Uemae Youji, Ishikawa Eiichi, Osuka Satoru, Matsuda Masahide, Sakamoto Noriaki, Takano Shingo, Nakai Kei, Yamamoto Tetsuya, Matsumura Akira
Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
J Neurooncol. 2014 Mar;117(1):43-51. doi: 10.1007/s11060-014-1364-y. Epub 2014 Jan 19.
Emerging evidence suggests that the chemokine CXCL12 and its receptor CXCR4, which are expressed by glioma stem cells (GSCs), play an important role in tumorigenesis. To provide evidence for establishing a new therapy targeting the CXCL12/CXCR4 pathway, we investigated whether CXCL12 secreted from GSCs contributed to their proliferation and promoted angiogenesis in murine GSCs. Angiogenetic functions and proliferation of GSCs with or without CXCL12 inhibitors were evaluated in an in vitro model using tube formation assays, RT-PCR, and proliferation, as well as in an in vivo syngenic model. In endothelial culture, the morphology and gene expression of GSCs changed from stem cell-like characteristics to endothelial cell-like features. CXCL12 expression increased in endothelial cell-like GSCs. CXCL12 blockage with siRNA or shRNA markedly inhibited cell proliferation in vitro. CXCL12 knockdown with shRNA also inhibited tumor growth in vivo. On the other hand, CXCL12/CXCR4 blockage affected neither tube formation in vitro nor angiogenesis in vivo. The CXCL12 secreted from GSCs (autocrine/paracrine CXCL12) regulates their proliferation, but probably not angiogenesis.
新出现的证据表明，胶质瘤干细胞（GSCs）表达的趋化因子CXCL12及其受体CXCR4在肿瘤发生中起重要作用。为了为建立一种针对CXCL12/CXCR4通路的新疗法提供证据，我们研究了GSCs分泌的CXCL12是否有助于其增殖并促进小鼠GSCs中的血管生成。使用管形成试验、RT-PCR和增殖在体外模型以及体内同基因模型中评估有无CXCL12抑制剂时GSCs的血管生成功能和增殖。在内皮细胞培养中，GSCs的形态和基因表达从干细胞样特征转变为内皮细胞样特征。在内皮细胞样GSCs中CXCL12表达增加。用siRNA或shRNA阻断CXCL12可显著抑制体外细胞增殖。用shRNA敲低CXCL12也可抑制体内肿瘤生长。另一方面，CXCL12/CXCR4阻断对体外管形成和体内血管生成均无影响。GSCs分泌的CXCL12（自分泌/旁分泌CXCL12）调节其增殖，但可能不调节血管生成。
