Mao Ping, Smith Luke, Xie Wanfu, Wang Maode
Department of Neurosurgery, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China ; ; Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, OH 43210, USA.
Oncol Lett. 2013 May;5(5):1615-1620. doi: 10.3892/ol.2013.1223. Epub 2013 Mar 1.
Emerging evidence has indicated that apoptotic cells have a compensatory effect on the proliferation of neighboring cells. However, the potential role of dying vascular endothelial cells (ECs) in glioma tumor proliferation remains unclear. In the present study, three glioma cell lines were cocultured with dying ECs under various conditions to evaluate the effect of dying ECs on tumor proliferation using alamarBlue and trypan blue assays to assess cell proliferation and viability, respectively. The results suggested that dying ECs had a marked ability to facilitate glioma cell growth via a caspase 3-mediated pathway. Furthermore, calcium-independent phospholipase A (iPLA), a downstream gene regulated by caspase 3, is highly involved in this process. Prostaglandin E (PGE) was the final effector of the caspase 3-iPLA signaling pathway in glioma cell proliferation. Knockdown of caspase 3 or iPLA using shRNA negated the growth stimulating effect of dying ECs. By contrast, the overexpression of iPLA in ECs via the pLEX lentiviral vector system or addition of PGE into culture medium had a growth promoting effect on glioma cells. Overall, the present data revealed a paracrine signal released from dying ECs which promotes the proliferation of surrounding glioma cells, demonstrating the importance of blocking compensatory proliferation during tumor therapy. Additionally, targeting caspase 3-mediated pathways combined with current therapeutic strategies may be a promising approach for improving the dismal prognosis associated with these malignant tumors.
新出现的证据表明，凋亡细胞对邻近细胞的增殖具有补偿作用。然而，濒死的血管内皮细胞（ECs）在胶质瘤肿瘤增殖中的潜在作用仍不清楚。在本研究中，将三种胶质瘤细胞系在不同条件下与濒死的ECs共培养，分别使用alamarBlue和台盼蓝测定法评估濒死的ECs对肿瘤增殖的影响，以评估细胞增殖和活力。结果表明，濒死的ECs具有通过半胱天冬酶3介导的途径促进胶质瘤细胞生长的显著能力。此外，半胱天冬酶3调节的下游基因钙非依赖性磷脂酶A（iPLA）高度参与这一过程。前列腺素E（PGE）是半胱天冬酶3-iPLA信号通路在胶质瘤细胞增殖中的最终效应物。使用shRNA敲低半胱天冬酶3或iPLA可消除濒死的ECs的生长刺激作用。相比之下，通过pLEX慢病毒载体系统在ECs中过表达iPLA或向培养基中添加PGE对胶质瘤细胞具有促生长作用。总体而言，目前的数据揭示了濒死的ECs释放的一种旁分泌信号，该信号促进周围胶质瘤细胞的增殖，证明了在肿瘤治疗期间阻断代偿性增殖的重要性。此外，靶向半胱天冬酶3介导的途径并结合当前的治疗策略可能是改善这些恶性肿瘤不良预后的一种有前景的方法。
