Plasticity underlies tumor progression: role of Nodal signaling.
Plasticity underlies tumor progression: role of Nodal signaling.
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DOI：
10.1007/s10555-016-9605-5
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Hendrix MJ
中科院分区：
文献类型：
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作者：
Bodenstine TM;Chandler GS;Seftor RE;Seftor EA;Hendrix MJ
转化生长因子 β (TGFβ) 超家族成员 Nodal 是早期胚胎发育的既定调节因子，在内胚层诱导、左右不对称和原条形成中起主要作用。节点通过质膜上的 TGFβ 家族受体发出信号，并诱导信号级联反应，从而导致多种转录调节。虽然概念上很简单，但 Nodal 的调节及其分子效应非常复杂且依赖于环境。发育生物学家的开创性工作描述了信号通路、调节成分的特征，并提供了对 Nodal 介导细胞和有机体水平变化的机制的详细见解。节点也是通过调节核心转录程序维持胚胎干细胞多能性的重要因素。总的来说，这项工作使人们认识到 Nodal 是一种强大的形态发生素，能够协调多种细胞表型。尽管 Nodal 在大多数成人组织中不活跃，但其重新表达和信号传导与多种类型的人类癌症有关，并且 Nodal 已成为肿瘤生长和细胞可塑性的驱动因素。体外和体内实验证据表明，抑制 Nodal 信号传导可降低癌细胞的侵袭性特征，而临床数据已建立与 Nodal 表达和患者结果的关联。因此，人们对在癌症患者的治疗环境中潜在靶向 Nodal 活性产生了极大的兴趣，这可能为抑制肿瘤生长和转移提供新途径。在这篇综述中，我们评估了我们目前对癌症中 Nodal 功能复杂性的理解，并强调了最近的实验证据，这些证据揭示了其抑制的治疗潜力。
The transforming growth factor beta (TGFβ) superfamily member Nodal is an established regulator of early embryonic development, with primary roles in endoderm induction, left-right asymmetry and primitive streak formation. Nodal signals through TGFβ family receptors at the plasma membrane and induces signaling cascades leading to diverse transcriptional regulation. While conceptually simple, the regulation of Nodal and its molecular effects are profoundly complex and context dependent. Pioneering work by developmental biologists has characterized the signaling pathways, regulatory components, and provided detailed insight into the mechanisms by which Nodal mediates changes at the cellular and organismal levels. Nodal is also an important factor in maintaining pluripotency of embryonic stem cells through regulation of core transcriptional programs. Collectively, this work has led to an appreciation for Nodal as a powerful morphogen capable of orchestrating multiple cellular phenotypes. Although Nodal is not active in most adult tissues, its re-expression and signaling have been linked to multiple types of human cancer, and Nodal has emerged as a driver of tumor growth and cellular plasticity. In vitro and in vivo experimental evidence has demonstrated that inhibition of Nodal signaling reduces cancer cell aggressive characteristics, while clinical data have established associations with Nodal expression and patient outcomes. As a result, there is great interest in the potential targeting of Nodal activity in a therapeutic setting for cancer patients that may provide new avenues for suppressing tumor growth and metastasis. In this review, we evaluate our current understanding of the complexities of Nodal function in cancer and highlight recent experimental evidence that sheds light on the therapeutic potential of its inhibition.