Lawn Samuel, Krishna Niveditha, Pisklakova Alexandra, Qu Xiaotao, Fenstermacher David A, Fournier Michelle, Vrionis Frank D, Tran Nam, Chan Jennifer A, Kenchappa Rajappa S, Forsyth Peter A
From the Tom Baker Cancer Centre, Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta T2N 4N2, Canada.
the Departments of Neuro-Oncology.
J Biol Chem. 2015 Feb 6;290(6):3814-24. doi: 10.1074/jbc.M114.599373. Epub 2014 Dec 23.
Neurotrophins and their receptors are frequently expressed in malignant gliomas, yet their functions are largely unknown. Previously, we have shown that p75 neurotrophin receptor is required for glioma invasion and proliferation. However, the role of Trk receptors has not been examined. In this study, we investigated the importance of TrkB and TrkC in survival of brain tumor-initiating cells (BTICs). Here, we show that human malignant glioma tissues and also tumor-initiating cells isolated from fresh human malignant gliomas express the neurotrophin receptors TrkB and TrkC, not TrkA, and they also express neurotrophins NGF, BDNF, and neurotrophin 3 (NT3). Specific activation of TrkB and TrkC receptors by ligands BDNF and NT3 enhances tumor-initiating cell viability through activation of ERK and Akt pathways. Conversely, TrkB and TrkC knockdown or pharmacologic inhibition of Trk signaling decreases neurotrophin-dependent ERK activation and BTIC growth. Further, pharmacological inhibition of both ERK and Akt pathways blocked BDNF, and NT3 stimulated BTIC survival. Importantly, attenuation of BTIC growth by EGFR inhibitors could be overcome by activation of neurotrophin signaling, and neurotrophin signaling is sufficient for long term BTIC growth as spheres in the absence of EGF and FGF. Our results highlight a novel role for neurotrophin signaling in brain tumor and suggest that Trks could be a target for combinatorial treatment of malignant glioma.
神经营养因子及其受体在恶性胶质瘤中经常表达，但其功能大多未知。此前，我们已经表明p75神经营养因子受体是胶质瘤侵袭和增殖所必需的。然而，Trk受体的作用尚未得到研究。在本研究中，我们调查了TrkB和TrkC在脑肿瘤起始细胞（BTICs）存活中的重要性。在此，我们表明人类恶性胶质瘤组织以及从新鲜人类恶性胶质瘤中分离出的肿瘤起始细胞表达神经营养因子受体TrkB和TrkC，而非TrkA，并且它们还表达神经营养因子NGF、BDNF和神经营养因子3（NT3）。配体BDNF和NT3对TrkB和TrkC受体的特异性激活通过激活ERK和Akt途径增强了肿瘤起始细胞的活力。相反，TrkB和TrkC基因敲低或Trk信号的药理学抑制会降低神经营养因子依赖性ERK激活和BTIC生长。此外，ERK和Akt途径的药理学抑制阻断了BDNF和NT3刺激的BTIC存活。重要的是，EGFR抑制剂对BTIC生长的抑制作用可通过神经营养因子信号的激活来克服，并且在没有EGF和FGF的情况下，神经营养因子信号足以使BTIC长期作为球体生长。我们的结果突出了神经营养因子信号在脑肿瘤中的新作用，并表明Trks可能是恶性胶质瘤联合治疗的一个靶点。
