Extracellular adenosine promotes cell migration/invasion of Glioblastoma Stem-like Cells through A3 Adenosine Receptor activation under hypoxia

Torres, Ángelo; Erices, José Ignacio; Sánchez, Fabiola A.; Ehrenfeld, Pamela; Turchi, Laurent; Virolle, Thierry; Uribe, Daniel; Niechi, Ignacio; Spichiger, Carlos; Rocha, José Dellis; Ramírez, Marcos; Salazar‐Onfray, Flavio; Martin, R. H.; Quezada, Claudia

doi:10.1016/j.canlet.2019.01.004

Cited by 66 publications

(72 citation statements)

References 45 publications

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“…[105] Hypoxia can also modulate the production of certain metabolite in extracellular GBM TME such as excess adenosine production, enhancing MES transformation through HIF-2/PAP-dependent activation of A3AR. [106] Hypoxia can modulate MES transition through other routes such as macrophage migrating inhibiting factor (MIF), through MIF-CXCR4-AKT regulatory pathway. [107] The crosstalk between immune cells and mesenchymal transition is a two-way interaction probably mediated by TAMs.…”

Section: The Tumor (Immune) Microenvironmentmentioning

confidence: 99%

Mesenchymal Transformation: The Rosetta Stone of Glioblastoma Pathogenesis and Therapy Resistance

Azam

Tannous

2020

Advanced Science

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Despite decades of research, glioblastoma (GBM) remains invariably fatal among all forms of cancers. The high level of inter-and intratumoral heterogeneity along with its biological location, the brain, are major barriers against effective treatment. Molecular and single cell analysis identifies different molecular subtypes with varying prognosis, while multiple subtypes can reside in the same tumor. Cellular plasticity among different subtypes in response to therapies or during recurrence adds another hurdle in the treatment of GBM. This phenotypic shift is induced and sustained by activation of several pathways within the tumor itself, or microenvironmental factors. In this review, the dynamic nature of cellular shifts in GBM and how the tumor (immune) microenvironment shapes this process leading to therapeutic resistance, while highlighting emerging tools and approaches to study this dynamic double-edged sword are discussed.

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Section: The Tumor (Immune) Microenvironmentmentioning

confidence: 99%

Mesenchymal Transformation: The Rosetta Stone of Glioblastoma Pathogenesis and Therapy Resistance

Azam

Tannous

2020

Advanced Science

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“…Studies on the nucleoside influence on different tumor cell lines and on the other cells of the TME are still conflicting. Some literature data indicate that ADO plays a prominent role in multiple areas of glioma pathogenesis, including promoting cell growth, angiogenesis and invasiveness [ 33 , 34 , 35 ]. Our results demonstrate that the chronic exposure of up to micromolar extracellular ADO concentration does not significantly modify glioblastoma cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…ADO treatment has been reported to promote the migration of breast cancer cells [ 81 ]. Moreover, the activation of A3 AR has been reported to increase the motility of glioma stem cells [ 34 ]. Herein, we demonstrate that the prolonged exposure to a high ADO concentration (100 µM) promotes the glioma motility in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Emerging evidences report the prominent role of adenosinergic signaling in multiple aspects of GBM aggressiveness, including GBM growth, angiogenesis and invasiveness [ 33 , 34 , 35 , 36 ]. The inhibition of CD73 activity and the pharmacological blockade of ARs decreased cell adhesion to the extracellular matrix of U138MG glioblastoma cells, demonstrating the pivotal role played by extracellular adenosine in controlling aggressive traits of GBM [ 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

“…The inhibition of CD73 activity and the pharmacological blockade of ARs decreased cell adhesion to the extracellular matrix of U138MG glioblastoma cells, demonstrating the pivotal role played by extracellular adenosine in controlling aggressive traits of GBM [ 37 , 38 ]. Furthermore, the activation of selective AR subtypes has been related to the promotion of the epithelial–mesenchymal transition (EMT) in GBM and other types of cancer [ 34 , 39 , 40 ]. The EMT is a complex process in which cell phenotype switches from the epithelial to mesenchymal one.…”

Section: Introductionmentioning

confidence: 99%

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High Adenosine Extracellular Levels Induce Glioblastoma Aggressive Traits Modulating the Mesenchymal Stromal Cell Secretome

Pietrobono

Giacomelli

Marchetti

et al. 2020

IJMS

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Glioblastoma is an aggressive, fast-growing brain tumor influenced by the composition of the tumor microenvironment (TME) in which mesenchymal stromal cell (MSCs) play a pivotal role. Adenosine (ADO), a purinergic signal molecule, can reach up to high micromolar concentrations in TME. The activity of specific adenosine receptor subtypes on glioma cells has been widely explored, as have the effects of MSCs on tumor progression. However, the effects of high levels of ADO on glioma aggressive traits are still unclear as is its role in cancer cells-MSC cross-talk. Herein, we first studied the role of extracellular Adenosine (ADO) on isolated human U343MG cells as a glioblastoma cellular model, finding that at high concentrations it was able to prompt the gene expression of Snail and ZEB1, which regulate the epithelial–mesenchymal transition (EMT) process, even if a complete transition was not reached. These effects were mediated by the induction of ERK1/2 phosphorylation. Additionally, ADO affected isolated bone marrow derived MSCs (BM-MSCs) by modifying the pattern of secreted inflammatory cytokines. Then, the conditioned medium (CM) of BM-MSCs stimulated with ADO and a co-culture system were used to investigate the role of extracellular ADO in GBM–MSC cross-talk. The CM promoted the increase of glioma motility and induced a partial phenotypic change of glioblastoma cells. These effects were maintained when U343MG cells and BM-MSCs were co-cultured. In conclusion, ADO may affect glioma biology directly and through the modulation of the paracrine factors released by MSCs overall promoting a more aggressive phenotype. These results point out the importance to deeply investigate the role of extracellular soluble factors in the glioma cross-talk with other cell types of the TME to better understand its pathological mechanisms.

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Extracellular adenosine oppositely regulates the purinome machinery in glioblastoma and mesenchymal stem cells

Pietrobono,

Russo,

Bertilacchi

et al. 2024

IUBMB Life

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Glioblastoma (GB) is a lethal brain tumor that rapidly adapts to the dynamic changes of the tumor microenvironment (TME). Mesenchymal stem/stromal cells (MSCs) are one of the stromal components of the TME playing multiple roles in tumor progression. GB progression is prompted by the immunosuppressive microenvironment characterized by high concentrations of the nucleoside adenosine (ADO). ADO acts as a signaling molecule through adenosine receptors (ARs) but also as a genetic and metabolic regulator. Herein, the effects of high extracellular ADO concentrations were investigated in a human glioblastoma cellular model (U343MG) and MSCs. The modulation of the purinome machinery, i.e., the ADO production (CD39, CD73, and adenosine kinase [ADK]), transport (equilibrative nucleoside transporters 1 (ENT1) and 2 (ENT2)), and degradation (adenosine deaminase [ADA]) were investigated in both cell lines to evaluate if ADO could affect its cell management in a positive or negative feed‐back loop. Results evidenced a different behavior of GB and MSC cells upon exposure to high extracellular ADO levels: U343MG were less sensitive to the ADO concentration and only a slight increase in ADK and ENT1 was evidenced. Conversely, in MSCs, the high extracellular ADO levels reduced the ADK, ENT1, and ENT2 expression, which further sustained the increase of extracellular ADO. Of note, MSCs primed with the GB‐conditioned medium or co‐cultured with U343MG cells were not affected by the increase of extracellular ADO. These results evidenced how long exposure to ADO could produce different effects on cancer cells with respect to MSCs, revealing a negative feedback loop that can support the GB immunosuppressive microenvironment. These results improve the knowledge of the ADO role in the maintenance of TME, which should be considered in the development of therapeutic strategies targeting adenosine pathways as well as cell‐based strategies using MSCs.

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Extracellular adenosine promotes cell migration/invasion of Glioblastoma Stem-like Cells through A3 Adenosine Receptor activation under hypoxia

Cited by 66 publications

References 45 publications

Mesenchymal Transformation: The Rosetta Stone of Glioblastoma Pathogenesis and Therapy Resistance

Mesenchymal Transformation: The Rosetta Stone of Glioblastoma Pathogenesis and Therapy Resistance

High Adenosine Extracellular Levels Induce Glioblastoma Aggressive Traits Modulating the Mesenchymal Stromal Cell Secretome

Extracellular adenosine oppositely regulates the purinome machinery in glioblastoma and mesenchymal stem cells

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