Abstract
Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor and a subpopulation of glioma stem-like cells (GSCs) is likely responsible for the invariable recurrence following maximum resection and chemoradiotherapy. As most GSCs that are located in the perivascular and perinecrotic niches should be removed during tumor resection, it is very important to know where surviving GSCs are localized. Here, we investigated the existence and functions of GSCs in the tumor periphery, which is considered to constitute the invasion niche for GSCs in GBM, by analyzing expression of stem cell markers and stem cell-related molecules and measuring particular activities of cultured GSCs. In addition, the relationship between GSCs expressing particular stem cell markers and pathological features on MRI and prognosis in GBM patients was analyzed. We showed that GSCs that express high levels of CD44 are present in the tumor periphery. We also found that vascular endothelial growth factor (VEGF) is characteristically expressed at a high level in the tumor periphery. Cultured GSCs obtained from the tumor periphery were highly invasive and have enhanced migration phenotype, both of which were markedly inhibited by CD44 knockdown. Higher expression of CD44 in the tumor periphery than in the core was correlated with a highly invasive feature on MRI and was associated with early tumor progression and worse survival, whereas lower expression of CD44 in the tumor periphery corresponded to low invasion and was associated with longer survival. The low invasion type on MRI tended to show high levels of VEGF expression in the tumor periphery, thus presenting the tumor with high proliferative activity. These results imply the significance of GSCs with high levels of CD44 expression in the tumor periphery compared to the core, not only in tumor invasion but also rapid tumor progression and short survival in patients with GBM.
Highlights
Glioblastoma multiforme (GBM) is the most malignant type of primary brain tumor with a median survival of 15 months, even after maximum resection of the tumor followed by the current standard chemoradiotherapy [1]
Focusing on the specific stem cell marker and stem cell-related molecule that we identified in the initial study, we investigated the pathological function of glioma stem-like cells (GSCs) expressing the specific stem cell marker by using cultured GSCs that were established from the tumor tissue in the tumor periphery and analyzed clinical significance of GSCs expressing the specific marker in the pathological features on magnetic resonance imaging (MRI) and prognosis of patients with GBM
Bien-Möller et al [25] analyzed the expression of seven stem cell markers as well as differentiation and microglia markers and demonstrated that CD44, ELF4, Nanog, and Nestin were elevated at both mRNA and protein levels in GBM, but only CD133 and Nestin were associated with survival rates
Summary
Glioblastoma multiforme (GBM) is the most malignant type of primary brain tumor with a median survival of 15 months, even after maximum resection of the tumor followed by the current standard chemoradiotherapy [1]. Survival, and invasion are dynamically regulated by intricate interactions between GSCs and various components of the microenvironment including host stromal cells [7, 8]. In GBM, two distinct regions, the perivascular niche and the hypoxic/perinecrotic niche, are considered specific niches where GSCs are enriched and their maintenance and survival are supported [9, 10]. GSCs located in the perivascular niche generally reside close to the endothelial cells of capillaries of the tumor neovasculature and play a central role in angiogenesis of highly disorganized vasculature to respond to a rapidly growing tumor [11, 12]. GSCs in these niches are thought to be critical for tumor proliferation, they are unlikely to be the main cause of tumor recurrence, when the tumor is completely resected including the area of these niches
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