Abstract
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.
Highlights
Glioblastoma (GBM) is the most frequent primary brain tumor, with associated poor prognosis
The tumor microenvironment (TME) consists of tumor cells, fibroblasts, endothelial cells, microglia, glioblastoma associated macrophages (GAMs), glioblastoma associated fibroblasts (TAFs), mesenchymal stromal cell (MSCs) and inflammatory cells, as well as cytokines and chemokines secreted by tumor and stromal cells [4,5]
The U343MG human glioblastoma cell line has been widely used to investigate the pathophysiological mechanisms of glioblastoma [45,46]; we selected this
Summary
Glioblastoma (GBM) is the most frequent primary brain tumor, with associated poor prognosis. Emerging evidence suggests the pivotal role of tumor microenvironment (TME) in GBM progression, immune escape, local invasion and metastasis [3]. The TME consists of tumor cells, fibroblasts, endothelial cells, microglia, glioblastoma associated macrophages (GAMs), glioblastoma associated fibroblasts (TAFs), mesenchymal stromal cell (MSCs) and inflammatory cells, as well as cytokines and chemokines secreted by tumor and stromal cells [4,5]. Multipotent MSCs, recruited to the tumor bulk by several soluble factors secreted by tumor cells, play complicated roles in carcinogenesis and in the modulation of tumor development [5,6,7,8,9,10]. Within the TME, MSC may interact with tumor cells and secrete a large range of cytokines and growth factors that may contribute to tumor cell survival, growth, motility and immune escape [14]. The link between MSC and GBM remains obscure, as well as whether MSCs play an active role in tumor promotion or suppression [5,18,19,20,21,22,23,24,25,26]
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