Hijacking the Neuronal NMDAR Signaling Circuit to Promote Tumor Growth and Invasion
Hijacking the Neuronal NMDAR Signaling Circuit to Promote Tumor Growth and Invasion
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DOI：
10.1016/j.cell.2013.02.051
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发表时间：
2013-03-28
期刊：
影响因子：
64.5
通讯作者：
Hanahan, Douglas
中科院分区：
文献类型：
--
作者：
Li, Leanne;Hanahan, Douglas
谷氨酸及其受体N-甲基-D-天冬氨酸受体(NMDAR)与癌症相关，但其功能尚不完全清楚。在此，我们将谷氨酸驱动的NMDAR信号与胰腺神经内分泌肿瘤发生(PNET)的小鼠模型和选定的人类癌症联系起来。NMDAR在PNET肿瘤的外围，特别是侵袭性前沿上调。此外，NMDAR和谷氨酸出口蛋白的共同表达升高与癌症患者的预后不良相关。用NMDAR拮抗剂处理肿瘤来源的细胞系会损害癌细胞的增殖和侵袭。模拟组织间流体压力的流动条件诱导自体谷氨酸分泌，激活NMDAR及其下游的MEK-MAPK和CaMK效应器，从而促进侵袭性。同样，药物抑制PNET小鼠的NMDAR可以减少肿瘤的生长和侵袭力。因此，除了其在神经元中的传统作用外，NMDAR在人类肿瘤中可能通过更高的间质压力引起的液体流动而被激活，从而诱导自分泌谷氨酸信号通路，从而刺激恶性肿瘤。
Glutamate and its receptor N-methyl-D-aspartate receptor (NMDAR) have been associated with cancer, although their functions are not fully understood. Herein, we implicate glutamate-driven NMDAR signaling in a mouse model of pancreatic neuroendocrine tumorigenesis (PNET) and in selected human cancers. NMDAR was upregulated at the periphery of PNET tumors, particularly invasive fronts. Moreover, elevated coexpression of NMDAR and glutamate exporters correlated with poor prognosis in cancer patients. Treatment of a tumor-derived cell line with NMDAR antagonists impaired cancer cell proliferation and invasion. Flow conditions mimicking interstitial fluid pressure induced autologous glutamate secretion, activating NMDAR and its downstream MEK-MAPK and CaMK effectors, thereby promoting invasiveness. Congruently, pharmacological inhibition of NMDAR in mice with PNET reduced tumor growth and invasiveness. Therefore, beyond its traditional role in neurons, NMDAR may be activated in human tumors by fluid flow consequent to higher interstitial pressure, inducing an autocrine glutamate signaling circuit with resultant stimulation of malignancy.