Extracellular vesicles and immunogenic stress in cancer

AbstractTumor progression requires bidirectional cell-to-cell communication within a complex tumor microenvironment (TME). Extracellular vesicles (EVs) as carriers have the capacity to shuttle regulatory molecules, including nucleic acids, proteins, and lipids, between cancer cells and multiple stromal cells, inducing remarkable phenotypic alterations in the TME. Recently proposed the concept “immunogenic stress”, which means in some stressed microenvironment, cancer cells can release EVs containing specific immunoregulatory mediators, depending on the initiating stress-associated pathway, thereby provoking the changes of immune status in the TME. Considerable evidence has revealed that the intracellular mechanisms underlying the response to diverse stresses are mainly autophagy, endoplasmic reticulum (ER) stress reactions and the DNA damage response (DDR). In addition, the activation of immunogenic stress responses endows hosts with immune surveillance capacity; in contrast, several cargoes in EVs under immunogenic stress trigger a passive immune response by mediating the function of immune cells. This review discusses the current understanding of the immunogenic stress pathways in cancer and describes the interrelation between EVs and immunogenic stress to propose potential treatment strategies and biomarkers.

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Emerging Role of Extracellular Vesicles and Cellular Communication in Metastasis

Cells ◽

10.3390/cells10123429 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3429

Author(s):

Aisling Forder ◽

Chi-Yun Hsing ◽

Jessica Trejo Vazquez ◽

Cathie Garnis

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Stromal Cells ◽

Therapeutic Potential ◽

Treatment Strategies ◽

Metastatic Niche ◽

Novel Treatment ◽

Membrane Bound ◽

Novel Treatment Strategies

Communication between cancer cells and the surrounding stromal cells of the tumor microenvironment (TME) plays a key role in promoting metastasis, which is the major cause of cancer death. Small membrane-bound particles called extracellular vesicles (EVs) are released from both cancer and stromal cells and have a key role in mediating this communication through transport of cargo such as various RNA species (mRNA, miRNA, lncRNA), proteins, and lipids. Tumor-secreted EVs have been observed to induce a pro-tumorigenic phenotype in non-malignant cells of the stroma, including fibroblasts, endothelial cells, and local immune cells. These cancer-associated cells then drive metastasis by mechanisms such as increasing the invasiveness of cancer cells, facilitating angiogenesis, and promoting the formation of the pre-metastatic niche. This review will cover the role of EV-mediated signaling in the TME during metastasis and highlight the therapeutic potential of targeting these pathways to develop biomarkers and novel treatment strategies.

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Wharton’s Jelly Mesenchymal Stromal Cells and Derived Extracellular Vesicles as Post-Myocardial Infarction Therapeutic Toolkit: An Experienced View

Pharmaceutics ◽

10.3390/pharmaceutics13091336 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1336

Author(s):

Noelia Muñoz-Domínguez ◽

Santiago Roura ◽

Cristina Prat-Vidal ◽

Joaquim Vives

Keyword(s):

Myocardial Infarction ◽

Extracellular Vesicles ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Cell Communication ◽

Multipotent Mesenchymal Stromal Cells ◽

Wharton’S Jelly ◽

Therapeutic Approaches ◽

Wharton's Jelly ◽

Evidence Based Therapy

Outstanding progress has been achieved in developing therapeutic options for reasonably alleviating symptoms and prolonging the lifespan of patients suffering from myocardial infarction (MI). Current treatments, however, only partially address the functional recovery of post-infarcted myocardium, which is in fact the major goal for effective primary care. In this context, we largely investigated novel cell and TE tissue engineering therapeutic approaches for cardiac repair, particularly using multipotent mesenchymal stromal cells (MSC) and natural extracellular matrices, from pre-clinical studies to clinical application. A further step in this field is offered by MSC-derived extracellular vesicles (EV), which are naturally released nanosized lipid bilayer-delimited particles with a key role in cell-to-cell communication. Herein, in this review, we further describe and discuss the rationale, outcomes and challenges of our evidence-based therapy approaches using Wharton’s jelly MSC and derived EV in post-MI management.

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Senescent stromal cells promote cancer resistance through SIRT1 loss-potentiated overproduction of small extracellular vesicles

10.1101/2020.03.22.002667 ◽

2020 ◽

Author(s):

Liu Han ◽

Qilai Long ◽

Shenjun Li ◽

Qixia Xu ◽

Boyi Zhang ◽

...

Keyword(s):

Drug Resistance ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Stromal Cells ◽

Cancer Resistance ◽

Term Outcome ◽

Long Term Outcome ◽

Age Related ◽

Lysosomal Acidification

ABSTRACTCellular senescence is a potent tumor-suppressive program that prevents neoplastic events. Paradoxically, senescent cells develop an inflammatory secretome, termed the senescence-associated secretory phenotype (SASP) and implicated in age-related pathologies including cancer. Here we report that senescent cells actively synthesize and release small extracellular vesicles (sEVs) with a distinctive size distribution. Mechanistically, SIRT1 loss supports accelerated sEV production despite enhanced proteome-wide ubiquitination, a process correlated with ATP6V1A downregulation and defective lysosomal acidification. Once released, senescent stromal sEVs significantly alter the expression profile of recipient cancer cells and enhance their aggressiveness, specifically drug resistance mediated by expression of ATP binding cassette subfamily B member 4 (ABCB4). Targeting SIRT1 with an agonist SRT2104 prevents development of cancer resistance through restraining sEV production by senescent stromal cells. In clinical oncology, sEVs in peripheral blood of posttreatment cancer patients are readily detectable by routine biotechniques, presenting a novel biomarker to monitor therapeutic efficacy and to predict long term outcome. Together, our study identifies a distinct mechanism supporting pathological activities of senescent cells, and provides a novel avenue to circumvent advanced human malignancies by co-targeting cancer cells and their surrounding microenvironment, which contributes to drug resistance via secretion of sEVs from senescent stromal cells.

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Comparative Evaluation of Methods for Isolating Small Extracellular Vesicles Derived from Pancreatic Cells

10.21203/rs.3.rs-110539/v1 ◽

2020 ◽

Author(s):

Jie-Min Wang ◽

Yong-Jiang Li ◽

Jun-Yong Wu ◽

Jia-Xin Cai ◽

Jing Wen ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Density Gradient ◽

Extracellular Vesicles ◽

Cell Communication ◽

Size Exclusion ◽

Density Gradient Ultracentrifugation ◽

Pancreatic Cancer Cells ◽

Co Precipitation ◽

Therapeutic Study

Abstract Background: Small extracellular vesicles (sEVs) are nanosized vesicles involved in cell-to-cell communication. sEVs have been widely studied for clinical applications such as early detection of diseases and as therapeutics. Various methods for sEVs isolation have been using, but different methods may result in different qualities of sEVs and impact downstream analysis and applications. Here, we compared current isolation methods and performed a comparative analysis of sEVs derived from pancreatic cancer cells.Results: Ultracentrifugation, ultrafiltration and co-precipitation as concentration methods were firstly evaluated for yield, size, morphology and protein level of pellets. Then, isolate sEVs obtained by four different purification methods: size exclusion chromatography, density gradient ultracentrifugation, ultracentrifugation, and immunoaffinity capturing, were analysed and compared. For the concentration process, ultracentrifugation method obtained high quality and concentration pellets. For the purification process, immunoaffinity capturing method obtained the purest sEVs with less contaminants, while density gradient ultracentrifugation-based method obtained sEVs with the smallest size. Proteomic analysis revealed distinct protein contents of purified sEVs. Conclusions: For isolating sEVs derived from pancreatic cancer cells, ultracentrifugation-based method is recommended for concentration of sEVs, density gradient ultracentrifugation-based method may be suitable for isolation of sEVs for therapeutic study, immunoaffinity capturing may be applied for studies exploring sEVs as biomarkers.

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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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Concise review: The role of cancer-derived exosomes in tumorigenesis and immune cell modulation

Biomedical Research and Therapy ◽

10.15419/bmrat.v7i12.654 ◽

2020 ◽

Vol 7 (12) ◽

pp. 4158-4169

Author(s):

Nhi Thao Huynh ◽

Khuong Duy Pham ◽

Nhat Chau Truong

Keyword(s):

Cancer Cells ◽

Immune Cells ◽

Immune Cell ◽

Vascular System ◽

Immune Surveillance ◽

Cell Communication ◽

Tumor Formation ◽

Concise Review ◽

The Relationship

Exosomes are subcellular entities which were first discovered in the 1980s. Over the past decade, scientists have discovered that they carry components of genetic information that allow for cell-cell communication and cell targeting. Exosomes secreted by cancer cells are termed cancer-derived exosomes (CDEs), and play an important role in tumor formation and progression. Specifically, CDEs mediate the communication between cancer cells, as well as between cancer cells and other cells in the tumor microenvironment, including cancer-associated fibroblasts, endothelial cells, mesenchymal stem cells, and effector immune cells. Additionally, through the vascular system and body fluids, CDEs can modulate response to drugs, increase angiogenesis, stimulate proliferation, promote invasion and metastasis, and facilitate escape from immune surveillance. This review will discuss the relationship between cancer cells and other cells (particularly immune cells), as mediated through CDEs, as well as the subsequent impact on tumorigenesis and immunomodulation. Understanding the role of CDEs in tumorigenesis and immune cell modulation will help advance their utilization in the diagnosis, prognosis, and treatment of 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/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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A stroma szerepe a tumorok kialakulásában és progressziójában

Orvosi Hetilap ◽

10.1556/650.2015.30294 ◽

2015 ◽

Vol 156 (45) ◽

pp. 1816-1823 ◽

Cited By ~ 1

Author(s):

Marcell Baranyi ◽

Mónika Lippai ◽

Zsuzsanna Szatmári

Keyword(s):

Cancer Cells ◽

Chronic Inflammation ◽

Early Development ◽

Stromal Cells ◽

Malignant Disease ◽

Immune Surveillance ◽

Short Review ◽

Main Effects

In the last decade, growing attention was paid to the observation that tumors did not only consist of cancer cells, they are rather a complex tissue-like mixture of tumor and stromal cells, which are playing an important role in the course of the malignant disease. Their contribution is so essential that without them, tumors are not even able to grow. This short review summarizes how stromal cells can help the cancerous transformation and early development of tumors, how chronic inflammation contributes to the progression of cancer and how stroma takes part in the induction of angiogenesis. The main mechanisms by which tumors can escape the immune surveillance will be demonstrated as well as the complex contributions of stroma to the invasion, intravasation and metastasis of cancer cells. Finally, possible and promising therapies will be presented that aim at the stroma and its main effects on the progression of tumors. Orv. Hetil., 2015, 156(45), 1816–1823.

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Multiple Facets of Plant-Microbiome Associations in Unlocking the Communication Paradigm through Extracellular Vesicles. s

Current Protein and Peptide Science ◽

10.2174/1389203722666211109101140 ◽

2021 ◽

Vol 22 ◽

Author(s):

Kanika Khanna ◽

Sukhmeen Kaur Kohli ◽

Vinod Kumar ◽

Jaspreet Kour ◽

Arun Dev Singh ◽

...

Keyword(s):

Extracellular Vesicles ◽

Stress Responses ◽

Protein Trafficking ◽

Immune Surveillance ◽

Long Distance ◽

Communication Paradigm ◽

Distance Communication ◽

Metabolic Activities ◽

A Chain ◽

Plant Microbiome

: Communication among different species across kingdoms occurs through a chain of regulatory molecules that are transferred around cellular boundaries. These molecules are also crucial for defense, virulence and pathogenesis. In the past, the transport of proteins in long distance communication was observed, but in the present era, the discovery of extracellular vesicles (EVs) has changed our understanding of molecular communication. EVs are not only involved in cell signaling and immunity, but also can transfer information by sRNAs, forming a basis for interactions among a wide variety of organisms. Despite extensive research on EVs in other areas, their role in communication between plants and the plant microbiome has been lacking. EVs are potentially involved in protein trafficking along with transport of lipids and nucleic acids. Interactions between hosts and their microbiomes may also be mediated by EVs, which can be involved in stress responses, immune surveillance and defense, virulence and signaling along with many metabolic activities within plant microbiomes. In this review, we have focused on recent information about the role of EVs and the molecules they transport between hosts and microbes. The connection between biofilms and the generation of EVs is also considered. These findings enhance our knowledge about plant-microbiome interactions in terms of immunity and virulence and challenge the conventional viewpoint of inter-kingdom signaling.

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Extracellular vesicle-mediated cell–cell communication in haematological neoplasms

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0484 ◽

2017 ◽

Vol 373 (1737) ◽

pp. 20160484 ◽

Cited By ~ 13

Author(s):

Junko H. Ohyashiki ◽

Tomohiro Umezu ◽

Kazuma Ohyashiki

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Extracellular Vesicles ◽

Stromal Cells ◽

Cell Communication ◽

Tumour Microenvironment ◽

Extracellular Vesicle ◽

Emerging Issues ◽

Haematological Neoplasms ◽

Cell Cell

Crosstalk between bone marrow tumour cells and surrounding cells, including bone marrow mesenchymal stromal cells (BM-MSCs), endothelial cells and immune cells, is important for tumour growth in haematological neoplasms. In addition to conventional signalling pathways, extracellular vesicles (EVs), which are endosome-derived vesicles containing proteins, mRNAs, lipids and miRNAs, can facilitate modulation of the bone marrow microenvironment without directly contacting non-tumourous cells. In this review, we discuss the current understanding of EV-mediated cell–cell communication in haematological neoplasms, particularly leukaemia and multiple myeloma. We highlight the actions of tumour and BM-MSC EVs in multiple myeloma. The origin of EVs, their tropism and mechanism of EV transfer are emerging issues that need to be addressed in EV-mediated cell–cell communication in haematological neoplasms. This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’.

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