Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Int J Mol Sci. 2020 Oct 18;21(20):7706. doi: 10.3390/ijms21207706.
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.
胶质母细胞瘤是一种侵袭性、快速生长的脑肿瘤，受肿瘤微环境（TME）组成的影响，其中间充质基质细胞（MSCs）起着关键作用。腺苷（ADO）作为一种嘌呤信号分子，在 TME 中可以达到高达高微摩尔浓度。特定的腺苷受体亚型在神经胶质瘤细胞上的活性以及 MSCs 对肿瘤进展的影响已经得到广泛研究。然而，ADO 对神经胶质瘤侵袭性特征的影响及其在癌细胞-MSC 串扰中的作用仍不清楚。在此，我们首先研究了细胞外腺苷（ADO）对作为神经胶质瘤细胞模型的分离的人 U343MG 细胞的作用，发现其在高浓度时能够促使调节上皮-间充质转化（EMT）过程的 Snail 和 ZEB1 的基因表达，即使未达到完全转化。这些作用是通过诱导 ERK1/2 磷酸化介导的。此外，ADO 通过改变分离的骨髓来源的间充质基质细胞（BM-MSCs）分泌的炎症细胞因子模式来影响 BM-MSCs。然后，使用 ADO 刺激的 BM-MSCs 的条件培养基（CM）和共培养系统来研究细胞外 ADO 在 GBM-MSC 串扰中的作用。CM 促进了神经胶质瘤运动性的增加，并诱导了神经胶质瘤细胞的部分表型改变。当 U343MG 细胞和 BM-MSCs 共培养时，这些作用得以维持。总之，ADO 可能直接影响神经胶质瘤生物学，并通过调节 MSC 释放的旁分泌因子，总体上促进更具侵袭性的表型。这些结果表明，深入研究细胞外可溶性因子在神经胶质瘤与 TME 中其他细胞类型的串扰中的作用非常重要，以便更好地了解其病理机制。
