文章：

用胚胎微环境重编程转移性肿瘤细胞

Reprogramming metastatic tumour cells with embryonic microenvironments

原文发布日期：2007-04-01

DOI: 10.1038/nrc2108

类型: Review Article

开放获取: 否

要点：

1. Aggressive tumour cells, such as melanoma, share many characteristics with embryonic progenitors, which contribute to the conundrum of tumour cell plasticity. The challenge is to better understand the aetiology of the plastic, multipotent phenotype and to develop strategies that might include their differentiation and subsequent targeting.
2. A complex and still enigmatic relationship exists between stem cells and their microenvironment that has a crucial role in the determination of cell fate. Current studies identifying the molecular pathways that regulate stem cell plasticity are also examining the epigenetic role of the microenvironment.
3. The microenvironment of human embryonic stem cells can epigenetically reprogramme multipotent metastatic melanoma cells to assume a melanocyte-like phenotype. In addition, the 'reverted' melanoma cells show significantly reduced invasive and tumorigenic ability.
4. The embryonic neural crest microenvironment of the chick provides an attractive model system to explore melanoma tumour cell reprogramming. Human metastatic melanoma cells transplanted into the chick embryonic microenvironment did not form tumours, and a subset of these tumour cells were reprogrammed to a neural crest cell-like phenotype. The melanoma cells also followed neural crest migratory pathways and populated host peripheral structures in a programmed manner.
5. Recent findings using the embryonic zebrafish have illuminated a convergence in the molecular messengers that metastatic tumour and normal stem cells implement during their respective bi-directional communication with the microenvironment, leading to the identification of Nodal.
6. The inhibition of Nodal signalling reduces melanoma cell invasiveness, colony formation and tumorigenicity. Nodal inhibition also promotes the reversion of melanoma cells towards a melanocytic phenotype concomitant with loss of the plastic phenotype.
7. Nodal may represent a new diagnostic marker for disease progression and a novel target for the treatment of aggressive cancers. Additional strategic targets contributing to the Nodal signalling pathway, including SMAD2 and SMAD3, cripto and the activin-like-kinase (ALK) receptor complex, are worth further consideration for inhibiting the plastic tumour cell phenotype.
8. The discovery of key signalling pathways that underlie the commonality of plasticity of embryonic stem cells and multipotent tumour cells will probably result in new therapeutic strategies to suppress the metastatic phenotype.

要点翻译：

1. 侵袭性肿瘤细胞（如黑色素瘤）与胚胎祖细胞具有诸多共同特征，这构成了肿瘤细胞可塑性难题的核心。当前面临的挑战在于更深入理解这种可塑性多能表型的病因学，并制定可能涵盖其分化及后续靶向治疗的策略。
2. 干细胞与其微环境之间存在着复杂而微妙的关系，这种关系在细胞命运决定中起着关键作用。目前针对干细胞可塑性调控分子通路的研究，也在深入探讨微环境的表观遗传调控作用。
3. 人胚胎干细胞微环境能够通过表观遗传重编程使多能性转移性黑色素瘤细胞呈现类黑色素细胞表型。此外，这些"逆转"的黑色素瘤细胞表现出显著降低的侵袭性和致瘤能力。
4. 鸡胚的胚胎神经嵴微环境为探索黑色素瘤细胞重编程提供了一个理想的模型系统。移植至鸡胚微环境中的人转移性黑色素瘤细胞未形成肿瘤，其中部分肿瘤细胞被重编程为神经嵴细胞样表型。这些黑色素瘤细胞还遵循神经嵴迁移路径，以程序化方式定植于宿主外周结构。
5. 近期利用斑马胚胎模型的研究揭示了转移性肿瘤细胞与正常干细胞在各自与微环境双向通讯过程中所使用的分子信使的汇聚点，从而鉴定出Nodal信号分子。
6. 抑制Nodal信号能降低黑色素瘤细胞的侵袭能力、集落形成能力和致瘤性。同时，Nodal信号抑制还会促进黑色素瘤细胞向黑色素细胞表型逆转，并伴随可塑性表型的消失。
7. Nodal可能成为疾病进展的新型诊断标志物和侵袭性癌症治疗的新靶点。针对Nodal信号通路中其他关键环节（包括SMAD2、SMAD3、Cripto以及激活素样激酶（ALK）受体复合物）的战略靶点，也值得进一步考虑用于抑制可塑性肿瘤细胞表型。
8. 揭示胚胎干细胞与多能性肿瘤细胞可塑性共同特征的关键信号通路，很可能催生抑制转移性表型的新治疗策略。

英文摘要：

Aggressive tumour cells share many characteristics with embryonic progenitors, contributing to the conundrum of tumour cell plasticity. Recent studies using embryonic models of human stem cells, the zebrafish and the chick have shown the reversion of the metastatic phenotype of aggressive melanoma cells, and revealed the convergence of embryonic and tumorigenic signalling pathways, which may help to identify new targets for therapeutic intervention. This Review will summarize the embryonic models used to reverse the metastatic melanoma phenotype, and highlight the prominent signalling pathways that have emerged as noteworthy targets for future consideration.

摘要翻译： 

侵袭性肿瘤细胞与胚胎祖细胞有许多共同特征，这加剧了肿瘤细胞可塑性的难题。最近利用人类干细胞胚胎模型、斑马鱼和鸡胚进行的研究显示，侵袭性黑色素瘤细胞的转移表型可被逆转，并揭示了胚胎与肿瘤发生信号通路的交汇点，这可能有助于发现新的治疗干预靶点。本综述将总结用于逆转转移性黑色素瘤表型的胚胎模型，并重点介绍已凸显为今后值得关注的关键信号通路。

原文链接：

Reprogramming metastatic tumour cells with embryonic microenvironments