Vesicles In Cancer Research Articles

Extracellular vesicles in cancer: Golden goose or trojan horse.

Intercellular communication can be mediated by direct cell-to-cell contact and indirect interactions through secretion of soluble chemokines, cytokines, and growth factors. Extracellular vesicles (EVs) have emerged as important mediators of cell-to-cell and cell-to-environment communications. EVs from tumor cells, immune cells, and stromal cells can remodel the tumor microenvironment and promote cancer cell survival, proliferation, metastasis, immune evasion, and therapeutic resistance. Most importantly, EVs as natural nanoparticles can be manipulated to serve as a potent delivery system for targeted cancer therapy. EVs can be engineered or modified to improve their ability to target tumors and deliver therapeutic substances, such as chemotherapeutic drugs, nucleic acids, and proteins, for the treatment of cancer. This review provides an overview of the biogenesis and recycling of EVs, discusses their roles in cancer development, and highlights their potential as a delivery system for targeted cancer therapy.

The role of extracellular vesicles in cancer.

Extracellular vesicles (EVs), which include small EVs such as exosomes, play a critical role in intercellular communication and are produced by both cancer and non-cancer cells. Several studies have shown that cancer cells exploit various strategies to regulate the biogenesis, composition, and functions of EVs primarily to promote cancer progression. Given that exosomes originate from major sorting hubs at the limiting membrane of endosomes, they are central to a signaling network that connects external stimuli with intrinsic tumor cell features. Exosomes contain diverse repertoires of molecular cargos, such as proteins, lipids, and nucleic acids, which determine their heterogeneity and functional properties in cancer progression. Therefore, targeting exosome biogenesis will enhance our understanding of tumorigenesis and also promote the discovery of novel approaches for cancer therapy. In this chapter we summarize the machinery of exosome biogenesis and the local, distant, and systemic effects of exosomes released by cancer cells. Furthermore, we explore how these exosomes regulate the anti-tumor immune response and epigenetic mechanisms to sustain cancer progression and their implications in cancer prevention and treatment.

Recent Advancements and Applications of Size Exclusion Chromatography in Modern Analysis

Abstract: In recent years, size exclusion chromatography (SEC) has gained valuable and impactable recognition among various chromatographic techniques. Also addressed as other names, viz. gel permeation chromatography, steric-exclusion chromatography, etc., SEC is typically taken into consideration for the fractionation and molecular weight determination of biomolecules and large macromolecules (proteins and polymers) using porous particles. A homogenous mixture of molecules dispersed in the mobile phase is introduced to the chromatographic column, which provides a solid support in the form of microscopic beads (the stationary phase). The beads act as “sieves” and purify small molecules, which become temporarily trapped inside the pores. Some of the advantages that SEC offers over other chromatographic techniques are short analysis time, no sample loss, good sensitivity, and requirement for less amount of mobile phase. In the proposed manuscript, we have deliberated various proteomic applications of size exclusion chromatography, which include the isolation of extracellular vesicles in cancer, isolation of human synovial fluid, separation of monoclonal antibodies, as well as several tandem techniques, such as deep glycoproteomic analysis using SEC-LC-MS/MS, analysis of mammalian polysomes in cells and tissues using tandem MS-SEC, SEC-SWATH-MS profiling of the proteome with a focus on complexity, etc.

Accessory ESCRT-III proteins are conserved and selective regulators of Rab11a-exosome formation.

Exosomes are secreted nanovesicles with potent signalling activity that are initially formed as intraluminal vesicles (ILVs) in late Rab7-positive multivesicular endosomes, and also in recycling Rab11a-positive endosomes, particularly under some forms of nutrient stress. The core proteins of the Endosomal Sorting Complex Required for Transport (ESCRT) participate in exosome biogenesis and ILV-mediated destruction of ubiquitinylated cargos. Accessory ESCRT-III components have reported roles in ESCRT-III-mediated vesicle scission, but their precise functions are poorly defined. They frequently only appear essential under stress. Comparative proteomics analysis of human small extracellular vesicles revealed that accessory ESCRT-III proteins, CHMP1A, CHMP1B, CHMP5 and IST1, are increased in Rab11a-enriched exosome preparations. We show that these proteins are required to form ILVs in Drosophila secondary cell recycling endosomes, but unlike core ESCRTs, they are not involved in degradation of ubiquitinylated proteins in late endosomes. Furthermore, CHMP5 knockdown in human HCT116 colorectal cancer cells selectively inhibits Rab11a-exosome production. Accessory ESCRT-III knockdown suppresses seminal fluid-mediated reproductive signalling by secondary cells and the growth-promoting activity of Rab11a-exosome-containing EVs from HCT116 cells. We conclude that accessory ESCRT-III components have a specific, ubiquitin-independent role in Rab11a-exosome generation, a mechanism that might be targeted to selectively block pro-tumorigenic activities of these vesicles in cancer.

The Role of Extracellular Vesicles in Cancer–Nerve Crosstalk of the Peripheral Nervous System

Although the pathogenic operations of cancer–nerve crosstalk (e.g., neuritogenesis, neoneurogensis, and perineural invasion—PNI) in the peripheral nervous system (PNS) during tumorigenesis, as well as the progression of all cancer types is continuing to emerge as an area of unique scientific interest and study, extensive, wide-ranging, and multidisciplinary investigations still remain fragmented and unsystematic. This is especially so in regard to the roles played by extracellular vesicles (EVs), which are lipid bilayer-enclosed nano- to microsized particles that carry multiple-function molecular cargos, facilitate intercellular communication in diverse processes. Accordingly, the biological significance of EVs has been greatly elevated in recent years, as there is strong evidence that they could contribute to important and possibly groundbreaking diagnostic and therapeutic innovations. This can be achieved and the pace of discoveries accelerated through cross-pollination from existing knowledge and studies regarding nervous system physiology and pathology, as well as thoroughgoing collaborations between oncologists, neurobiologists, pathologists, clinicians, and researchers. This article offers an overview of current and recent past investigations on the roles of EVs in cancer–nerve crosstalk, as well as in neural development, physiology, inflammation, injury, and regeneration in the PNS. By highlighting the mechanisms involved in physiological and noncancerous pathological cellular crosstalk, we provide hints that may inspire additional translational studies on cancer–nerve interplay.

Advances in Breast Cancer Management and Extracellular Vesicle Research, a Bibliometric Analysis.

Extracellular vesicles transport variable content and have crucial functions in cell–cell communication. The role of extracellular vesicles in cancer is a current hot topic, and no bibliometric study has ever analyzed research production regarding their role in breast cancer and indicated the trends in the field. In this way, we aimed to investigate the trends in breast cancer management involved with extracellular vesicle research. Articles were retrieved from Scopus, including all the documents published concerning breast cancer and extracellular vesicles. We analyzed authors, journals, citations, affiliations, and keywords, besides other bibliometric analyses, using R Studio version 3.6.2. and VOSviewer version 1.6.0. A total of 1151 articles were retrieved, and as the main result, our analysis revealed trending topics on biomarkers of liquid biopsy, drug delivery, chemotherapy, autophagy, and microRNA. Additionally, research related to extracellular vesicles in breast cancer has been focused on diagnosis, treatment, and mechanisms of action of breast tumor-derived vesicles. Future studies are expected to explore the role of extracellular vesicles on autophagy and microRNA, besides investigating the application of extracellular vesicles from liquid biopsies for biomarkers and drug delivery, enabling the development and validation of therapeutic strategies for specific cancers.

Molecular insights and clinical impacts of extracellular vesicles in cancer.

Cell-to-cell communication is a pivotal aspect of cancer biology. Recently, extracellular vesicles (EVs)have been shown to play essential roles in intercellular communications between cancer cells and the surrounding microenvironment owing to cancer development. EVs are small membrane-bound vesicles secreted by various cells containing proteins, lipids, mRNAs, and non-coding RNAs (microRNAs and long non-coding RNAs), which contribute to cancer cell development and progression. Here, we provide an overview of current research direction on EVs, especially biomolecules in EVs, and also point out the novel diagnostics, monitoring, predicting, and therapeutic aspects using EVs against cancer.

Biological Functions Driven by mRNAs Carried by Extracellular Vesicles in Cancer.

Extracellular vesicles (EVs), including exosomes and microvesicles, are extracellular nanovesicles released by most cells. EVs play essential roles in intercellular communication via the transport of a large variety of lipids, proteins, and nucleic acids to recipient cells. Nucleic acids are the most commonly found molecules inside EVs, and due to their small size, microRNAs and other small RNAs are the most abundant nucleic acids. However, longer molecules, such as messenger RNAs (mRNAs), have also been found. mRNAs encapsulated within EVs have been shown to be transferred to recipient cells and translated into proteins, altering the behavior of the cells. Secretion of EVs is maintained not only through multiple normal physiological conditions but also during aberrant pathological conditions, including cancer. Recently, the mRNAs carried by EVs in cancer have attracted great interest due to their broad roles in tumor progression and microenvironmental remodeling. This review focuses on the biological functions driven by mRNAs carried in EVs in cancer, which include supporting tumor progression by activating cancer cell growth, migration, and invasion; inducing microenvironmental remodeling via hypoxia, angiogenesis, and immunosuppression; and promoting modulation of the microenvironment at distant sites for the generation of a premetastatic niche, collectively inducing metastasis. Furthermore, we describe the potential use of mRNAs carried by EVs as a noninvasive diagnostic tool and novel therapeutic approach.

Intercellular communication through extracellular vesicles in cancer and evolutionary biology

Extracellular vesicles (EVs) are nano-sized membrane enclosed vesicles that are released by cells. While initially thought to be cellular detritus or particles involved in eliminating waste from cells, EVs have been recognised as important mediators of intercellular communication by transferring their bioactive cargoes. Notably, over the last two decades, a substantial research effort has been undertaken to understand the role of EVs in cancer. It is now understood that tumour derived EVs can transfer their contents to influence metastatic behaviour, as well as establish favourable microenvironments and pre-metastatic niches that support cancer development and progression. EV-mediated intercellular communication in cancer will be of importance to understanding the emerging paradigm which views cancer as the establishment of a new species within the host organism. Here, we provide a concise overview of EVs and the current understanding of their role and application in cancer. In addition, we explore the potential wider role of EVs in the transfer of inherited characteristics and evolutionary biology.

Oncogene-regulated release of extracellular vesicles.

Oncogenes can alter metabolism by changing the balance between anabolic and catabolic processes. However, how oncogenes regulate tumor cell biomass remains poorly understood. Using isogenic MCF10A cells transformed with nine different oncogenes, we show that specific oncogenes reduce the biomass of cancer cells by promoting extracellular vesicle (EV) release. While MYC and AURKB elicited the highest number of EVs, each oncogene selectively altered the protein composition of released EVs. Likewise, oncogenes alter secreted miRNAs. MYC-overexpressing cells require ceramide, whereas AURKB requires ESCRT to release high levels of EVs. We identify an inverse relationship between MYC upregulation and activation of the RAS/MEK/ERK signaling pathway for regulating EV release in some tumor cells. Finally, lysosome genes and activity are downregulated in the context of MYC and AURKB, suggesting that cellular contents, instead of being degraded, were released via EVs. Thus, oncogene-mediated biomass regulation via differential EV release is a new metabolic phenotype.

Interplay between Hypoxia and Extracellular Vesicles in Cancer and Inflammation.

Simple SummaryMounting evidence suggests a role for extracellular vesicles in cell-to-cell communication, in both physiological and pathological conditions. Moreover, the molecular content of vesicles can be exploited for diagnostic and therapeutic purposes. Inflamed tissues and tumors are often characterized by hypoxic areas, where oxygen levels drop dramatically. Several studies demonstrated that hypoxic stress affects the release of vesicles and their content. This review is intended to provide an exhaustive overview on the relationship between hypoxia and vesicles in inflammatory diseases and cancer.Hypoxia is a severe stress condition often observed in cancer and chronically inflamed cells and tissues. Extracellular vesicles play pivotal roles in these pathological processes and carry biomolecules that can be detected in many biofluids and may be exploited for diagnostic purposes. Several studies report the effects of hypoxia on extracellular vesicles’ release, molecular content, and biological functions in disease. This review summarizes the most recent findings in this field, highlighting the areas that warrant further investigation.

The Role of Extracellular Vesicles in the Progression of Human Neuroblastoma.

The long-underestimated role of extracellular vesicles in cancer is now reconsidered worldwide by basic and clinical scientists, who recently highlighted novel and crucial activities of these moieties. Extracellular vesicles are now considered as king transporters of specific cargoes, including molecular components of parent cells, thus mediating a wide variety of cellular activities both in normal and neoplastic tissues. Here, we discuss the multifunctional activities and underlying mechanisms of extracellular vesicles in neuroblastoma, the most frequent common extra-cranial tumor in childhood. The ability of extracellular vesicles to cross-talk with different cells in the tumor microenvironment and to modulate an anti-tumor immune response, tumorigenesis, tumor growth, metastasis and drug resistance will be pinpointed in detail. The results obtained on the role of extracellular vesicles may represent a panel of suggestions potentially useful in practice, due to their involvement in the response to chemotherapy, and, moreover, their ability to predict resistance to standard therapies—all issues of clinical relevance.

Filopodium-derived vesicles produced by MIM enhance the migration of recipient cells.

Extracellular vesicles (EVs) are classified as large EVs (l-EVs, or microvesicles) and small EVs (s-EVs, or exosomes). S-EVs are thought to be generated from endosomes through a process that mainly depends on the ESCRT protein complex, including ALG-2 interacting protein X (ALIX). However, the mechanisms of l-EV generation from the plasma membrane have not been identified. Membrane curvatures are generated by the bin-amphiphysin-rvs (BAR) family proteins, among which the inverse BAR (I-BAR) proteins are involved in filopodial protrusions. Here, we show that the I-BAR proteins, including missing in metastasis (MIM), generate l-EVs by scission of filopodia. Interestingly, MIM-containing l-EV production was promoted by invivo equivalent external forces and by the suppression of ALIX, suggesting an alternative mechanism of vesicle formation to s-EVs. The MIM-dependent l-EVs contained lysophospholipids and proteins, including IRS4 and Rac1, which stimulated the migration of recipient cells through lamellipodia formation. Thus, these filopodia-dependent l-EVs, which we named as filopodia-derived vesicles (FDVs), modify cellular behavior.

3D Cell Cultures as Prospective Models to Study Extracellular Vesicles in Cancer.

Simple Summary3D cell cultures are a qualitative improvement in cancer research because these models preserve cancer physiological characteristics better than traditional bi-dimensional cultures. Moreover, they facilitate the study of complex 3D interactions using extracellular matrices and the co-culture of different cell types. In this manner, the cells can contact themselves in a fully physiological but also controlled arrangement. In the context of tumor interactions, extracellular vesicles are essential in number of key aspects in oncology: as major interactors with extracellular matrix, as cell-to-cell messengers, as carriers of diagnostic-valuable biomarkers, and as target-specific treatment-deliver agents. The present article aims to discuss the findings achieved using 3D culture models in oncology. We further review the involvement of extracellular vesicles in the pathogenesis of cancer as well as their potential use in diagnostics and therapeutics.The improvement of culturing techniques to model the environment and physiological conditions surrounding tumors has also been applied to the study of extracellular vesicles (EVs) in cancer research. EVs role is not only limited to cell-to-cell communication in tumor physiology, they are also a promising source of biomarkers, and a tool to deliver drugs and induce antitumoral activity. In the present review, we have addressed the improvements achieved by using 3D culture models to evaluate the role of EVs in tumor progression and the potential applications of EVs in diagnostics and therapeutics. The most employed assays are gel-based spheroids, often utilized to examine the cell invasion rate and angiogenesis markers upon EVs treatment. To study EVs as drug carriers, a more complex multicellular cultures and organoids from cancer stem cell populations have been developed. Such strategies provide a closer response to in vivo physiology observed responses. They are also the best models to understand the complex interactions between different populations of cells and the extracellular matrix, in which tumor-derived EVs modify epithelial or mesenchymal cells to become protumor agents. Finally, the growth of cells in 3D bioreactor-like systems is appointed as the best approach to industrial EVs production, a necessary step toward clinical translation of EVs-based therapy.

Size-Exclusion Chromatography as a Technique for the Investigation of Novel Extracellular Vesicles in Cancer.

Simple SummaryExtracellular vesicles (EVs) are small particles that are released by cancer cells, and they may hold vital information for researchers looking for early markers for diagnosis. Size-exclusion chromatography (SEC) is a classical technique that has become increasingly popular and can be used for rapid isolation and investigation of both their cargo and functionality. This systematic review highlights its main technical aspects, the type of materials involved and by covering the findings of the identified papers hopes to demonstrate the utility of this method in cancer research to date.Cancer cells release extracellular vesicles, which are a rich target for biomarker discovery and provide a promising mechanism for liquid biopsy. Size-exclusion chromatography (SEC) is an increasingly popular technique, which has been rediscovered for the purposes of extracellular vesicle (EV) isolation and purification from diverse biofluids. A systematic review was undertaken to identify all papers that described size exclusion as their primary EV isolation method in cancer research. In all, 37 papers were identified and discussed, which showcases the breadth of applications in which EVs can be utilised, from proteomics, to RNA, and through to functionality. A range of different methods are highlighted, with Sepharose-based techniques predominating. EVs isolated using SEC are able to identify cancer cells, highlight active pathways in tumourigenesis, clinically distinguish cohorts, and remain functionally active for further experiments.

Emerging role of bacterial extracellular vesicles in cancer.

Shedding of microbial extracellular vesicles constitutes a universal mechanism for inter-kingdom and intra-kingdom communication that is conserved among prokaryotic and eukaryotic microbes. In this review we delineate fundamental aspects of bacterial extracellular vesicles (BEVs) including their biogenesis, cargo composition, and interactions with host cells. We critically examine the evidence that BEVs from the host gut microbiome can enter the circulatory system to disseminate to distant organs and tissues. The potential involvement of BEVs in carcinogenesis is evaluated and future research ideas explored. We further discuss the potential of BEVs in microbiome-based liquid biopsies for cancer diagnostics and bioengineering strategies for cancer therapy.

MicroRNA exchange via extracellular vesicles in cancer.

Cells utilize different means of inter‐cellular communication to function properly. Here, we review the crosstalk between cancer cells and their surrounding environment through microRNA (miRNA)‐containing extracellular vesicles (EVs). The current findings suggest that the export of miRNAs and uptake of miRNA‐containing EVs might be an active process. As post‐transcriptional regulators of gene expression, cancer‐derived miRNAs that are taken up by normal cells can change the translational profile of the recipient cell towards a transformed proteome. Stromal cells can also deliver miRNAs via EVs to cancer cells to support tumour growth and cancer progression. Therefore, gaining a better understanding of EV‐mediated inter‐cellular communication in the tumour microenvironment might lead to the development of novel diagnostic and therapeutic strategies.

The evolving translational potential of small extracellular vesicles in cancer.

Cancer-derived extracellular vesicles (EVs) are regarded as having promising potential to be used as therapeutics and disease biomarkers. Mechanistically, EVs have been shown to function in most, if not all, steps of cancer progression. Cancer EVs, including small EVs (sEVs), contain unique biomolecular cargo, consisting of protein, nucleic acid and lipids. Through progress in the identification of this specific cargo, cancer biomarkers have been identified and developed, opening up novel and interesting opportunities for cancer diagnosis and prognosis. Intriguingly, we still lack a comprehensive understanding of the cancer-specific pathways that govern EV biogenesis in cancer cells. Filling this knowledge gap will rapidly improve cancer EV biomarkers, as it will also allow discrimination of the procancer and anticancer actions of those EVs. Even more promising is uncovering therapeutically targetable, tumour-specific EV pathways and content, which will generate novel classes of cancer therapies. This Review highlights the progress the cancer sEV field has made in the areas of biomarker discovery and validation as well as sEV-based therapeutics, highlights the challenges we are facing and identifies gaps in our knowledge, which currently prevent us from developing the full potential of sEVs in cancer diagnostic and therapy.

Regulatory Role of Immune Cell-Derived Extracellular Vesicles in Cancer: The Message Is in the Envelope.

Extracellular vesicles (EVs) are a heterogenous group of membrane-surrounded structures. Besides serving as a harbor for the unwanted material exocytosed by cells, EVs play a critical role in conveying intact protein, genetic, and lipid contents that are important for intercellular communication. EVs, broadly comprised of microvesicles and exosomes, are released to the extracellular environment from nearly all cells either via shedding from the plasma membrane or by originating from the endosomal system. Exosomes are 40–150 nm, endosome-derived small EVs (sEVs) that are released by cells into the extracellular environment. This review focuses on the biological properties of immune cell-derived sEVs, including composition and cellular targeting and mechanisms by which these immune cell-derived sEVs influence tumor immunity either by suppressing or promoting tumor growth, are discussed. The final section of this review discusses how the biological properties of immune cell-derived sEVs can be manipulated to improve their immunogenicity.

The functional role of surface molecules on extracellular vesicles in cancer, autoimmune diseases, and coagulopathy.

Extracellular vesicles (EVs) are nanosized particles that have emerged as mediators for intercellular communication in physiologic and pathologic conditions. EVs carry signaling information on their bilipid membrane as well as cargo within, allowing them to perform a wide range of biologic processes and contribute to pathophysiologic roles in a wide range of diseases, including cancer, autoimmune diseases and coagulopathy. This review will specifically address the function of surface molecules on EVs under normal and diseased conditions, as well as their potential to emerge as therapeutic targets in clinical settings, and the importance of further research on the surface topography of EVs.