Biomimetic models to examine microenvironmental regulation of glioblastoma stem cells

Abstract Glioblastoma multiforme (GBM), a malignant brain tumor, is the deadliest form of human cancer with low survival rates because of its highly invasive nature. In recent years, there has been a growing appreciation for the role that glioblastoma stem cells (GSCs) play during tumorigenesis and tumor recurrence of GBM. GSCs are a specialized subset of GBM cells with stem cell-like features that contribute to tumor initiation and therapeutic resistance. Thus, to enhance therapeutic efficiency and improve survival, targeting GSCs and their microenvironmental niche appears to be a promising approach. To develop this approach, understanding GSC-microenvironment interactions is crucial. This review discusses various biomimetic model systems to understand the impact of biophysical, biochemical, and cellular microenvironmental cues on GSC behaviors. These models include two-dimensional or matrix-free environment models, engineered biomaterial-based three-dimensional models, co-culture models, and mouse and rat in vivo models. These systems have been used to study the effects of biophysical factors, modulation of signaling pathways, extracellular matrix components, and culture conditions on the GSC phenotype. The advantages and disadvantages of these model systems and their impact in the field of GSC research are discussed.