Abstract
Simple Summary5-ALA Fluorescence Guided Surgery aims at extending the boundaries of glioblastoma (GBM) resection. It is based on the use of a fluorescent dye, 5-aminolevulinic acid (5-ALA). Depending on the fluorescence levels, it is possible to distinguish the core of the tumor, the infiltrating borders and the healthy tissue. Since GBM progression is supported by tumor cells and their interaction with the surrounding microenvironment, we hypothesized that 5-ALA intensity could identify microenvironments with different tumor supporting properties. Taking advantage of glioma-associated stem cells; a human in vitro model of the glioma microenvironment, we demonstrate that all regions of the tumor support the tumor growth, but through different pathways. This study highlights the importance of understanding the TME to obtain key information on GBM biology and develop new therapeutic approaches.The glioblastoma microenvironment plays a substantial role in glioma biology. However, few studies have investigated its spatial heterogeneity. Exploiting 5-ALA Fluorescence Guided Surgery (FGS), we were able to distinguish between the tumor core (ALA+), infiltrating area (ALA-PALE) and healthy tissue (ALA−) of the glioblastoma, based on the level of accumulated fluorescence. The aim of this study was to investigate the properties of the microenvironments associated with these regions. For this purpose, we isolated glioma-associated stem cells (GASC), resident in the glioma microenvironment, from ALA+, ALA-PALE and ALA− samples and compared them in terms of growth kinetic, phenotype and for the expression of 84 genes associated with cancer inflammation and immunity. Differentially expressed genes were correlated with transcriptomic datasets from TCGA/GTEX. Our results show that GASC derived from the three distinct regions, despite a similar phenotype, were characterized by different transcriptomic profiles. Moreover, we identified a GASC-based genetic signature predictive of overall survival and disease-free survival. This signature, highly expressed in ALA+ GASC, was also well represented in ALA PALE GASC. 5-ALA FGS allowed to underline the heterogeneity of the glioma microenvironments. Deepening knowledge of these differences can contribute to develop new adjuvant therapies targeting the crosstalk between tumor and its supporting microenvironment.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive primary tumor affecting the adult central nervous system, characterized by a rapid and unavoidable lethal prognosis [1,2]
Glioma-Associated Stem Cells Were Efficiently Isolated from the Regions with Different 5-Aminolevulinic acid (5-ALA) Positivity
glioma-associated stem cells (GASC) isolated from ALA− regions took significantly longer time to reach confluence, compared to those isolated from the respective ALA+ and ALA-PALE regions
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive primary tumor affecting the adult central nervous system, characterized by a rapid and unavoidable lethal prognosis [1,2]. Despite current therapies based on maximal surgical resection combined with concomitant radio and chemotherapy, GBM patients show a median survival time of less than 2 years [3]. The failure of therapies is partly due to the impossibility to achieve a radical resection, as cancer cells tend to escape the tumor site and infiltrate the adjacent brain, causing recurrences a few months after surgery [4]. Discriminating normal brain from tissue infiltrated by tumor cells is difficult, even for experienced neurosurgeons, adopting surgical microscopy. To overcome this limitation and maximize the EOR, in the past decades, advanced techniques, such as neuro-navigation and intraoperative imaging, were initiated to support the intraoperative identification of tumor and tumor borders [10,11]
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