Personalized medicine aims at identifying patient- and tumor-specific factors useful both for the prognostic stratification of patients and for the identification of therapeutic options that maximize effectiveness, minimizing treatment-related toxicity . This is especially important in neuro-oncology, given the high morbidity and mortality of brain tumors, the rarity of valuable treatment options, and the possible toxicity of therapy [1, 43]. In this article, we have demonstrated that: (a) human gliomas host a novel population of nontumorigenic stem cells, named GASC, that support tumor growth; (b) the optimized method for GASC in vitro expansion is a robust and highly reproducible model of the stromal compartment of both HGG and LGG; (c) GASC support tumor growth releasing exosomes; (d) both tumor stem cells and tumor-supporting cells can be expanded from HGG; (e) GASC features have a strong prognostic value in LGG. The translational nature of this article imposes us to discuss all the basic research findings and their clinical application. (a) Since 2000, Hanahan and Weinberg have postulated that the non-neoplastic component of tumors plays an active role in tumor biology [15, 16]. However, little is known regarding the presence of non-neoplastic stem cells within tumors. These latter may arise from normal progenitors, in analogy with what occurs in Platelet-Derived Growth Factor (PDGF)-induced gliomas of the adult or neonatal rat, where a small population of neural stem cells are “recruited” into the glioma and are induced to proliferate . Accordingly, Kong's group has isolated from a single glioblastoma patient a stem cell line with some mesenchymal features (GS-MSLC) that showed the ability to influence a GSC line by increasing, in vitro, its proliferation, and, in vivo, the size of the formed tumors via an incremented angiogenesis [45, 46]. Our article newly shows that normal stem cells with mesenchymal features and a wide differentiation potential can be isolated both from LGG and HGG, support tumor growth releasing exosomes, and can predict patient prognosis. (b) The presence of GASC raises issues regarding their origin. There is a limited presence of fibroblasts in the CNS and their proliferation has never been described in the course of pathology . Instead, the cell type that characterizes the CNS' response to injury is represented by reactive astrocytes [48, 49]. Importantly, in murine models, non-neoplastic astrocytes could be converted, by the glioma microenvironment, into a reactive phenotype [50, 51] that could acquire stem cell features similar to GASC . Alternatively, GASC may derive from a recently described population of perivascular mesenchymal stem cells endowed with both mesodermal and neuroectodermal differentiation capacities . However, the identification of the in vivo counterpart of GASC in humans is limited since lineage tracing from the cell-of-origin cannot be done in humans . (c) GASC exert their in vitro tumor-supporting action through the release of exosomes. This finding is in line with recent data from Skog's group, who showed that glioblastoma tumor cells could release exosomes, containing mRNA, miRNA, and angiogenic proteins, able to act on endothelial cells, possibly favoring the development of a tumor-permissive microenvironment . Accordingly, the proteome and mRNA profiles of exosome closely reflect the oxygenation status of donor glioma cells and patient tumors . Conversely, it has been recently shown that TAF, through the release of exosomes, could induce, in breast tumor cells, the acquisition of a metastatic phenotype . This suggests the existence of a continuous tumor/stroma crosstalk mediated by exosomes. Accordingly, our article shows that GASC can produce exosomes able to influence GSC obtained from the same patient. Interestingly, exosomes can be also released into the bloodstream  and act on distant sites taking part to the formation of a premetastatic niche . Therefore, a deeper comprehension of exosome biology will open new avenues for the treatment of neoplastic lesions. (d) Concerning the surface proteins entering in the GASC score, they essentially belong to three classes: stem cell antigens (CD271, CD133, and ABCG2), adhesion proteins (CD49a, CD49d, and E-Cadherin), and mesenchymal markers (CD90, CD73, and CD105). Specifically, GASC obtained from patients with poor prognosis were characterized by an increase in stem cell-related markers, a downregulation in integrin expression, and a variable modulation of mesenchymal markers. When we evaluated, by multiparametric-cytofluorimetric assays, whether these markers identified the same population or distinct subpopulations, we concluded that, while CD133+ cells frequently coexpressed the other stem cell markers CD271, ABCG2, and E-Cadherin, the majority of the CD271+, ABCG2+, and E-Cadherin+ cells did not express CD133, constituting distinct subpopulations. Therefore, the score seems to take into account distinct subpopulations whose specific role in the natural history of glioma deserves future investigations. Nevertheless, CD133 is a well-established, although debated , marker of both neural stem cells and glioma-initiating stem cells [11, 12]. Since GASC were devoid of tumor-initiating properties in vivo, we cannot exclude that human gliomas may contain, as in the murine model previously mentioned , a small population of neural stem cells. Alternatively, CD133+ cells may derive from a recently described circulating CD133+ABCG2+ mesenchymal stem cells endowed with neurogenic potential . (e) Despite the lack of class I evidence, surgical treatment is considered the first option in LGG management [4, 5]. However, the aptitude of LGG to infiltrate eloquent areas represents the major limitation in achieving radical resection . The choice between the different postsurgical therapeutic options for LGG patients is still a challenge, because there are not definitive criteria to classify a lesion as at high-risk or low-risk to progress and side effects of adjuvant treatments are not justifiable in patients at low-risk of relapse/progression [4, 5]. Recently, some advances in defining novel biomarkers able to better classify LGG have been done [58, 59]. IDH mutations and 1p/19q codeletions seem to be independent prognostic markers for OS . The prognostic/predictive role of the methylation of the MGMT promoter is now under investigation, while that of p53 and Ki67 has been questioned . In this article, considering the state-of the art clinical, histological, and molecular LGG prognostic factors, we confirmed the ability of some of these latter to predict OS, MPFS, and PFS. However, in multivariate analysis, the GASC-based score was the only independent predictor of both OS and MPFS, outperforming all the available criteria in stratifying LGG patients and thus allowing a better clinical management . This can prospects the use of this in vitro model of disease both to predict response to therapy and to identify innovative interventions aimed at interrupting the crosstalk between tumor cells and their supporting stroma. Notably, stromal cells are optimal therapeutic targets for their genetic stability and lower potential to develop drug resistance .