Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy; Dept. Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; Center for Complex Systems in Molecular Biology and Medicine, University of Torino, Torino, Italy.
Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy; Dept. Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Semin Cancer Biol. 2020 Feb;60:214-224. doi: 10.1016/j.semcancer.2019.07.024. Epub 2019 Aug 3.
Cancer is a multistep disease based on crucial interactions between tumor cells and the microenvironment (extracellular matrix and stroma/immune cells). In fact, during dissemination, tumor cells have to escape from the primary tumor mass, cross the basal membrane, interact with endothelial cells to enter blood vessels (intravasation), survive in the bloodstream, get in contact with endothelial cells again to exit the bloodstream (extravasation) and seed in distant organs. Interactions between tumor and stroma cells are strongly coordinated by microRNAs (miRNAs), small non-coding RNAs able to silence protein coding genes by binding to specific recognition sites, mostly located at the 3' UTR of mature mRNAs. Relevantly, miRNA expression is often altered (overexpression or downregulation) in tumor cells and influenced by stroma cells. At the same time, miRNAs are abundant and essential in stroma cells during tumor cell dissemination and their expression is influenced by tumor cells. In fact, for instance, conditional ablation of Dicer in the endothelium of tumor bearing-mice leads to reduced tumor growth and microvessel density. In this review, we specifically focus on the role of miRNAs in endothelial cells regarding their positive or negative intervention on tumor angiogenesis or lymphoangiogenesis or when tumor cells detach from the tumor mass and intravasate or extravasate in/out of the blood vessels. Examples of pro-angiogenic miRNAs are miR-9 or miR-494, often overexpressed in tumors, which accumulate in tumor cell microvescicles and, therefore, get transferred to endothelial cells where they induce migration and angiogenesis. Differently, miR-200 and miR-128 are often downregulated in tumors and inhibit angiogenesis and lymphoangiogenesis. Instead, miR-126 controls intravasation while miR-146a, miR-214, miR-148b govern extravasation, in a positive or negative manner. Finally, at the end, we summarize opportunities for therapeutic interventions based on miRNAs acting on endothelial cells.
癌症是一种多步骤的疾病，基于肿瘤细胞与微环境（细胞外基质和基质/免疫细胞）之间的关键相互作用。事实上，在扩散过程中，肿瘤细胞必须从原发性肿瘤块中逃脱，穿过基底膜，与内皮细胞相互作用进入血管（血管内渗），在血流中存活，再次与内皮细胞接触以退出血流（血管外渗）并在远处器官中播种。肿瘤细胞与基质细胞之间的相互作用受到微小 RNA（miRNA）的强烈协调，miRNA 是一种小的非编码 RNA，能够通过结合到成熟 mRNA 的 3'UTR 上的特定识别位点来沉默蛋白编码基因。重要的是，miRNA 的表达在肿瘤细胞中经常被改变（过表达或下调），并受到基质细胞的影响。同时，miRNA 在肿瘤细胞扩散过程中在基质细胞中丰富且必不可少，其表达受肿瘤细胞影响。事实上，例如，在荷瘤小鼠的内皮细胞中条件性缺失 Dicer 会导致肿瘤生长和微血管密度降低。在这篇综述中，我们特别关注 miRNA 在血管内皮细胞中的作用，以及它们对肿瘤血管生成或淋巴管生成的积极或消极干预，或者当肿瘤细胞从肿瘤块上脱落并进入或离开血管时。促血管生成 miRNA 的例子有 miR-9 或 miR-494，它们通常在肿瘤中过表达，在肿瘤细胞微泡中积累，并因此被转移到内皮细胞，在那里它们诱导迁移和血管生成。相反，miR-200 和 miR-128 通常在肿瘤中下调，抑制血管生成和淋巴管生成。相反，miR-126 控制血管内渗，而 miR-146a、miR-214、miR-148b 则以积极或消极的方式控制血管外渗。最后，在结束时，我们总结了基于作用于内皮细胞的 miRNA 进行治疗干预的机会。
