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首页> 外文期刊>Cell cycle >Ligand-driven activation of the notch pathway in T-ALL and solid tumors: why Not(ch)?
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Ligand-driven activation of the notch pathway in T-ALL and solid tumors: why Not(ch)?

机译：配体驱动的T-ALL和实体瘤中刻槽途径的激活：为什么选择Not（ch）？

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摘要

The Notch pathway is an evolutionally conserved cell-cell interaction signalling system involved in several key aspects of cell life, ranging from differentiation and proliferation to apoptosis. As such, it plays an important role in development, homeostasis, angiogenesis and various diseases. Over-activation of the Notch pathway has often been reported in cancer, leading to a variety of effects including increased proliferation, protection from apoptosis and maintenance of cancer initiating cells. Additionally, this signalling pathway has also been involved in tumor angiogenesis. The clearest example of oncogenic Notch signalling is observed in T acute lymphoblastic leukemia (T-ALL), an aggressive neoplasm of immature T-cells, due to genetic alterations leading to ligand-independent increased Notch1 receptor signalling. In solid tumors, however, extrinsic regulation through canonical cell-cell interactions appears to drive activation of the pathway. We recently found that triggering of Notch3 signalling by DLL4 expressed on angiogenic endothelial cells promotes escape of T-ALL cells from tumor dormancy in a xenograft model. This observation discloses un unsuspected role for ligand-dependent regulation of Notch receptors in T-ALL cells, suggesting that blocking extrinsic Notch activation by anti-DLL4 or other ligand-targeted drugs could represent a novel therapeutic approach for this aggressive malignancy.
机译：Notch途径是一种进化保守的细胞间相互作用信号系统，涉及细胞生命的几个关键方面，范围从分化，增殖到凋亡。因此，它在发育，体内平衡，血管生成和各种疾病中起重要作用。 Notch通路的过度激活在癌症中经常有报道，导致多种作用，包括增加增殖，防止凋亡和维持癌症起始细胞。另外，该信号传导途径也已经参与了肿瘤血管生成。最明显的致癌Notch信号实例是在T急性淋巴细胞白血病（T-ALL）（一种未成熟T细胞的侵袭性肿瘤）中观察到的，原因是遗传变异导致配体非依赖性的Notch1受体信号传导增加。然而，在实体瘤中，通过规范的细胞间相互作用进行的外部调节似乎可以驱动该途径的激活。我们最近发现，在异种移植模型中，由在血管生成内皮细胞上表达的DLL4引起的Notch3信号的触发促进T-ALL细胞从肿瘤休眠中逃逸。该观察揭示了在T-ALL细胞中Notch受体的配体依赖性调节的不可预料的作用，这表明通过抗DLL4或其他以配体为靶标的药物阻断外在Notch激活可以代表针对这种侵袭性恶性肿瘤的新颖治疗方法。

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