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

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.

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Extracellular Vesicles Are Key Regulators of Tumor Neovasculature

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.611039 ◽

2020 ◽

Vol 8 ◽

Author(s):

Naoya Kuriyama ◽

Yusuke Yoshioka ◽

Shinsuke Kikuchi ◽

Nobuyoshi Azuma ◽

Takahiro Ochiya

Keyword(s):

Extracellular Vesicles ◽

Cancer Progression ◽

Tumor Angiogenesis ◽

Current Knowledge ◽

Cell Communication ◽

Multiple Roles ◽

Mesenchymal Transition ◽

Surrounding Environment ◽

Endothelial To Mesenchymal Transition ◽

Review Current

Tumor progression involves a series of biologically important steps in which the crosstalk between cancer cells and the surrounding environment is an important issue. Angiogenesis is a key tumorigenic phenomenon for cancer progression. Tumor-related extracellular vesicles (EVs) modulate the tumor microenvironment (TME) through cell-to-cell communication. Tumor cells in a hypoxic TME release more EVs than cells in a normoxic environment due to uncontrollable tumor proliferation. Tumor-derived EVs in the TME influence endothelial cells (ECs), which then play multiple roles, contributing to tumor angiogenesis, loss of the endothelial vascular barrier by binding to ECs, and subsequent endothelial-to-mesenchymal transition. In contrast, they also indirectly induce tumor angiogenesis through the phenotype switching of various cells into cancer-associated fibroblasts, the activation of tumor-associated ECs and platelets, and remodeling of the extracellular matrix. Here, we review current knowledge regarding the involvement of EVs in tumor vascular-related cancer progression.

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Snail Overexpression Alters the microRNA Content of Extracellular Vesicles Released from HT29 Colorectal Cancer Cells and Activates Pro-Inflammatory State In Vivo

Cancers ◽

10.3390/cancers13020172 ◽

2021 ◽

Vol 13 (2) ◽

pp. 172

Author(s):

Izabela Papiewska-Pająk ◽

Patrycja Przygodzka ◽

Damian Krzyżanowski ◽

Kamila Soboska ◽

Izabela Szulc-Kiełbik ◽

...

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Colorectal Cancer Cells ◽

Microrna Profile ◽

Inflammatory State ◽

Metastatic Process

During metastasis, cancer cells undergo phenotype changes in the epithelial-mesenchymal transition (EMT) process. Extracellular vesicles (EVs) released by cancer cells are the mediators of intercellular communication and play a role in metastatic process. Knowledge of factors that influence the modifications of the pre-metastatic niche for the migrating carcinoma cells is important for prevention of metastasis. We focus here on how cancer progression is affected by EVs released from either epithelial-like HT29-cells or from cells that are in early EMT stage triggered by Snail transcription factor (HT29-Snail). We found that EVs released from HT29-Snail, as compared to HT29-pcDNA cells, have a different microRNA profile. We observed the presence of interstitial pneumonias in the lungs of mice injected with HT29-Snail cells and the percent of mice with lung inflammation was higher after injection of HT29-Snail-EVs. Incorporation of EVs released from HT29-pcDNA, but not released from HT29-Snail, leads to the increased secretion of IL-8 from macrophages. We conclude that Snail modifications of CRC cells towards more invasive phenotype also alter the microRNA cargo of released EVs. The content of cell-released EVs may serve as a biomarker that denotes the stage of CRC and EVs-specific microRNAs may be a target to prevent cancer progression.

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Characterizing Intercellular Communication of Pan-Cancer Reveals SPP1+ Tumor-Associated Macrophage Expanded in Hypoxia and Promoting Cancer Malignancy Through Single-Cell RNA-Seq Data

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.749210 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jinfen Wei ◽

Zixi Chen ◽

Meiling Hu ◽

Ziqing He ◽

Dawei Jiang ◽

...

Keyword(s):

Single Cell ◽

Cancer Cells ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Single Cells ◽

Matrix Remodeling ◽

Rna Seq ◽

Mesenchymal Transition ◽

Tumor Associated Macrophage ◽

Cancer Types

Hypoxia is a characteristic of tumor microenvironment (TME) and is a major contributor to tumor progression. Yet, subtype identification of tumor-associated non-malignant cells at single-cell resolution and how they influence cancer progression under hypoxia TME remain largely unexplored. Here, we used RNA-seq data of 424,194 single cells from 108 patients to identify the subtypes of cancer cells, stromal cells, and immune cells; to evaluate their hypoxia score; and also to uncover potential interaction signals between these cells in vivo across six cancer types. We identified SPP1+ tumor-associated macrophage (TAM) subpopulation potentially enhanced epithelial–mesenchymal transition (EMT) by interaction with cancer cells through paracrine pattern. We prioritized SPP1 as a TAM-secreted factor to act on cancer cells and found a significant enhanced migration phenotype and invasion ability in A549 lung cancer cells induced by recombinant protein SPP1. Besides, prognostic analysis indicated that a higher expression of SPP1 was found to be related to worse clinical outcome in six cancer types. SPP1 expression was higher in hypoxia-high macrophages based on single-cell data, which was further validated by an in vitro experiment that SPP1 was upregulated in macrophages under hypoxia-cultured compared with normoxic conditions. Additionally, a differential analysis demonstrated that hypoxia potentially influences extracellular matrix remodeling, glycolysis, and interleukin-10 signal activation in various cancer types. Our work illuminates the clearer underlying mechanism in the intricate interaction between different cell subtypes within hypoxia TME and proposes the guidelines for the development of therapeutic targets specifically for patients with high proportion of SPP1+ TAMs in hypoxic lesions.

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Extracellular vesicles: their role in cancer biology and epithelial–mesenchymal transition

Biochemical Journal ◽

10.1042/bcj20160006 ◽

2016 ◽

Vol 474 (1) ◽

pp. 21-45 ◽

Cited By ~ 46

Author(s):

Shashi K. Gopal ◽

David W. Greening ◽

Alin Rai ◽

Maoshan Chen ◽

Rong Xu ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cancer Biology ◽

Epithelial Mesenchymal Transition ◽

Current Knowledge ◽

Cell Communication ◽

Metastatic Potential ◽

Messenger Rnas ◽

Mesenchymal Transition ◽

Non Coding Rna ◽

Long Non Coding Rna

Cell–cell communication is critical across an assortment of physiological and pathological processes. Extracellular vesicles (EVs) represent an integral facet of intercellular communication largely through the transfer of functional cargo such as proteins, messenger RNAs (mRNAs), microRNA (miRNAs), DNAs and lipids. EVs, especially exosomes and shed microvesicles, represent an important delivery medium in the tumour micro-environment through the reciprocal dissemination of signals between cancer and resident stromal cells to facilitate tumorigenesis and metastasis. An important step of the metastatic cascade is the reprogramming of cancer cells from an epithelial to mesenchymal phenotype (epithelial–mesenchymal transition, EMT), which is associated with increased aggressiveness, invasiveness and metastatic potential. There is now increasing evidence demonstrating that EVs released by cells undergoing EMT are reprogrammed (protein and RNA content) during this process. This review summarises current knowledge of EV-mediated functional transfer of proteins and RNA species (mRNA, miRNA, long non-coding RNA) between cells in cancer biology and the EMT process. An in-depth understanding of EVs associated with EMT, with emphasis on molecular composition (proteins and RNA species), will provide fundamental insights into cancer biology.

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Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Into Extracellular Vesicles

10.21203/rs.3.rs-42528/v1 ◽

2020 ◽

Author(s):

Shun Wilford Tse ◽

Chee Fan Tan ◽

Jung Eun Park ◽

JebaMercy Gnanasekaran ◽

Nikhil Gupta ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Membrane Trafficking ◽

Tumour Cell ◽

Host Immunity ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Functional Clustering

Abstract Background: Extracellular vesicles (EVs) mediate critical intercellular communication within healthy tissues, but are also exploited by tumour cells to promote angiogenesis, metastasis, and host immunosuppression under hypoxic stress. We hypothesize that oxygen starvation in developing tumours induces specific hypoxia-sensitive proteins for packing into small EVs to modulate its microenvironment for cancer progression and enhance malignancy. Methods: We employed a heavy isotope pulse/trace quantitative proteomic approach to study hypoxia-sensitive EVs proteins (HSEPs) in hypoxic A549 lung adenocarcinoma cells derived small EVs (<200 nm). Proteomics data mining and pathway analysis were used to reveal potential roles of the HSEPs in enhancing tumour cell progression and in modulating host immunity. Functional clustering was applied to study enhanced EVs biogenesis and secretion in hypoxic cancer cells. Subsequent biochemical functional assays were performed in A549 and H1299 lung cancer cells to validate the hypoxic cancer-derived EVs in promoting cancer progression.Results: Results revealed that hypoxia stimulated cancer cells to synthesize EVs proteins involved in enhancing tumour cell proliferation (NRSN2, WISP2, SPRX1, LCK), metastasis (GOLM1, STC1, MGAT5B), stemness (STC1, TMEM59), angiogenesis (ANGPTL4), and suppressing host immunity (CD70). In addition, functional clustering analyses revealed that tumour hypoxia was strongly associated with rapid synthesis and EV loading of lysosome-related hydrolases and membrane-trafficking proteins to enhance EVs secretion. Moreover, lung cancer-derived EVs were also enriched in signalling molecules capable of inducing epithelial-mesenchymal transition in recipient cancer cells to promote their migration and invasion. Conclusion: Together, these data indicate that lung cancer-derived EVs can act as paracrine/autocrine mediators of tumorigenesis and metastasis in hypoxic microenvironments. Tumour EVs may therefore offer novel opportunities for useful biomarkers discovery and therapeutic targeting of different cancer types and at different stages according to microenvironmental conditions.

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Glypican-1 Level Is Elevated in Extracellular Vesicles Released from MC38 Colon Adenocarcinoma Cells Overexpressing Snail

Cells ◽

10.3390/cells9071585 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1585

Author(s):

Izabela Papiewska-Pająk ◽

Damian Krzyżanowski ◽

Maria Katela ◽

Romain Rivet ◽

Sylwia Michlewska ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Protein Level ◽

Colon Adenocarcinoma ◽

Mesenchymal Transition ◽

Adenocarcinoma Cells ◽

Colon Adenocarcinoma Cells

The transcription factor Snail triggers epithelial-to-mesenchymal transition (EMT), endowing cancer cells with invasive properties during tumor progression. Extracellular vesicles (EVs) released from cancer cells at various stages of cancer progression are known to influence the tumor pre-metastatic niche and metastatic potential. The aim of this study was to analyze the effect of Snail on murine colon adenocarcinoma cells (MC38 line) and on the characteristics of their EVs. Stable clones of Snail-overexpressing MC38 cells were investigated in vitro versus Mock cells. Increased expression of matrix metalloproteinase MMP-14 and augmented activity of MMP-9 and -14 were observed in Snail-MC38 cells. There was no change in the transcriptomic profile of proteoglycans in Snail-MC38 cells; however, the protein level of Glypican-1 (GPC1) was enhanced in EVs released from those cells. Our finding that GPC1 protein level was enhanced in EVs released from MC38 cells that overexpressed Snail and were in an early EMT stage might explain the specificity of the GPC1 biomarker in colon cancer diagnosis. Further, our data suggest that Snail, by changing the level of GPC1 on EVs released by colon cancer cells, may affect the generation of a distant premetastatic niche and metastatic organotropism in colon adenocarcinoma.

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

Cancers ◽

10.3390/cancers12010171 ◽

2020 ◽

Vol 12 (1) ◽

pp. 171 ◽

Cited By ~ 8

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.

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Extracellular Vesicles Containing MicroRNA-92a-3p Facilitate Partial Endothelial-Mesenchymal Transition and Angiogenesis in Endothelial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20184406 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4406 ◽

Cited By ~ 8

Author(s):

Nami O. Yamada ◽

Kazuki Heishima ◽

Yukihiro Akao ◽

Takao Senda

Keyword(s):

Gene Expression ◽

Endothelial Cells ◽

Extracellular Vesicles ◽

Epithelial To Mesenchymal Transition ◽

Ectopic Expression ◽

Cell Communication ◽

Related Gene ◽

Mesenchymal Transition ◽

Essential Components ◽

Endothelial To Mesenchymal Transition

Extracellular vesicles (EVs) are nanometer-sized membranous vesicles used for primitive cell-to-cell communication. We previously reported that colon cancer-derived EVs contain abundant miR-92a-3p and have a pro-angiogenic function. We previously identified Dickkopf-3 (Dkk-3) as a direct target of miR-92a-3p; however, the pro-angiogenic function of miR-92a-3p cannot only be attributed to downregulation of Dkk-3. Therefore, the complete molecular mechanism by which miR-92a-3p exerts pro-angiogenic effects is still unclear. Here, we comprehensively analyzed the gene sets affected by ectopic expression of miR-92a-3p in endothelial cells to elucidate processes underlying EV-induced angiogenesis. We found that the ectopic expression of miR-92a-3p upregulated cell cycle- and mitosis-related gene expression and downregulated adhesion-related gene expression in endothelial cells. We also identified a novel target gene of miR-92a-3p, claudin-11. Claudin-11 belongs to the claudin gene family, which encodes essential components expressed at tight junctions (TJs). Disruption of TJs with a concomitant loss of claudin expression is a significant event in the process of epithelial-to-mesenchymal transition. Our findings have unveiled a new EV-mediated mechanism for tumor angiogenesis through the induction of partial endothelial-to-mesenchymal transition in endothelial cells.

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A Comprehensive Picture of Extracellular Vesicles and Their Contents. Molecular Transfer to Cancer Cells

Cancers ◽

10.3390/cancers12020298 ◽

2020 ◽

Vol 12 (2) ◽

pp. 298 ◽

Cited By ~ 15

Author(s):

Ancuta Jurj ◽

Oana Zanoaga ◽

Cornelia Braicu ◽

Vladimir Lazar ◽

Ciprian Tomuleasa ◽

...

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Tumor Development ◽

Cell Communication ◽

Cancer Diagnostics ◽

Target Cells ◽

Chemotherapeutic Response ◽

Non Coding Rna ◽

Comprehensive Picture

Critical processes such as growth, invasion, and metastasis of cancer cells are sustained via bidirectional cell-to-cell communication in tissue complex environments. Such communication involves the secretion of soluble factors by stromal cells and/or cancer cells within the tumor microenvironment (TME). Both stromal and cancer cells have been shown to export bilayer nanoparticles: encapsulated regulatory molecules that contribute to cell-to-cell communication. These nanoparticles are known as extracellular vesicles (EVs) being classified into exosomes, microvesicles, and apoptotic bodies. EVs carry a vast repertoire of molecules such as oncoproteins and oncopeptides, DNA fragments from parental to target cells, RNA species (mRNAs, microRNAs, and long non-coding RNA), and lipids, initiating phenotypic changes in TME. According to their specific cargo, EVs have crucial roles in several early and late processes associated with tumor development and metastasis. Emerging evidence suggests that EVs are being investigated for their implication in early cancer detection, monitoring cancer progression and chemotherapeutic response, and more relevant, the development of novel targeted therapeutics. In this study, we provide a comprehensive understanding of the biophysical properties and physiological functions of EVs, their implications in TME, and highlight the applicability of EVs for the development of cancer diagnostics and therapeutics.

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Eribulin and Paclitaxel Differentially Alter Extracellular Vesicles and Their Cargo from Triple-Negative Breast Cancer Cells

Cancers ◽

10.3390/cancers13112783 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2783

Author(s):

Petra J. Pederson ◽

Huiyun Liang ◽

Daria Filonov ◽

Susan L. Mooberry

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Anticancer Efficacy ◽

Mesenchymal Transition ◽

Microtubule Targeting Agents

Extracellular vesicles play a central role in intercellular communication and contribute to cancer progression, including the epithelial-to-mesenchymal transition (EMT). Microtubule targeting agents (MTAs) including eribulin and paclitaxel continue to provide significant value in cancer therapy and their abilities to inhibit oncogenic signaling pathways, including eribulin’s capacity to reverse EMT are being revealed. Because microtubules are involved in the intracellular trafficking required for the formation and cargo loading of small extracellular vesicles (sEVs), we investigated whether MTA-mediated disruption of microtubule-dependent transport would impact sEV release and their cargo. Eribulin and paclitaxel caused an intracellular accumulation of CD63, a tetraspanin component of sEVs, in late/multivesicular endosomes of triple-negative breast cancer cells, consistent with the disruption of endosomal sorting and exosome cargo loading in these cells. While the concentrations of sEVs released from MTA-treated cells were not significantly altered, levels of CD63 and the CD63-associated cargos, ILK and β-integrin, were reduced in sEVs isolated from eribulin-treated HCC1937 cells as compared to vehicle or paclitaxel-treated cells. These results show that eribulin can reduce specific sEV cargos, including ILK, a major transducer of EMT in the tumor microenvironment, which may contribute to eribulin’s ability to reverse EMT to promote anticancer efficacy.

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