Role of Extracellular Vesicles (EVs) in Cell Stress Response and Resistance to Cancer Therapy

Extracellular vesicles (EVs) are nanosized particles released by all cells that have been heralded as novel regulators of cell-to-cell communication. It is becoming increasingly clear that in response to a variety of stress conditions, cells employ EV-mediated intercellular communication to transmit a pro-survival message in the tumor microenvironment and beyond, supporting evasion of cell death and transmitting resistance to therapy. Understanding changes in EV cargo and secretion pattern during cell stress may uncover novel, targetable mechanisms underlying disease progression, metastasis and resistance to therapy. Further, the profile of EVs released into the circulation may provide a circulating biomarker predictive of response to therapy and indicative of microenvironmental conditions linked to disease progression, such as hypoxia. Continued progress in this exciting and rapidly expanding field of research will be dependent upon widespread adoption of transparent reporting standards and implementation of guidelines to establish a consensus on methods of EV isolation, characterisation and nomenclature employed.

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The Power of Extracellular Vesicles in Myeloproliferative Neoplasms: “Crafting” a Microenvironment That Matters

Cells ◽

10.3390/cells10092316 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2316

Author(s):

Lucia Catani ◽

Michele Cavo ◽

Francesca Palandri

Keyword(s):

Extracellular Vesicles ◽

Immune Escape ◽

Myeloproliferative Neoplasms ◽

Cell Communication ◽

Bioactive Molecules ◽

Driver Genes ◽

Hematopoietic Stem ◽

Increased Risk ◽

Patients Experience

Myeloproliferative Neoplasms (MPN) are acquired clonal disorders of the hematopoietic stem cells and include Essential Thrombocythemia, Polycythemia Vera and Myelofibrosis. MPN are characterized by mutations in three driver genes (JAK2, CALR and MPL) and by a state of chronic inflammation. Notably, MPN patients experience increased risk of thrombosis, disease progression, second neoplasia and evolution to acute leukemia. Extracellular vesicles (EVs) are a heterogeneous population of microparticles with a role in cell-cell communication. The EV-mediated cross-talk occurs via the trafficking of bioactive molecules such as nucleic acids, proteins, metabolites and lipids. Growing interest is focused on EVs and their potential impact on the regulation of blood cancers. Overall, EVs have been suggested to orchestrate the complex interplay between tumor cells and the microenvironment with a pivotal role in “education” and “crafting” of the microenvironment by regulating angiogenesis, coagulation, immune escape and drug resistance of tumors. This review is focused on the role of EVs in MPN. Specifically, we will provide an overview of recent findings on the involvement of EVs in MPN pathogenesis and discuss opportunities for their potential application as diagnostic and prognostic biomarkers.

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Platelet Extracellular Vesicles

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314644 ◽

2020 ◽

Author(s):

Florian Puhm ◽

Eric Boilard ◽

Kellie R. Machlus

Keyword(s):

Bone Marrow ◽

Synovial Fluid ◽

Nucleic Acids ◽

Extracellular Vesicles ◽

Cell Communication ◽

Biological Processes ◽

Vascular Integrity ◽

Pathological Conditions ◽

Broad Array

Extracellular vesicles (EVs) are a means of cell-to-cell communication and can facilitate the exchange of a broad array of molecules between adjacent or distant cells. Platelets are anucleate cells derived from megakaryocytes and are primarily known for their role in maintaining hemostasis and vascular integrity. Upon activation by a variety of agonists, platelets readily generate EVs, which were initially identified as procoagulant particles. However, as both platelets and their EVs are abundant in blood, the role of platelet EVs in hemostasis may be redundant. Moreover, findings have challenged the significance of platelet-derived EVs in coagulation. Looking beyond hemostasis, platelet EV cargo is incredibly diverse and can include lipids, proteins, nucleic acids, and organelles involved in numerous other biological processes. Furthermore, while platelets cannot cross tissue barriers, their EVs can enter lymph, bone marrow, and synovial fluid. This allows for the transfer of platelet-derived content to cellular recipients and organs inaccessible to platelets. This review highlights the importance of platelet-derived EVs in physiological and pathological conditions beyond hemostasis.

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Emerging role of extracellular vesicles in liver diseases

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00183.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. G739-G749 ◽

Cited By ~ 10

Author(s):

Harmeet Malhi

Keyword(s):

Extracellular Vesicles ◽

Cell Communication ◽

Cell Types ◽

Cell Responses ◽

Therapeutic Delivery ◽

Disease States ◽

Therapeutic Uses ◽

Potential Biomarker ◽

Secretion Pathways

Extracellular vesicles (EVs) are membrane-defined nanoparticles released by most cell types. The EVs released by cells may differ quantitatively and qualitatively from physiological states to disease states. There are several unique properties of EVs, including their proteins, lipids and nucleic acid cargoes, stability in circulation, and presence in biofluids, which make them a critical vector for cell-to-cell communication and impart utility as a biomarker. EVs may also serve as a vehicle for selective cargo secretion. Similarly, EV cargo may be selectively manipulated for targeted therapeutic delivery. In this review an overview is provided on the EV classification, biogenesis, and secretion pathways, which are conserved across cell types. Next, cargo characterization and effector cell responses are discussed in the context of nonalcoholic steatohepatitis, alcoholic hepatitis, and acetaminophen-induced liver injury. The review also discusses the potential biomarker and therapeutic uses of circulating EVs.

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Extracellular vesicles in diagnosis and therapy of kidney diseases

AJP Renal Physiology ◽

10.1152/ajprenal.00429.2016 ◽

2016 ◽

Vol 311 (5) ◽

pp. F844-F851 ◽

Cited By ~ 55

Author(s):

Wei Zhang ◽

Xiangjun Zhou ◽

Hao Zhang ◽

Qisheng Yao ◽

Yutao Liu ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cross Talk ◽

Cultured Cells ◽

Therapeutic Potential ◽

Kidney Diseases ◽

Cell Communication ◽

Therapeutic Effects ◽

Glomerular Diseases ◽

The Cross

Extracellular vesicles (EV) are endogenously produced, membrane-bound vesicles that contain various molecules. Depending on their size and origins, EVs are classified into apoptotic bodies, microvesicles, and exosomes. A fundamental function of EVs is to mediate intercellular communication. In kidneys, recent research has begun to suggest a role of EVs, especially exosomes, in cell-cell communication by transferring proteins, mRNAs, and microRNAs to recipient cells as nanovectors. EVs may mediate the cross talk between various cell types within kidneys for the maintenance of tissue homeostasis. They may also mediate the cross talk between kidneys and other organs under physiological and pathological conditions. EVs have been implicated in the pathogenesis of both acute kidney injury and chronic kidney diseases, including renal fibrosis, end-stage renal disease, glomerular diseases, and diabetic nephropathy. The release of EVs with specific molecular contents into urine and plasma may be useful biomarkers for kidney disease. In addition, EVs produced by cultured cells may have therapeutic effects for these diseases. However, the role of EVs in kidney diseases is largely unclear, and the mechanism underlying EV production and secretion remains elusive. In this review, we introduce the basics of EVs and then analyze the present information about the involvement, diagnostic value, and therapeutic potential of EVs in major kidney diseases.

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The Role of Cytokines in the Different Stages of Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13194876 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4876

Author(s):

Noe Rico Montanari ◽

Chimaobi M. Anugwom ◽

Andre Boonstra ◽

Jose D. Debes

Keyword(s):

Hepatocellular Carcinoma ◽

Early Detection ◽

Underlying Disease ◽

Tumor Formation ◽

Response To Therapy ◽

Common Denominator ◽

Immune Parameters ◽

Genetic Complexity ◽

Inflammatory Molecules

Hepatocellular carcinoma (HCC) is the primary form of liver cancer and a leading cause of cancer-related death worldwide. Early detection remains the most effective strategy in HCC management. However, the spectrum of underlying liver diseases preceding HCC, its genetic complexity, and the lack of symptomatology in early stages challenge early detection. Regardless of underlying etiology, unresolved chronic inflammation is a common denominator in HCC. Hence, many inflammatory molecules, including cytokines, have been investigated as potential biomarkers to predict different stages of HCC. Soluble cytokines carry cell-signaling functions and are easy to detect in the bloodstream. However, its biomarkers’ role remains limited due to the dysregulation of immune parameters related to the primary liver process and their ability to differentiate carcinogenesis from the underlying disease. In this review, we discuss and provide insight on cytokines with clinical relevance for HCC differentiating those implicated in tumor formation, early detection, advanced disease, and response to therapy.

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The potential role of miRNAs and exosomes in chemotherapy in ovarian cancer

Endocrine Related Cancer ◽

10.1530/erc-18-0019 ◽

2018 ◽

Vol 25 (12) ◽

pp. R663-R685 ◽

Cited By ~ 15

Author(s):

Mona Alharbi ◽

Felipe Zuñiga ◽

Omar Elfeky ◽

Dominic Guanzon ◽

Andrew Lai ◽

...

Keyword(s):

Ovarian Cancer ◽

Disease Progression ◽

Potential Role ◽

Chemotherapy Resistance ◽

Predictive Biomarker ◽

Response To Therapy ◽

Target Cells ◽

Repair Mechanisms ◽

Drug Efflux Pumps

Chemoresistance is one of the major obstacles in the treatment of cancer patients. It poses a fundamental challenge to the effectiveness of chemotherapy and is often linked to relapse in patients. Chemoresistant cells can be identified in different types of cancers; however, ovarian cancer has one of the highest rates of chemoresistance-related relapse (50% of patients within 5 years). Resistance in cells can either develop through prolonged cycles of treatment or through intrinsic pathways. Mechanistically, the problem of drug resistance is complex mainly because numerous factors are involved, such as overexpression of drug efflux pumps, drug inactivation, DNA repair mechanisms and alterations to and/or mutations in the drug target. Additionally, there is strong evidence that circulating miRNAs participate in the development of chemoresistance. Recently, miRNAs have been identified in exosomes, where they are encapsulated and hence protected from degradation. These miRNAs within exosomes (exo-miRNAs) can regulate the gene expression of target cells both locally and systemically. Exo-miRNAs play an important role in disease progression and can potentially facilitate chemoresistance in cancer cells. In addition, and from a diagnostic perspective, exo-miRNAs profiles may contribute to the development of predictive models to identify responder and non-responder chemotherapy. Such model may also be used for monitoring treatment response and disease progression. Exo-miRNAs may ultimately serve as both a predictive biomarker for cancer response to therapy and as a prognostic marker for the development of chemotherapy resistance. Therefore, this review examines the potential role of exo-miRNAs in chemotherapy in ovarian cancer.

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Inhibition of a v b 3 integrin impairs adhesion and uptake of tumor-derived small extracellular vesicles

10.21203/rs.3.rs-17483/v1 ◽

2020 ◽

Author(s):

Wanessa Altei ◽

Bianca Pachane ◽

Patty K. Santos ◽

Ligia Ribeiro ◽

Bong Hwan Sung ◽

...

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Cell Communication ◽

Organ Specific ◽

Breast Cells ◽

Mediate Cell ◽

First Time ◽

Cd63 Expression ◽

Cell Cell

Abstract Background: Extracellular vesicles (EVs) are lipid-bound particles that are naturally released from cells and mediate cell-cell communication. Integrin adhesion receptors are enriched in small EVs (SEVs) and SEV-carried integrins have been shown to promote cancer cell migration and to mediate organ-specific metastasis; however, how integrins mediate these effects is not entirely clear and could represent a combination of EV binding to extracellular matrix and cells.Methods: To probe integrin role in EVs binding and uptake, we employed a disintegrin inhibitor (DisBa-01) of integrin binding with specificity for avb3 integrin. EVs were purified from MDA-MB-231 cells conditioned media by serial centrifugation method. Isolated EVs were characterized by different techniques and further employed in adhesion, uptake and co-culture experiments.Results: We find that SEVs secreted from MDA-MB-231 breast cancer cells carry avb3 integrin and bind directly to fibronectin-coated plates, which is inhibited by DisBa-01. SEV coating on tissue culture plates also induces adhesion of MDA-MB-231 cells, which is inhibited by DisBa-01 treatment. Analysis of EV uptake and interchange between cells reveals that the amount of CD63-positive EVs delivered from malignant MDA-MB-231 breast cells to non-malignant MCF10A breast epithelial cells is reduced by DisBa-01 treatment. Inhibition of avb3 integrin decreases CD63 expression in cancer cells suggesting an effect on SEV content.Conclusion: In summary, our findings demonstrate for the first time a key role of avb3 integrin in cell-cell communication through SEVs.

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Inhibition of a v b 3 integrin impairs adhesion and uptake of tumor-derived small extracellular vesicles

10.21203/rs.3.rs-17483/v2 ◽

2020 ◽

Author(s):

Wanessa Altei ◽

Bianca Pachane ◽

Patty K. Santos ◽

Ligia Ribeiro ◽

Bong Hwan Sung ◽

...

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Cell Communication ◽

Αvβ3 Integrin ◽

Organ Specific ◽

Breast Cells ◽

Mediate Cell ◽

First Time ◽

Cell Cell

Abstract Background: Extracellular vesicles (EVs) are lipid-bound particles that are naturally released from cells and mediate cell-cell communication. Integrin adhesion receptors are enriched in small EVs (SEVs) and SEV-carried integrins have been shown to promote cancer cell migration and to mediate organ-specific metastasis; however, how integrins mediate these effects is not entirely clear and could represent a combination of EV binding to extracellular matrix and cells. Methods: To probe integrin role in EVs binding and uptake, we employed a disintegrin inhibitor (DisBa-01) of integrin binding with specificity for αvβ3 integrin. EVs were purified from MDA-MB-231 cells conditioned media by serial centrifugation method. Isolated EVs were characterized by different techniques and further employed in adhesion, uptake and co-culture experiments. Results: We find that SEVs secreted from MDA-MB-231 breast cancer cells carry αvβ3 integrin and bind directly to fibronectin-coated plates, which is inhibited by DisBa-01. SEV coating on tissue culture plates also induces adhesion of MDA-MB-231 cells, which is inhibited by DisBa-01 treatment. Analysis of EV uptake and interchange between cells reveals that the amount of CD63-positive EVs delivered from malignant MDA-MB-231 breast cells to non-malignant MCF10A breast epithelial cells is reduced by DisBa-01 treatment. Inhibition of αvβ3 integrin decreases CD63 expression in cancer cells suggesting an effect on SEV content. Conclusion: In summary, our findings demonstrate for the first time a key role of αvβ3 integrin in cell-cell communication through SEVs.

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Emerging role of extracellular vesicles in mediating cancer cachexia

Biochemical Society Transactions ◽

10.1042/bst20180213 ◽

2018 ◽

Vol 46 (5) ◽

pp. 1129-1136 ◽

Cited By ~ 12

Author(s):

Sai V. Chitti ◽

Pamali Fonseka ◽

Suresh Mathivanan

Keyword(s):

Extracellular Vesicles ◽

Cancer Progression ◽

Tissue Repair ◽

Skeletal Muscles ◽

Cancer Cachexia ◽

Cell Communication ◽

Rapid Weight Loss ◽

Rapid Loss ◽

Patients Experience

Cancer cachexia is a multifactorial metabolic syndrome characterized by the rapid loss of skeletal muscle mass with or without the loss of fat mass. Nearly 50–80% of all cancer patients' experience rapid weight loss results in ∼20% of cancer-related deaths. The levels of pro-inflammatory and pro-cachectic factors were significantly up-regulated in cachexia patients when compared with the patients who were without cachexia. It is becoming evident that these factors work synergistically to induce cancer cachexia. Extracellular vesicles (EVs) including exosomes and microvesicles are implicated in cell–cell communication, immune response, tissue repair, epigenetic regulation, and in various diseases including cancer. It has been reported that these EVs regulate cancer progression, metastasis, organotropism and chemoresistance. In recent times, the role of EVs in regulating cancer cachexia is beginning to unravel. The aim of this mini article is to review the recent knowledge gained in the field of EVs and cancer cachexia. Specifically, the role of tumour cell-derived EVs in promoting catabolism in distally located skeletal muscles and adipose tissue will be discussed.

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Biology and Role of Extracellular Vesicles (EVs) in the Pathogenesis of Thrombosis

International Journal of Molecular Sciences ◽

10.3390/ijms20112840 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2840 ◽

Cited By ~ 24

Author(s):

Marta Zarà ◽

Gianni Francesco Guidetti ◽

Marina Camera ◽

Ilaria Canobbio ◽

Patrizia Amadio ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cell Communication ◽

Parental Cell ◽

Biochemical Properties ◽

Protein Markers ◽

Surface Receptors ◽

The Impact ◽

Physiological And Biochemical ◽

Physiological And Biochemical Properties

Extracellular vesicles (EVs) are well-established mediators of cell-to-cell communication. EVs can be released by every cell type and they can be classified into three major groups according to their biogenesis, dimension, density, and predominant protein markers: exosomes, microvesicles, and apoptotic bodies. During their formation, EVs associate with specific cargo from their parental cell that can include RNAs, free fatty acids, surface receptors, and proteins. The biological function of EVs is to maintain cellular and tissue homeostasis by transferring critical biological cargos to distal or neighboring recipient cells. On the other hand, their role in intercellular communication may also contribute to the pathogenesis of several diseases, including thrombosis. More recently, their physiological and biochemical properties have suggested their use as a therapeutic tool in tissue regeneration as well as a novel option for drug delivery. In this review, we will summarize the impact of EVs released from blood and vascular cells in arterial and venous thrombosis, describing the mechanisms by which EVs affect thrombosis and their potential clinical applications.

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