Cancer biology: extracellular proteinases in malignancy.

Secreted, matrix-degrading proteinases have been viewed as contributing to tumor metastasis. A recent study indicates that the gene for one of these enzymes, the matrix metalloproteinase stromelysin-1, can actually cause cancer when expressed in transgenic mice.     

Controlling centrosome number: licenses and blocks

Centrosomes organize microtubule structures in animal cells. The centrosome duplicates once per cell cycle in most dividing cells via a pathway that relies on a pre-existing centrosome. The molecular mechanism of this 'once and only once' control is not understood, and recent results show that centrosomes can also be assembled by a de novo pathway that bypasses this control. These results require a rethinking of how proper centrosome number is maintained. We propose that the engagement of centrioles with each other normally blocks centrosome re-duplication, and that disengagement of centrioles from each other at the end of mitosis licenses them for duplication in the subsequent cell cycle.     

Evolutionary problems in centrosome and centriole biology

Centrosomes have been an enigma to evolutionary biologists. Either they have been the subject of ill‐founded speculation or they have been ignored. Here, we highlight evolutionary paradoxes and problems of centrosome and centriole evolution and seek to understand them in the light of recent advances in centrosome biology. Most evolutionary accounts of centrosome evolution have been based on the hypothesis that centrosomes are replicators, independent of the nucleus and cytoplasm. It is now clear, however, that this hypothesis is not tenable. Instead, centrosomes are formed de novo each cell division, with the presence of an old centrosome regulating, but not essential for, the assembly of a new one. Centrosomes are the microtubule‐organizing centres of cells. They can potentially affect sensory and motor characters (as the basal body of cilia), as well as the movements of chromosomes during cell division. This latter role does not seem essential, however, except in male meiosis, and the reasons for this remain unclear. Although the centrosome is absent in some taxa, when it is present, its structure is extraordinarily conserved: in most taxa across eukaryotes, it does not appear to evolve at all. And yet a few insect groups display spectacular hypertrophy of the centrioles. We discuss how this might relate to the unusual reproductive system found in these insects. Finally, we discuss why the fate of centrosomes in sperm and early embryos might differ between different groups of animals.     

From fundamental biology to the search for innovation: The story of fungal extracellular vesicles

Fungal extracellular vesicles (EVs) have attracted increased attention in recent years. Originated from a serendipitous discovery, the initial observation of fungal EVs resulted in a set of data repetitively rejected by several scientific journals, which raised questions about their authenticity. However, after the most fundamental experimental issues related to their observation were addressed, fungal EVs were characterized in dozens of species and became an emerging field. In this essay, we will discuss these fundamental findings and the potential of fungal EVs for the development of vaccines and antifungals.     

Cancer extracellular vesicles as novel regulators of NK cell response

Natural killer (NK) cells are innate lymphoid cells that play a major role in the immune surveillance against tumors and their activity is regulated through signals derived by a number of NK cell inhibitory and activating receptors as well as cytokines and other soluble factors released in the tumor microenvironment. Extracellular vesicles (EVs) are membrane-enclosed particles secreted by all cell types, both in healthy and diseased conditions, and are important mediators of intercellular communication. Depending on the molecular cargo, tumor-derived extracellular vesicles have the capability to either promote or suppress NK cell-mediated functions.Anti-cancer therapies designed to sustain host anti-tumor immune response represent an appealing strategy to control tumor growth avoiding tumor immune escape. The ability of anticancer chemotherapy to enhance the immunogenic potential of malignant cells mainly relies on the establishment of the immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs). Moreover, the activation of the DNA damage response (DDR) and the induction of senescence represent two crucial modalities aimed at promoting the clearance of drug-treated tumor cells by NK cells. Herein, we will address the main mechanisms used by cancer-derived extracellular vesicles to modulate NK cell activity, and we will discuss how anti-cancer therapies might impact on the secretion and the immunomodulatory function of these vesicles.     

Breaking the ties that bind: new advances in centrosome biology

The centrosome, which consists of two centrioles and the surrounding pericentriolar material, is the primary microtubule-organizing center (MTOC) in animal cells. Like chromosomes, centrosomes duplicate once per cell cycle and defects that lead to abnormalities in the number of centrosomes result in genomic instability, a hallmark of most cancer cells. Increasing evidence suggests that the separation of the two centrioles (disengagement) is required for centrosome duplication. After centriole disengagement, a proteinaceous linker is established that still connects the two centrioles. In G2, this linker is resolved (centrosome separation), thereby allowing the centrosomes to separate and form the poles of the bipolar spindle. Recent work has identified new players that regulate these two processes and revealed unexpected mechanisms controlling the centrosome cycle.     

Cancer cells copy migratory behavior and exchange signaling networks via extracellular vesicles

Recent data showed that cancer cells from different tumor subtypes with distinct metastatic potential influence each other's metastatic behavior by exchanging biomolecules through extracellular vesicles (EVs). However, it is debated how small amounts of cargo can mediate this effect, especially in tumors where all cells are from one subtype, and only subtle molecular differences drive metastatic heterogeneity. To study this, we have characterized the content of EVs shed in vivo by two clones of melanoma (B16) tumors with distinct metastatic potential. Using the Cre‐LoxP system and intravital microscopy, we show that cells from these distinct clones phenocopy their migratory behavior through EV exchange. By tandem mass spectrometry and RNA sequencing, we show that EVs shed by these clones into the tumor microenvironment contain thousands of different proteins and RNAs, and many of these biomolecules are from interconnected signaling networks involved in cellular processes such as migration. Thus, EVs contain numerous proteins and RNAs and act on recipient cells by invoking a multi‐faceted biological response including cell migration.     

Exosomes: endosomal-derived vesicles shipping extracellular messages

Exosomes are membrane vesicles released into the extracellular environment upon exocytic fusion of multivesicular endosomes with the cell surface. They have a particular composition reflecting their origin in endosomes as intraluminal vesicles. In vitro and in vivo studies support the contribution of exosomes to an acellular mode of communication, leading to intercellular transfer of molecules. Exosomes may have regulatory functions in the immune system and their application in cancer immunotherapy is promising. The mechanisms involved in exosome secretion and interaction with target cells are as yet unclear. A better understanding of these mechanisms is also essential to determine the link between exosomes and retroviruses.     

Large extracellular vesicles: Size matters in tumor progression

Extracellular Vesicles (EVs) represent a heterogeneous population of particles naturally released from all cells, delimited by a lipid bilayer and able to horizontally transfer their cargos to recipient cells. These features imply the growing interest on EVs in cancer biology as biomarkers and therapeutic targets. In this review, we will highlight the specific process related to biogenesis and release of large EVs (L-EVs) derived from the plasma membrane (PM) compared to the small and well described exosomes, generated through the classical endosome-multivesicular body (MVB) pathway. The control of PM rigidity by cells depends on lipid/protein composition, cytoskeleton dynamics, cytoplasmic viscosity, ions balance, metabolic reprogramming and specific intracellular signaling pathways, all critical determinants of L-EVs biogenesis. We will focus in details on a specific class of L-EVs, named Large Oncosomes (LO), exclusively shed by cancer cells and with a size ranging from 1 μm up to 10 μm. We will examine LO specific cargos, either proteins or nucleic acids (i.e. mRNA, microRNAs, single/double-stranded DNA), as well as their functional role in cancer development and progression, also discussing the mechanisms of L-EVs internalization by recipient cells. Overall we will highlight the potential of LO as specific diagnostic/prognostic cancer biomarkers discussing the associated challenges.     

MicroRNAs and extracellular vesicles in cholangiopathies

Cholangiopathies encompass a heterogeneous group of disorders affecting biliary epithelial cells (i.e. cholangiocytes). Early diagnosis, prognosis and treatment still remain clinically challenging for most of these diseases and are critical for adequate patient care. In the past decade, extensive research has emphasized microRNAs (miRs) as potential non-invasive biomarkers and tools to accurately identify, predict and treat cholangiopathies. MiRs can be released extracellularly conjugated with lipoproteins or encapsulated in extracellular vesicles (EVs). Research on EVs is also gaining attention since they are present in multiple biological fluids and may represent a relevant source of novel non-invasive biomarkers and be vehicles for new therapeutic approaches. This review highlights the most promising candidate miRs and EV-related biomarkers in cholangiopathies, as well as their relevant roles in biliary pathophysiology. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

细菌胞外囊泡的研究进展

胞外囊泡(extracellular vesicles,EVs)是自然界中细胞生命活动的产物，是一种包裹核酸、蛋白、脂类等分子的纳米级磷脂双分子层颗粒。近年来，越来越多的研究证实细菌可以分泌EVs作为抗生素和噬菌体的“诱饵”，从而发挥防御功能；此外，EVs还在传递毒力因子、细胞间通讯、介导基因水平转移、营养和电子传递、促进生物膜的形成中发挥重要作用。因此，EVs对生物个体和群体都具有十分重要的作用。本文综述了细菌EVs形成机制、提取及鉴定方法、影响EVs分泌的因素等，重点总结了EVs的生物学功能以及在环境科学领域的研究进展，为EVs的进一步研究提供参考。     

Imaging extracellular vesicles: current and emerging methods

Extracellular vesicles (EVs) are lipid bilayer-enclosed nanoparticles released by cells. They range from 30?nm to several micrometers in diameter, and ferry biological cargos such as proteins, lipids, RNAs and DNAs for local and distant intercellular communications. EVs have since been found to play a role in development, as well as in diseases including cancers. To elucidate the roles of EVs, researchers have established different methods to visualize and study their spatiotemporal properties. However, since EV are nanometer-sized, imaging them demands a full understanding of each labeling strategy to ensure accurate monitoring. This review covers current and emerging strategies for EV imaging for prospective studies.     

益生菌胞外囊泡与疾病的相关研究进展

益生菌是对宿主健康有益的活的微生物, 具有广泛的促健康作用。它可以缓解和改善肠道相关炎症性疾病的症状, 降低血清胆固醇, 调节肠道菌群平衡, 对恶性肿瘤的治疗和预防有重要作用。胞外囊泡(extracellular vesicles, EVs)是革兰阴性菌及少数革兰阳性菌释放的含有多种生物活性物质的一种纳米级囊泡结构。EVs通过携带生物信息分子在细菌与细菌或细菌与宿主之间的交流中起着非常重要的作用。虽然近年来研究者们对革兰阳性和阴性病原体来源的EVs的研究越来越多, 但对益生菌产生的EVs的研究却很少。本文综述了近年来益生菌释放的EVs在治疗相关疾病中的研究进展, 并对未来的发展形势进行分析。希望本文能围绕益生菌EVs这一新兴领域的最新进展, 寻找基于EVs的相关疾病的诊断工具和有效治疗方法。

     

Dependence of the number of vesicles in vascular smooth muscle cells on the presence of noradrenaline in the extracellular space

Noradrenaline (NA) effect on the number of vesicles in smooth muscle cells was investigated in small mesenteric arteries of spontaneously hypertensive rats (SHR), aged 8 or 12 weeks, and age-matched normotensive Wistar-Kyoto (WKY) rats. The presence of NA in the incubation medium resulted in an increase in the number of vesicles in SHR of both age groups, but not in WKY. The results are discussed in view of the relationship between the vesicles and Ca transport in smooth muscle cells.     

Active endocannabinoids are secreted on extracellular membrane vesicles

Endocannabinoids primarily influence neuronal synaptic communication within the nervous system. To exert their function, endocannabinoids need to travel across the intercellular space. However, how hydrophobic endocannabinoids cross cell membranes and move extracellularly remains an unresolved problem. Here, we show that endocannabinoids are secreted through extracellular membrane vesicles produced by microglial cells. We demonstrate that microglial extracellular vesicles carry on their surface N-arachidonoylethanolamine (AEA), which is able to stimulate type-1 cannabinoid receptors (CB₁), and inhibit presynaptic transmission, in target GABAergic neurons. This is the first demonstration of a functional role of extracellular vesicular transport of endocannabinoids.     

革兰氏阳性菌细胞外囊泡的研究现状

细胞外囊泡(EVs),也称为膜小泡,是真核细胞和细菌分泌的囊泡状小体.它通过携带蛋白质、DNA、RNA和各种代谢物进行细胞间物质的交流传递.根据内容物的不同发挥不同的生理功能,如传递营养物质、参与免疫反应、治疗癌症等.目前大多数研究专注于真核细胞和革兰氏阴性菌囊泡的探索,而对革兰氏阳性菌中分泌的囊泡研究较少.这篇综述总...