Epithelial-mesenchymal transition and the invasive potential of tumors

The development of metastasis requires the movement and invasion of cancer cells from the primary tumor into the surrounding tissue. To acquire such invasive abilities, epithelial cancer cells must undergo several phenotypic changes. Some of these, including alterations in cell adhesion and migration, are reminiscent of those observed during the developmental process termed epithelial-mesenchymal transition (EMT). Several master gene regulatory programs known to promote EMT during development have recently been discovered to play key roles in cancer progression. In particular, the regulation of cell adhesion molecules and the signaling pathways linking them to mechanisms of gene regulation has emerged as an important determinant of tumor cell invasion and metastasis. A deeper understanding of these mechanisms should allow both better diagnosis and the development of specific treatments for invasive cancer.     

MicroRNA对EMT的调节作用及其与肿瘤侵袭的关系

上皮间质转化（epithelial mesenchymal transition,EMT）是指上皮细胞表型由上皮向间质转换的生物学过程,可发生在生理过程中促进发育、组织愈合和修复。近年对肿瘤的研究发现,EMT与肿瘤的发生发展密切相关。肿瘤细胞发生EMT时,伴随着迁移、侵袭能力的增强,进而促进肿瘤的转移。EMT发生的程度以及相关标志分子的检测还可以用于判断肿瘤转移的危险和评估预后。MicroRNA(miRNA)作为非编码小RNA,通过与特定mRNA的3′UTR结合,在蛋白翻译水平抑制基因表达。本文主要综述目前发现的作用于EMT相关转录因子,如ZEB、SNAIL、TWIST的miRNA,以及在各种肿瘤中的表达情况和作用。其中,有些转录因子和miRNA之间,还存在相互抑制的复杂调节网络,因此,了解miRNA在肿瘤中对EMT的作用可能为肿瘤的治疗提供新的方法和策略。     

Hypoxia,partial EMT and collective migration: Emerging culprits in metastasis

Epithelial-mesenchymal transition (EMT) is a cellular biological process involved in migration of primary cancer cells to secondary sites facilitating metastasis. Besides, EMT also confers properties such as stemness, drug resistance and immune evasion which can aid a successful colonization at the distant site. EMT is not a binary process; recent evidence suggests that cells in partial EMT or hybrid E/M phenotype(s) can have enhanced stemness and drug resistance as compared to those undergoing a complete EMT. Moreover, partial EMT enables collective migration of cells as clusters of circulating tumor cells or emboli, further endorsing that cells in hybrid E/M phenotypes may be the ‘fittest’ for metastasis. Here, we review mechanisms and implications of hybrid E/M phenotypes, including their reported association with hypoxia. Hypoxia-driven activation of HIF-1α can drive EMT. In addition, cyclic hypoxia, as compared to acute or chronic hypoxia, shows the highest levels of active HIF-1α and can augment cancer aggressiveness to a greater extent, including enriching for a partial EMT phenotype. We also discuss how metastasis is influenced by hypoxia, partial EMT and collective cell migration, and call for a better understanding of interconnections among these mechanisms. We discuss the known regulators of hypoxia, hybrid EMT and collective cell migration and highlight the gaps which needs to be filled for connecting these three axes which will increase our understanding of dynamics of metastasis and help control it more effectively.     

Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation

Cancer metastasis consists of a sequential series of events, and the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are recognized as critical events for metastasis of carcinomas. A current area of focus is the histopathological similarity between primary and metastatic tumors, and MET at sites of metastases has been postulated to be part of the process of metastatic tumor formation. Here, we summarize accumulating evidence from experimental studies that directly supports the role of MET in cancer metastasis, and we analyze the main mechanisms that regulate MET or reverse EMT in carcinomas. Given the critical role of MET in metastatic tumor formation, the potential to effectively target the MET process at sites of metastasis offers new hope for inhibiting metastatic tumor formation.     

Feedback modulation of endothelial cells promotes epithelial-mesenchymal transition and metastasis of osteosarcoma cells by Von Willebrand Factor release

Endothelial cells (ECs), as a tumor niche cell, generate and secrete Von Willebrand factor (VWF) that is linked to osteosarcoma (OS) progression. However, the role and regulatory mechanisms of VWF that underpin OS progression remain unclear. Here, using a coculture system ex vivo, we showed that ECs promoted the epithelial-mesenchymal transition (EMT) process in OS cells via enhanced VWF secretion. VWF secreted by ECs directly contributed to OS EMT and metastasis by activating NF-κB signaling. In addition, OS cells exerted a feedback effect on ECs to promote VWF release via activation of phospholipase D 1 signaling, through which enhanced VWF secretion results in further tumor deterioration. To conclude, ECs served as a modulator and an effector of OS, accelerating OS exacerbation by VWF release.     

EMT——联系免疫炎症反应与肿瘤发生发展的桥梁

恶性肿瘤严重威胁着人们的健康,肿瘤细胞侵袭和转移是恶性肿瘤患者死亡的重要原因。研究表明,肿瘤恶性转化的过程需要适宜的微环境,即肿瘤微环境,肿瘤细胞在肿瘤微环境中受到细胞因子、蛋白酶等多种因素的影响,发生免疫炎性反应、上皮间质转化（EMT）、刺激肿瘤血管形成等一系列病理生理改变,从而促进肿瘤的侵袭和转移。本文概述了机体免疫炎性反应、EMT和肿瘤微环境在肿瘤中的相互联系及其作用,以期为深入研究肿瘤发生发展的分子机制提供新的思路,并为肿瘤的分子靶向治疗提供理论依据。     

上皮间质转化在肿瘤侵袭转移中的研究进展

上皮-间质转化（epithelial-mesenchymal transitions,EMT）是上皮细胞向间质细胞转化的现象,不仅参与胚胎发育和正常生理,还参与许多病理过程。同样EMT也参与肿瘤的发生与发展,尤其在促进肿瘤侵袭转移中发挥着重要作用。研究表明,肿瘤细胞借助EMT方式增强肿瘤细胞迁移和运动能力,促进肿瘤的侵袭与转移。在肿瘤侵袭转移历程中,关于EMT发生的分子调控机制研究已取得了良好的进展,但其详细机制仍然不是十分清楚。本文主要介绍生长因子、转录因子、miRNAs、甲基化及其他调控因子在肿瘤EMT中的调控功能,进一步综述EMT在肿瘤侵袭转移中的作用。     

去泛素化酶在肿瘤上皮间质转化中的作用

肿瘤的侵袭和转移是加剧肿瘤恶化的主要原因,也是导致患者预后不良的根本原因。近年来大量研究发现,大部分肿瘤的转移都依赖于上皮间质转化(epithelial-mesenchymal transition, EMT)的发生,此外EMT也与肿瘤干性和肿瘤耐药等诸多肿瘤恶性行为密切相关,因此有效的抑制EMT的发生将可能极大的有利于肿瘤的治疗。去泛素化酶(deubiquitinating enzymes, DUBs)的主要功能之一就是通过移除底物蛋白质上泛素链,避免其通过泛素蛋白酶体途径降解,来维持细胞内蛋白质水平的动态平衡。去泛素化酶作为调节蛋白质泛素化修饰的一类重要酶类,其异常表达或酶活性的改变通常都会导致疾病的发生。众多研究发现,部分去泛素化酶在肿瘤侵袭和转移过程中表达失衡,在肿瘤转移的过程中扮演着重要的角色。EMT是指由上皮型细胞转变为间质型细胞的动态细胞生物学过程,在该过程中涉及到例如Snial1、Slug、ZEB1等EMT相关转录因子和细胞表面的例如E-钙黏着蛋白、N-钙黏着蛋白等分子标志物表达水平的变化。这些蛋白质通常具有不稳定性,易被降解等特征。EMT过程的发生,涉及到许多蛋白质稳定性的调节,而去泛素化酶作为一类维持蛋白质稳定的重要酶类,在调节这些蛋白质的稳定性方面发挥着重要的作用。EMT的发生也与TGF-β通路、Wnt通路等细胞内众多信号通路的异常活化密不可分,去泛素化酶通过介导这些信号通路的活化,从而间接的调节EMT发生发展。去泛素化酶通过调节EMT相关分子或EMT相关信号通路等多种方式直接或间接影响EMT进展,因此,通过靶向于去泛素化酶抑制肿瘤的侵袭和转移,将为肿瘤治疗提供新的治疗手段和方案,从而有效的推动肿瘤的治疗。本文主要就去泛素化酶在调节EMT相关分子以及信号通路等方面,阐述去泛素化酶在EMT过程中所发挥的重要作用及其作为肿瘤治疗靶点的可能性。     

The tumor microenvironment: An irreplaceable element of tumor budding and epithelial-mesenchymal transition-mediated cancer metastasis

Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo-resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy.     

Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment

Every year about 500,000 people in the United States die as a result of cancer. Among them, 90% exhibit systemic disease with metastasis. Considering this high rate of incidence and mortality, it is critical to understand the mechanisms behind metastasis and identify new targets for therapy. In recent years, two broad mechanisms for metastasis have received significant attention: epithelial-to-mesenchymal transition (EMT) and tumor microenvironment interactions. EMT is believed to be a major mechanism by which cancer cells become migratory and invasive. Various cancer cells--both in vivo and in vitro--demonstrate features of epithelial-to-mesenchymal-like transition. In addition, many steps of metastasis are influenced by host contributions from the tumor microenvironment, which help determine the course and severity of metastasis. Here we evaluate the diverse mechanisms of EMT and tumor microenvironment interactions in the progression of cancer, and construct a rational argument for targeting these pathways to control metastasis.     

Glycoproteomic analysis of two mouse mammary cell lines during transforming growth factor (TGF)-β induced epithelial to mesenchymal transition

Background  

TGF-β acts as an antiproliferative factor in normal epithelial cells and at early stages of oncogenesis. However, later in tumor development TGF-β can become tumor promoting through mechanisms including the induction of epithelial-to-mesenchymal transition (EMT), a process that is thought to contribute to tumor progression, invasion and metastasis. To identify EMT-related breast cancer therapeutic targets and biomarkers, we have used two proteomic approaches to find proteins that change in abundance upon the induction of EMT by TGF-β in two mouse mammary epithelial cell lines, NMuMG and BRI-JM01.     

调控肿瘤上皮–间质转化及肿瘤干细胞样特性的信号通路串话

上皮–间质转化（epithelial-mesenchymal transition,EMT）是上皮来源肿瘤细胞获得侵袭和转移能力的重要生物学过程。肿瘤干细胞样细胞（cancer stem-like cells,CSLCs）在肿瘤发生、侵袭、转移和复发中亦起着关键作用。近年发现,EMT与肿瘤干细胞样特性获得存在密切关联,二者通过TGF-β、Wnt/β-catenin、Notch、Hedgehog、FGF、PI3k/Akt等多种信号通路及通路间的信号串话而交互作用,共同影响着肿瘤发生、侵袭及转移,了解调控EMT/CSLCs关键信号分子的功能及相互作用对于肿瘤靶向治疗具有重要意义。     

核转录因子Snail调控上皮-间质转型机制的研究

上皮-间质转型在纤维化及肿瘤侵袭转移中发挥着重要作用,多种因子作用于核转录因子Snail诱导细胞通路改变,以实现对上皮．间质转型进行调控。因此对Snail调控上皮．间质转化信号转导机制的研究,为发展新的治疗策略提供了重要信息。     

Autophagy provides a conceptual therapeutic framework for bone metastasis from prostate cancer

Prostate cancer is a common malignant tumor, which can spread to multiple organs in the body. Metastatic disease is the dominant reason of death for patients with prostate cancer. Prostate cancer usually transfers to bone. Bone metastases are related to pathologic fracture, pain, and reduced survival. There are many known targets for prostate cancer treatment, including androgen receptor (AR) axis, but drug resistance and metastasis eventually develop in advanced disease, suggesting the necessity to better understand the resistance mechanisms and consider multi-target medical treatment. Because of the limitations of approved treatments, further research into other potential targets is necessary. Metastasis is an important marker of cancer development, involving numerous factors, such as AKT, EMT, ECM, tumor angiogenesis, the development of inflammatory tumor microenvironment, and defect in programmed cell death. In tumor metastasis, programmed cell death (autophagy, apoptosis, and necroptosis) plays a key role. Malignant cancer cells have to overcome the different forms of cell death to transfer. The article sums up the recent studies on the mechanism of bone metastasis involving key regulatory factors such as macrophages and AKT and further discusses as to how regulating autophagy is crucial in relieving prostate cancer bone metastasis.Subject terms: Cancer models, Prostate cancer     

Real-Time Imaging of the Epithelial-Mesenchymal Transition Using microRNA-200a Sequence-Based Molecular Beacon-Conjugated Magnetic Nanoparticles

The epithelial-mesenchymal transition (EMT) plays important roles in tumor progression to metastasis. Thus, the development of an imaging probe that can monitor transient periods of the EMT process in live cells is required for a better understanding of metastatic process. Inspired by the fact that the mRNA expression levels of zinc finger E-box-binding homeobox 1 (ZEB1) increase when cells adopt mesenchyme characteristics and that microRNA-200a (miR-200a) can bind to ZEB1 mRNA, we conjugated molecular beacon (MB) mimicking mature miR-200a to magnetic nanoparticles (miR-200a-MB-MNPs) and devised an imaging method to observe transitional changes in the cells during EMT. Transforming growth factor-β1 treated epithelial cells and breast cancer cell lines representing both epithelial and mesenchymal phenotypes were used for the validation of miR-200a-MB-MNPs as an EMT imaging probe. The real-time imaging of live cells acquired with the induction of EMT revealed an increase in fluorescence signals by miR-200a-MB-MNPs, cell morphology alterations, and the loss of cell-cell adhesion. Our results suggest that miR-200a-MB-MNPs can be used as an imaging probe for the real-time monitoring of the EMT process in live cells.