Department of Anatomy and Cell Biology, University of Western Ontario and Robarts Research Institute, London, ON, Canada.
Int J Biochem Cell Biol. 2013 Apr;45(4):885-98. doi: 10.1016/j.biocel.2012.12.021. Epub 2013 Jan 3.
With few exceptions, most cells in adult organisms have lost the expression of stem cell-associated proteins and are instead characterized by tissue-specific gene expression and function. This cell fate specification is dictated spatially and temporally during embryogenesis. It has become increasingly apparent that the elegant and complicated process of cell specification is "undone" in cancer. This may be because cancer cells respond to their microenvironment and mutations by acquiring a more permissive, plastic epigenome, or because cancer cells arise from mutated stem cells. Regardless, these advanced cancer cells must use stem cell-associated proteins to sustain their phenotype. One such protein is Nodal, an embryonic morphogen belonging to the transforming growth factor-β (TGF-β) superfamily. First described in early developmental models, Nodal orchestrates embryogenesis by regulating a myriad of processes, including mesendoderm induction, left-right asymmetry and embryo implantation. Nodal is relatively restricted to embryonic and reproductive cell types and is thus absent from most normal adult tissues. However, recent studies focusing on a variety of malignancies have demonstrated that Nodal expression re-emerges during cancer progression. Moreover, in almost every cancer studied thus far, the acquisition of Nodal expression is associated with increased tumourigenesis, invasion and metastasis. As the list of cancers that express Nodal grows, it is essential that the scientific and medical communities fully understand how this morphogen is regulated in both normal and neoplastic conditions. Herein, we review the literature relating to normal and pathological Nodal signalling. In particular, we emphasize the role that this secreted protein plays during morphogenic events and how it signals to support stem cell maintenance and tumour progression.
除了少数例外，成年生物体内的大多数细胞都失去了与干细胞相关的蛋白表达，而是具有组织特异性的基因表达和功能。这种细胞命运的特化是在胚胎发生过程中空间和时间上决定的。越来越明显的是，细胞特化的优雅而复杂的过程在癌症中被“逆转”了。这可能是因为癌细胞通过获得更具许可性、可塑性的表观基因组，或者因为癌细胞起源于突变的干细胞，而对其微环境和突变做出反应。无论如何，这些晚期癌细胞必须利用与干细胞相关的蛋白来维持其表型。其中一种蛋白是 Nodal，它是一种属于转化生长因子-β（TGF-β）超家族的胚胎形态发生素。Nodal 最初在早期发育模型中被描述，通过调节包括中胚层诱导、左右不对称和胚胎着床在内的无数过程来协调胚胎发生。Nodal 相对局限于胚胎和生殖细胞类型，因此在大多数正常成年组织中不存在。然而，最近的研究集中在各种恶性肿瘤上，表明 Nodal 的表达在癌症进展过程中重新出现。此外，在迄今为止研究的几乎所有癌症中，获得 Nodal 表达与增加肿瘤发生、侵袭和转移有关。随着表达 Nodal 的癌症种类的增加，科学界和医学界必须充分了解这种形态发生素在正常和肿瘤条件下是如何被调节的。在此，我们回顾了与正常和病理性 Nodal 信号相关的文献。特别是，我们强调了这种分泌蛋白在形态发生事件中的作用，以及它如何发出信号来支持干细胞维持和肿瘤进展。
