Abstract
Glioblastoma multiforme (GBM) is the most frequent primary brain tumor in adults with a 5-year survival rate of 5% despite intensive research efforts. The poor prognosis is due, in part, to aggressive invasion into the surrounding brain parenchyma. Invasion is a complex process mediated by cell-intrinsic pathways, extrinsic microenvironmental cues, and biophysical cues from the peritumoral stromal matrix. Recent data have attributed GBM invasion to the glioma stem-like cell (GSC) subpopulation. GSCs are slowly dividing, highly invasive, therapy resistant, and are considered to give rise to tumor recurrence. GSCs are localized in a heterogeneous cellular niche, and cross talk between stromal cells and GSCs cultivates a fertile environment that promotes GSC invasion. Pro-migratory soluble factors from endothelial cells, astrocytes, macrophages, microglia, and non-stem-like tumor cells can stimulate peritumoral invasion of GSCs. Therefore, therapeutic efforts designed to target the invasive GSCs may enhance patient survival. In this review, we summarize the current understanding of extrinsic pathways and major stromal and immune players facilitating GSC maintenance and survival.
Highlights
Glioblastoma multiforme (GBM) is the most frequently occurring primary brain tumor in adults [1]
This review summarizes the paracrine, autocrine, and intrinsic molecular pathways that have been reported to facilitate glioma stem-like cell (GSC) maintenance and survival
GBM cells activate TLR signaling in microglia, which results in MT1-matrix metalloproteinase (MMP) expression [76, 77]
Summary
Glioblastoma multiforme (GBM) is the most frequently occurring primary brain tumor in adults [1]. Recent analyses have been focused on the identification of genetic alterations in the patient’s tumor as a potential means for individualized therapy This approach utilizes biopsy samples from the tumor core, which is subsequently removed during surgical resection [8,9,10]. This approach provides little insight into the genetic alterations in the residual invasive cells that give rise to tumor recurrence or the microenvironmental factors that influence their survival. Results have revealed differential activation of transcription factors and significant gene expression differences in antiapoptotic and survival pathways in the invasive cells relative to cells in the tumor core [25,26,27]. This review summarizes the paracrine, autocrine, and intrinsic molecular pathways that have been reported to facilitate GSC maintenance and survival
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