PNAS：揭秘癌症如何将“好细胞”转化为恶性细胞

  近日，来自美国莱斯大学等处的研究人员通过研究鉴别出了一种锯齿状的蛋白质，其在肿瘤拦截细胞信号通路过程中扮演着重要角色，相关研究刊登于国际杂志PNAS上。研究者表示，癌症可以利用一种鲜为人知的细胞信号元件来拦截细胞的交流过程从而实现将良性细胞转化为恶性细胞的目的。

  研究者Eshel Ben-Jacob表示，我们发现，癌细胞会利用一种名为notch信号通路的细胞间作用机制来促进癌症的转移，这种notch信号通路机制在胚胎发育和伤口愈合过程中发挥着重要作用；当细胞中的δ或锯齿状配体同notch信号受体相互作用时就会激活上述信号机制。

  研究者认为癌症发生转移的最初介质是一种不会移动的混合上皮细胞团以及一些间质细胞，随着疾病发展这些混合上皮细胞就会在细胞迁移过程中趁机对免疫细胞进行入侵，而且随着血液循环来生存和转移。

  截止目前为止研究人员并不知道信号通路中的notchδ锯齿状信号是如何促进癌症恶化的，但有研究表明这种锯齿状配体在肿瘤发展过程中扮演着重要的作用；本文研究为揭示细胞的命运提供了一定的线索，结果显示，锯齿状配体可以刺激发送或者接收上皮细胞从而用于进行胚胎发育及伤口愈合，但这一过程往往会被癌细胞所劫持。

  Notch锯齿状信号可以帮助细胞对化疗和放疗产生耐受性，同时也会通过在新转移位点促进癌细胞和间质细胞之间的交流来协助癌症转移的形成；有研究就发现在肿瘤微环境中间质细胞会分泌锯齿状配体，而研究者发现癌细胞可以劫持附近的间质细胞来促进其产生配体，进而增强癌细胞的生存率。研究者指出，细胞内在不规则的表达往往会增加耐药性癌症干细胞的产生，由于癌症干细胞很容易获得干细胞样的特性，因此当其到达器官远端时就会利用细胞的可塑性来分化并且适应癌症新转移部位的微环境。

  下一步研究人员将利用模型进行研究来揭示癌细胞如何利用新型信号机制来躲避免疫系统的，最后研究者说道，研究单一细胞或并不能给我们准确的答案，我们需要对细胞间的信号通路进行更多深入的研究才能给出准确的答案；本文研究对于开发有效抑制癌细胞转移的新型靶向性疗法提供了新的研究思路和线索。（转化医学网360zhyx.com）

  以上为转化医学网原创翻译整理，如需转载，请联系 info@360zhyx.com
转化医学网推荐的原文阅读：

Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype
PNAS doi:10.1073/pnas.1416287112
Marcelo Boareto, Mohit Kumar Jolly, Mingyang Lu, José N. Onuchic, Cecilia Clementi, and Eshel Ben-Jacob
Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular Domain (NICD) that activates many downstream target genes. NICD affects ligand production asymmetrically––it represses Delta, but activates Jagged. Although the dynamical role of Notch–Jagged signaling remains elusive, it is widely recognized that Notch–Delta signaling behaves as an intercellular toggle switch, giving rise to two distinct fates that neighboring cells adopt––Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Here, we devise a specific theoretical framework that incorporates both Delta and Jagged in Notch signaling circuit to explore the functional role of Jagged in cell-fate determination. We find that the asymmetric effect of NICD renders the circuit to behave as a three-way switch, giving rise to an additional state––a hybrid Sender/Receiver (medium ligand, medium receptor). This phenotype allows neighboring cells to both send and receive signals, thereby attaining similar fates. We also show that due to the asymmetric effect of the glycosyltransferase Fringe, different outcomes are generated depending on which ligand is dominant: Delta-mediated signaling drives neighboring cells to have an opposite fate; Jagged-mediated signaling drives the cell to maintain a similar fate to that of its neighbor. We elucidate the role of Jagged in cell-fate determination and discuss its possible implications in understanding tumor–stroma cross-talk, which frequently entails Notch–Jagged communication.