Swiss Institute for Experimental Cancer Research, School of Life Science, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne 1015, Switzerland.
Cell. 2013 Mar 28;153(1):86-100. doi: 10.1016/j.cell.2013.02.051.
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.
谷氨酸及其受体 N-甲基-D-天冬氨酸受体（NMDAR）与癌症有关，尽管其功能尚未完全阐明。在此，我们在胰腺神经内分泌肿瘤发生（PNET）的小鼠模型中以及在一些人类癌症中表明谷氨酸驱动的 NMDAR 信号转导。NMDAR 在 PNET 肿瘤的外围上调，特别是在侵袭前沿。此外，NMDAR 和谷氨酸外排体的升高共表达与癌症患者的预后不良相关。用 NMDAR 拮抗剂处理肿瘤衍生细胞系会损害癌细胞的增殖和侵袭。模拟间质液压力的流动条件诱导自身谷氨酸分泌，激活 NMDAR 及其下游 MEK-MAPK 和 CaMK 效应物，从而促进侵袭性。一致地，在患有 PNET 的小鼠中用药物抑制 NMDAR 可减少肿瘤生长和侵袭性。因此，除了其在神经元中的传统作用外，由于间质压力较高，NMDAR 可能会在人类肿瘤中被流体流动激活，诱导自主谷氨酸信号通路，从而刺激恶性肿瘤。
