Department of Experimental Medicine, La Sapienza University, Viale Regina Elena, 324, 00161 Rome, Italy.
Neuro Oncol. 2010 Jul;12(7):701-10. doi: 10.1093/neuonc/nop076. Epub 2010 Feb 8.
The chemokine CX3CL1 is constitutively expressed in the central nervous system by neurons and astrocytes controlling neuronal survival and neurotransmission. In this work, we analyzed the expression and function of the chemokine CX3CL1 and its receptor, CX3CR1, by human glioma cells. We show that both molecules are expressed on the tumor cell plasma membrane and that soluble CX3CL1 accumulates in the culture supernatants, indicating that the chemokine is constitutively released. We found that CX3CR1 is functional, as all the cell lines adhered to immobilized recombinant CX3CL1 and migrated in response to the soluble form of this chemokine. In addition, the blockade of endogenous CX3CL1 function by means of a neutralizing monoclonal antibody markedly delayed tumor cell aggregation and increased their invasiveness. We also show that CX3CL1 expression is potently modulated by the transforming growth factor-beta1 (TGF-beta1), a key regulator of glioma cell invasiveness. Indeed, both the treatment of glioma cells with recombinant TGF-beta1 and the inhibition of its endogenous expression by siRNA showed that TGF-beta1 decreases CX3CL1 mRNA and protein expression. Overall, our results indicate that endogenously expressed CX3CL1 negatively regulates glioma invasion likely by promoting tumor cell aggregation, and that TGF-beta1 inhibition of CX3CL1 expression might contribute to glioma cell invasive properties.
趋化因子 CX3CL1 由神经元和星形胶质细胞组成性表达于中枢神经系统，调控神经元的存活和神经递质传递。在这项工作中，我们通过人神经胶质瘤细胞分析了趋化因子 CX3CL1 及其受体 CX3CR1 的表达和功能。我们表明这两种分子都表达在肿瘤细胞膜上，并且可溶性 CX3CL1 积累在培养上清液中，表明趋化因子组成性释放。我们发现 CX3CR1 是功能性的，因为所有细胞系都黏附于固定化重组 CX3CL1 并响应该趋化因子的可溶性形式迁移。此外，通过中和单克隆抗体阻断内源性 CX3CL1 功能显著延迟了肿瘤细胞聚集并增加了它们的侵袭性。我们还表明，转化生长因子-β1（TGF-β1）强烈调节 CX3CL1 的表达，TGF-β1 是神经胶质瘤细胞侵袭性的关键调节因子。事实上，用重组 TGF-β1 处理神经胶质瘤细胞和用 siRNA 抑制其内源性表达都表明 TGF-β1 降低了 CX3CL1 mRNA 和蛋白表达。总体而言，我们的结果表明，内源性表达的 CX3CL1 通过促进肿瘤细胞聚集负调控神经胶质瘤侵袭，而 TGF-β1 抑制 CX3CL1 的表达可能有助于神经胶质瘤细胞的侵袭特性。
