cell-based endpoints.

FIGURE 1

Theories proposed for explaining the origin and evolution of cancer.(A) Different mutant clones cohabit the tumor, each one with the same ability to proliferate and to retain tumorigenicity, and the random occurrence of genetic events confers dominant traits to some of them, (B) the CSC model originally postulated that a stem-like cell located at the apex of the tumor pyramid is the precursor of the whole tumor population, and (C) the combined clonal-stem cell model suggests that CSCs can undergo clonal evolution, and therefore multiple CSC clones coexist within the tumor.