Modeling Microenvironmental Regulation of Glioblastoma Stem Cells: A Biomaterials Perspective

Heffernan, John M.; Sirianni, Rachael W.

doi:10.3389/fmats.2018.00007

Cited by 22 publications

(19 citation statements)

References 175 publications

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“…This phenomenon ensures the maintenance and progression of the tumor. A so-called "vascular or perivascular niche" concept of GBM, in which tumor areas are potentially invulnerable due to shielding from chemotherapy, has been highlighted [75]. Vascular "strengthening" in GBM is confirmed, in our work, by the fact that there are 10 times more CD117 + Tcs in this tumor than in astrocytomas.…”

Section: Discussionsupporting

confidence: 68%

Morphological and immunophenotypic characterization of perivascular interstitial cells in human glioma: Telocytes, pericytes, and mixed immunophenotypes

et al. 2020

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Telocytes (Tcs) and pericytes (Pcs) are two types of perivascular interstitial cell known to be widespread in various organs and tissues, including the brain. We postulated that Tcs and Pcs may be involved in glioblastoma (GBM) neovascularization. Objective: Morphological study of Tc and Pc roles in GBM. Materials and Methods: Samples from 15 GBM, 10 diffuse astrocytoma, as well as 5 control samples were studied. We used immunohistochemistry (IHC) with antibodies (Abs) to GFAP, Ki-67, CD117, NeuroD1, NG2, CD34, and SMA. Confocal laser scanning microscopy (CLSM) of 4 glioma tissue cultures and 4 GBM sections was performed with GFAP, CD117, CD34/connexin43, NeuroD1/connexin43, CD34/NG2 and CD13/ CD117 Abs. Electron microscopy (EM) of GBM was performed in 4 cases. Results: The presence of Tcs and Pcs was shown in GBM (IHC, EM, CLSM) and glioma cultures (CLSM). The Tc immunophenotype was CD117 + /CD34 + /connexin43 + / NeuroD1 +. The Pc immunophenotype was SMA + /NG2 + /CD13 +. The number of Tcs in GBM specimens was 10 times higher than in astrocytoma. We also identified CD13/ CD117 and CD34/NG2 co-expressing cells in GBM blood vessels. Conclusion: Four immunophenotypes were found in GBM vessels, corresponding to endotheliocytes, Pcs, Tcs, and a mixed Pc/Tc immunophenotype. These and forthcoming improvements in our understanding of the origin and function of Tcs, including their relationship with Pcs, are necessary steps in oncology. Study of these cell types (Tcs, Pcs) and their roles in brain tumor oncogenesis will likely enable improved targeted therapies and support development of new forms of anti-neoplastic drugs.

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Section: Discussionsupporting

confidence: 68%

Morphological and immunophenotypic characterization of perivascular interstitial cells in human glioma: Telocytes, pericytes, and mixed immunophenotypes

et al. 2020

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“…As a result of neo-vascularisation, the subsequent GBM vasculature markedly differs from that of healthy vasculature, comprising a highly dense, disorganised and leaky network of vessels [30]. The irregularity of neoangiogenesis in GBM results in areas of extreme chronic hypoxia [31], promoting necrosis and invasion of GBM cells into healthy tissue in order to evade the adverse conditions [18].…”

Section: Extracellular Vesicle-based Interactions Of Glioblastoma Cells With Stromal Counterparts In the Tumour Micro-environmentmentioning

confidence: 99%

Breaking through the glioblastoma micro-environment via extracellular vesicles

2020

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Glioblastoma (GBM) is the most common and most aggressive brain tumour. Prognosis remains poor, despite the combined treatment of radio- and chemotherapy following surgical removal. GBM cells coexist with normal non-neoplastic cells, including endothelial cells, astrocytes and immune cells, constituting a complex and dynamic tumour micro-environment (TME). Extracellular vesicles (EVs) provide a critical means of bidirectional inter-cellular communication in the TME. Through delivery of a diverse range of genomic, lipidomic and proteomic cargo to neighbouring and distant cells, EVs can alter the phenotype and function of the recipient cell. As such, EVs have demonstrated their role in promoting angiogenesis, immune suppression, invasion, migration, drug resistance and GBM recurrence. Moreover, EVs can reflect the phenotype of the cells within the TME. Thus, in conjunction with their accessibility in biofluids, they can potentially serve as a biomarker reservoir for patient prognosis, diagnosis and predictive therapeutic response as well as treatment follow-up. Furthermore, together with the ability of EVs to cross the blood–brain barrier undeterred and through the exploitation of their cargo, EVs may provide an effective mean of drug delivery to the target site. Unveiling the mechanisms by which EVs within the GBM TME are secreted and target recipient cells may offer an indispensable understanding of GBM that holds the potential to provide a better prognosis and overall quality of life for GBM patients.

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“…Several pre-clinical models such as cell lines, tissue culture and mouse models have been designed to test and evaluate the efficacy of drug therapies to successfully translate into clinical trials in glioblastoma patients. However, these frequently fail to accurately recapitulate the biology of glioblastoma tumors in humans [ 38 , 39 , 40 ]. For example, traditional two-dimensional (2D) culture of immortalized cell lines lacks the capabilities to replicate important features of primary tumors such as stemness, genetic heterogeneity and tumor microenvironment [ 41 ].…”

Section: Introductionmentioning

confidence: 99%

A Drug Screening Pipeline Using 2D and 3D Patient-Derived In Vitro Models for Pre-Clinical Analysis of Therapy Response in Glioblastoma

Lenin

Ponthier

Scheer

et al. 2021

IJMS

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Glioblastoma is one of the most common and lethal types of primary brain tumor. Despite aggressive treatment with chemotherapy and radiotherapy, tumor recurrence within 6–9 months is common. To overcome this, more effective therapies targeting cancer cell stemness, invasion, metabolism, cell death resistance and the interactions of tumor cells with their surrounding microenvironment are required. In this study, we performed a systematic review of the molecular mechanisms that drive glioblastoma progression, which led to the identification of 65 drugs/inhibitors that we screened for their efficacy to kill patient-derived glioma stem cells in two dimensional (2D) cultures and patient-derived three dimensional (3D) glioblastoma explant organoids (GBOs). From the screening, we found a group of drugs that presented different selectivity on different patient-derived in vitro models. Moreover, we found that Costunolide, a TERT inhibitor, was effective in reducing the cell viability in vitro of both primary tumor models as well as tumor models pre-treated with chemotherapy and radiotherapy. These results present a novel workflow for screening a relatively large groups of drugs, whose results could lead to the identification of more personalized and effective treatment for recurrent glioblastoma.

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Modeling Microenvironmental Regulation of Glioblastoma Stem Cells: A Biomaterials Perspective

Cited by 22 publications

References 175 publications

Morphological and immunophenotypic characterization of perivascular interstitial cells in human glioma: Telocytes, pericytes, and mixed immunophenotypes

Morphological and immunophenotypic characterization of perivascular interstitial cells in human glioma: Telocytes, pericytes, and mixed immunophenotypes

Breaking through the glioblastoma micro-environment via extracellular vesicles

A Drug Screening Pipeline Using 2D and 3D Patient-Derived In Vitro Models for Pre-Clinical Analysis of Therapy Response in Glioblastoma

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