scholarly journals Extracellular Vesicles and Cancer: A Focus on Metabolism, Cytokines, and Immunity

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 171 ◽  
Author(s):  
Donatella Lucchetti ◽  
Claudio Ricciardi Tenore ◽  
Filomena Colella ◽  
Alessandro Sgambato
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cell Fate ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Cell Communication ◽  
Metabolic Effects ◽  
Metabolic Phenotype ◽  
Metabolic Switch

A better understanding of the mechanisms of cell communication between cancer cells and the tumor microenvironment is crucial to develop personalized therapies. It has been known for a while that cancer cells are metabolically distinct from other non-transformed cells. This metabolic phenotype is not peculiar to cancer cells but reflects the characteristics of the tumor microenvironment. Recently, it has been shown that extracellular vesicles are involved in the metabolic switch occurring in cancer and tumor-stroma cells. Moreover, in an immune system, the metabolic programs of different cell subsets are distinctly associated with their immunological function, and extracellular vesicles could be a key factor in the shift of cell fate modulating cancer immunity. Indeed, during tumor progression, tumor-associated immune cells and fibroblasts acquire a tumor-supportive and anti-inflammatory phenotype due to their interaction with tumor cells and several findings suggest a role of extracellular vesicles in this phenomenon. This review aims to collect all the available evidence so far obtained on the role of extracellular vesicles in the modulation of cell metabolism and immunity. Moreover, we discuss the possibility for extracellular vesicles of being involved in drug resistance mechanisms, cancer progression and metastasis by inducing immune-metabolic effects on surrounding cells.

Extracellular vesicles in cancer progression: are they part of the problem or part of the solution?

Nanomedicine ◽  
2020 ◽  
Vol 15 (26) ◽  
pp. 2625-2641
Author(s):  
Juliete Nathali Scholl ◽  
Camila Kehl Dias ◽  
Laurent Muller ◽  
Ana Maria Oliveira Battastini ◽  
Fabrício Figueiró
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Immune Cells ◽  
Cell Function ◽  
Cytokine Release

Extracellular vesicles (EVs) are released especially by cancer cells. They modulate the tumor microenvironment by interacting with immune cells while carrying immunosuppressive or immunostimulatory molecules. In this review, we will explore some conflicting reports regarding the immunological outcomes of EVs in cancer progression, in which they might initiate an antitumor immune response or an immunosuppressive response. Concerning immunosuppression, the role of tumor-derived EVs’ in the adenosinergic system is underexplored. The enhancement of adenosine (ADO) levels in the tumor microenvironment impairs T-cell function and cytokine release. However, some tumor-derived EVs may deliver immunostimulatory factors, promoting immunogenic activity, even with ADO production. The modulatory role of ADO over the tumor progression represents a piece in an intricate microenvironment with anti and pro tumoral seesaw-like mechanisms.

The Role of Cytokines in Interactions of Mesenchymal Stem Cells and Breast Cancer Cells

2020 ◽  
Vol 15 ◽  
Author(s):  
Hariharan Jayaraman ◽  
Nalinkanth V. Ghone ◽  
Ranjith Kumaran R ◽  
Himanshu Dashora
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cell Communication ◽  
Extra Cellular Matrix ◽  
Cytokine Signaling ◽  
Cellular Matrix

: Mesenchymal stem cells because of its high proliferation, differentiation, regenerative capacity, and ease of availability have been a popular choice in cytotherapy. Mesenchymal Stem Cells (MSCs) have a natural tendency to home in a tumor microenvironment and acts against it, owing to the similarity of the latter to an injured tissue environment. Several studies have confirmed the recruitment of MSCs by tumor through various cytokine signaling that brings about phenotypic changes to cancer cells, thereby promoting migration, invasion, and adhesion of cancer cells. The contrasting results on MSCs as a tool for cancer cytotherapy may be due to the complex cell to cell interaction in the tumor microenvironment, which involves various cell types such as cancer cells, immune cells, endothelial cells, and cancer stem cells. Cell to cell communication can be simple or complex and it is transmitted through various cytokines among multiple cell phenotypes, mechano-elasticity of the extra-cellular matrix surrounding the cancer cells, and hypoxic environments. In this article, the role of the extra-cellular matrix proteins and soluble mediators that acts as communicators between mesenchymal stem cells and cancer cells has been reviewed specifically for breast cancer, as it is the leading member of cancer malignancies. The comprehensive information may be beneficial in finding a new combinatorial cytotherapeutic strategy using MSCs by exploiting the cross-talk between mesenchymal stem cells and cancer cells for treating breast cancer.

scholarly journals Nerves in the Tumor Microenvironment: Origin and Effects

2020 ◽  
Vol 8 ◽  
Author(s):  
Wenjun Wang ◽  
Lingyu Li ◽  
Naifei Chen ◽  
Chao Niu ◽  
Zhi Li ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Perineural Invasion ◽  
Vital Role ◽  
Cancer Growth ◽  
Alternative Route ◽  
Sympathetic Nervous ◽  
Molecular Bases

Studies have reported the vital role of nerves in tumorigenesis and cancer progression. Nerves infiltrate the tumor microenvironment thereby enhancing cancer growth and metastasis. Perineural invasion, a process by which cancer cells invade the surrounding nerves, provides an alternative route for metastasis and generation of tumor-related pain. Moreover, central and sympathetic nervous system dysfunctions and psychological stress-induced hormone network disorders may influence the malignant progression of cancer through multiple mechanisms. This reciprocal interaction between nerves and cancer cells provides novel insights into the cellular and molecular bases of tumorigenesis. In addition, they point to the potential utility of anti-neurogenic therapies. This review describes the evolving cross-talk between nerves and cancer cells, thus uncovers potential therapeutic targets for cancer.

scholarly journals Cancer associated-fibroblast-derived exosomes in cancer progression

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Chao Li ◽  
Adilson Fonseca Teixeira ◽  
Hong-Jian Zhu ◽  
Peter ten Dijke
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Chemotherapy Resistance ◽  
Cell Types ◽  
Cancer Therapies ◽  
Cancer Associated Fibroblast

AbstractTo identify novel cancer therapies, the tumor microenvironment (TME) has received a lot of attention in recent years in particular with the advent of clinical successes achieved by targeting immune checkpoint inhibitors (ICIs). The TME consists of multiple cell types that are embedded in the extracellular matrix (ECM), including immune cells, endothelial cells and cancer associated fibroblasts (CAFs), which communicate with cancer cells and each other during tumor progression. CAFs are a dominant and heterogeneous cell type within the TME with a pivotal role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis and chemotherapy resistance. CAFs mediate their effects in part by remodeling the ECM and by secreting soluble factors and extracellular vesicles. Exosomes are a subtype of extracellular vesicles (EVs), which contain various biomolecules such as nucleic acids, lipids, and proteins. The biomolecules in exosomes can be transmitted from one to another cell, and thereby affect the behavior of the receiving cell. As exosomes are also present in circulation, their contents can also be explored as biomarkers for the diagnosis and prognosis of cancer patients. In this review, we concentrate on the role of CAFs-derived exosomes in the communication between CAFs and cancer cells and other cells of the TME. First, we introduce the multiple roles of CAFs in tumorigenesis. Thereafter, we discuss the ways CAFs communicate with cancer cells and interplay with other cells of the TME, and focus in particular on the role of exosomes. Then, we elaborate on the mechanisms by which CAFs-derived exosomes contribute to cancer progression, as well as and the clinical impact of exosomes. We conclude by discussing aspects of exosomes that deserve further investigation, including emerging insights into making treatment with immune checkpoint inhibitor blockade more efficient.

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

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.

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

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.

Emerging role of extracellular vesicles in mediating cancer cachexia

2018 ◽  
Vol 46 (5) ◽  
pp. 1129-1136 ◽  
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.

scholarly journals Involvement of Extracellular Vesicles in Vascular-Related Functions in Cancer Progression and Metastasis

2019 ◽  
Vol 20 (10) ◽  
pp. 2584 ◽  
Author(s):  
Shinsuke Kikuchi ◽  
Yusuke Yoshioka ◽  
Marta Prieto-Vila ◽  
Takahiro Ochiya
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Current Knowledge ◽  
Cell Communication ◽  
Matrix Remodeling ◽  
Mesenchymal Transition ◽  
Patients With Cancer ◽  
Tumor Environment ◽  
Endothelial To Mesenchymal Transition

The primary cause of mortality among patients with cancer is the progression of the tumor, better known as cancer invasion and metastasis. Cancer progression involves a series of biologically important steps in which the cross-talk between cancer cells and the cells in the surrounding environment is positioned as an important issue. Notably, angiogenesis is a key tumorigenic phenomenon for cancer progression. Cancer-related extracellular vesicles (EVs) commonly contribute to the modulation of a microenvironment favorable to cancer cells through their function of cell-to-cell communication. Vascular-related cells such as endothelial cells (ECs) and platelets activated by cancer cells and cancer-derived EVs develop procoagulant and proinflammatory statuses, which help excite the tumor environment, and play major roles in tumor progression, including in tumor extravasation, tumor cell microthrombi formation, platelet aggregation, and metastasis. In particular, cancer-derived EVs influence ECs, which then play multiple roles such as contributing to tumor angiogenesis, loss of endothelial vascular barrier by binding to ECs, and the subsequent endothelial-to-mesenchymal transition, i.e., extracellular matrix remodeling. Thus, cell-to-cell communication between cancer cells and ECs via EVs may be an important target for controlling cancer progression. This review describes the current knowledge regarding the involvement of EVs, especially exosomes derived from cancer cells, in EC-related cancer progression.

scholarly journals Extracellular Vesicles from Human Advanced-Stage Prostate Cancer Cells Modify the Inflammatory Response of Microenvironment-Residing Cells

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1276 ◽  
Author(s):  
Letizia Mezzasoma ◽  
Egidia Costanzi ◽  
Paolo Scarpelli ◽  
Vincenzo Nicola Talesa ◽  
Ilaria Bellezza
Keyword(s):  
Prostate Cancer ◽  
Inflammatory Response ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cell Communication ◽  
Advanced Stage ◽  
Prostate Cell ◽  
Caspase 1 ◽  
Pc3 Cells

Prostate cancer (PCa) progression is strictly associated with microenvironmental conditions, which can be modified by cancer-released extracellular vesicles (EVs), important mediators of cell-cell communication. However, the role of EVs in the inflammatory cross-talk between cancer cells and microenvironment-residing cells remains largely unknown. To evaluate the role of EVs in the tumour microenvironment, we treated the non-cancerous prostate cell line PNT2 with EVs isolated from advanced-stage prostate cancer PC3 (PC3-EVs). Caspase-1-mediated IL-1β maturation was evaluated after 24 h incubation with EVs. Moreover, the effect of PC3-EVs on differentiated macrophagic THP-1 cells was assessed by analyzing cytokine expression and PC3 cells migration and proliferation profiles. We illustrated that PC3 cells contain active NLRP3-inflammasome cascade and secrete IL-1β. PC3-EVs affect the PNT2 inflammatory response, inducing caspase-1-mediated IL-1β maturation via ERK1/2-mediated lysosomal destabilization and cathepsin B activation. We also verified that PC3-EVs induce a functional TAM-like polarization in differentiated THP-1 cells. Our results demonstrated that cancer-derived EVs induce an inflammatory response in non-cancerous prostate cells, while inducing an immunomodulatory phenotype in immune cells. These apparently contradictory effects are both committed to strengthening the tumour-promoting microenvironment

scholarly journals Inhibition of αvβ3 integrin impairs adhesion and uptake of tumor-derived small extracellular vesicles

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Wanessa F. Altei ◽  
Bianca C. Pachane ◽  
Patty K. dos Santos ◽  
Lígia N. M. 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. Graphical abstract

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