Open access peer-reviewed chapter - ONLINE FIRST

The Role of Extracellular Vesicles in the Progression of Tumors towards Metastasis

By Bhaskar Basu and Subhajit Karmakar

Submitted: October 25th 2021Reviewed: November 15th 2021Published: December 29th 2021

DOI: 10.5772/intechopen.101635

Downloaded: 108

Abstract

Extracellular vesicles (EVs) are cell-derived lipid membrane bound vesicles that serve as mediators of intercellular communication. EVs have been found to regulate a wide range of cellular processes through the transference of genetic, protein and lipid messages from the host cell to the recipient cell. Unsurprisingly, this major mode of intracellular communication would be abrogated in cancer. Ever increasing evidence points towards a key role of EVs in promoting tumor development and in contributing to the various stages of metastasis. Tumor released EVs have been shown to facilitate the transference of oncogenic proteins and nucleic acids to other tumor cells and to the surrounding stromal cells, thereby setting up a tumor permissive microenvironment. EVs released from tumor cells have been shown to promote extracellular matrix (ECM) remodeling through the modulation of neighboring tumor cells and stromal cells. EVs released from disseminated tumor cells have been reported to attract circulating tumor cells (CTCs) via chemotaxis and induce the production of specific extracellular matrix components from neighboring stromal cells so as to support the growth of metastatic cells at the secondary tumor site. Circulating levels of tumor derived EVs of patients have been correlated with incidence of metastasis and disease relapse.

Keywords

  • Extracellular vesicles (EVs)
  • exosomes
  • microvesicles
  • PMN
  • cancer
  • metastasis

1. Introduction

Extracellular vesicles (EVs) are essentially naturally occurring, lipid membrane-bound nanoparticles that are secreted by a diverse host of cells ranging from unicellular organisms to higher multicellular organisms [1, 2, 3, 4]. The contents of EVs consist of cellular proteins, nucleic acids and even lipids. EVs have been demonstrated to serve as a major mode of inter-cellular communication by mediating the transfer of active nucleic acid, protein and lipid-based messages from the host cell to the recipient cell [3, 5]. EVs are naturally secreted by cells as a physiological response to various stimuli such as cellular damage, host-pathogen interaction, inception of disease states or even changes in ambient conditions – pH, oxygen and nutrient availability [6, 7, 8].

1.1 A brief history on extracellular vesicles

The concept of EVs can be traced as far as Charles Darwin, who had proposed (as a part of his theory of pangenesis) the production of ‘gemmules’ by all cell types of an organism. Though they were not specified to be lipid-bound vesicles, Darwin did propose that these ‘gemmules’ contained biological molecules and transferred them from one cell type to the other [9, 10]. The first real world observation of EVs is widely believed to have taken place in 1946 in a study carried out by Chargaff and West wherein they reported the presence of platelet derived particles with procoagulant properties in the plasma [11]. These particles later on came to be known as “platelet dust” [12].

Later on, during the 1970–1980s the presence of membranous vesicles in different biological fluids were reported in several independent studies [13, 14, 15]. The generation of EVs from multi-vesicular endosomes/bodies (MVEs/MVBs) fusing with the plasma membrane was first reported in 1983 and was further elaborated in subsequent studies [16, 17]. In 1996, it was demonstrated that EVs, which were then termed as exosomes, isolated from Epstein-Barr virus infected B lymphocytes were antigen presenting in nature and could activate T lymphocyte response [18]. The role of EVs as mediators of intercellular communication gained significant interest following the discovery that EVs contained RNA species, including miRNA, and so offered a novel means of horizontal genetic exchange in higher eukaryotes [19, 20]. Based on these pioneering works, several studies carried out in the past few decades have served to further highlight the importance of EVs in intercellular communication and their association with different physiological states of the body.

1.2 Classification of extracellular vesicles

EVs can be classified on the basis of different criteria such as size, nature of contents, cellular origin, and mechanism or route employed in their biogenesis. The 3 major types of EVs include exosomes, microvesicles (MVs) and apoptotic bodies.

Exosomes – These are the smallest type of EVs, with size ranging between 30 and 150 nm in diameter. These EVs originate within endosomes as inward buddings of the endosomal limiting membrane which are subsequently shed off. These vesicles are termed as intraluminal vesicles (ILVs) and the endosomes harboring these vesicles represent the MVEs [4, 16, 17, 21]. These MVEs can suffer one of two fates. Firstly, they may be targeted to lysosomes wherein they are degraded along with their contents. Secondly, these MVEs may be targeted towards the cell membrane, and upon fusion with the membrane, release their ILV cargo in to the extracellular space which from thereon are termed as exosomes. During the process of ILV formation, exosome-specific proteins and other biomolecules are sorted into them by means of a large, multiprotein complex termed the endosomal sorting complex required for transport (ESCRT) [22, 23]. However, ESCRT-independent modes of ILV formation have also been reported and these involve the function of various proteins such as the GTP-binding protein ARF6 which modulates cytoskeletal remodeling [24, 25, 26]. The composition of exosomes has been shown to vary with the type of cell they originate from. In general, they have been shown to harbor structural proteins (e.g., actin and tubulin), metabolic enzymes (e.g., peroxidases, pyruvate kinase, and lipid kinases), signal transducers (e.g., protein kinases and G proteins), heat shock proteins (e.g.: HSP70 and HSP90), proteins involved in MVB biogenesis (e.g., Alix and TSG101), and members of the tetraspanin family of membrane-bound proteins, particularly CD9, CD63, CD81, and CD82 [27].

Microvesicles—These EVs are generally larger than exosomes with size ranging between 50 nm and 1.5 μm in diameter. MVs are formed via outward budding of the cell membrane in to the extracellular space [1, 28, 29]. Several proteins involved in exosome formation have been shown to also participate in MV formation such as the ESCRT-I complex subunit tumor susceptibility gene protein101 (TSG101) and sphingomyelinases (SMases) [30, 31].

Apoptotic bodies—These are released by cells undergoing programmed cell death or apoptosis. These are much larger compared to the previous two EVs with size ranging between 50 nm and 2 μm in diameter [2, 27]. Similar to MVs, apoptotic bodies originate from the cell membrane through a process known as blebbing. During apoptosis the cell membrane is separated from the cytoskeleton as a result of the increased hydrostatic pressure due to contraction of the cell [31].

Cancer cells have been shown to release another type of EV which have been termed as large oncosomes. These EVs are the largest observed EVs so far and exhibit size ranging between 1 and 10 μm in diameter [32]. Analysis of their contents have revealed a prevalence of oncogenic biomolecules. Oncosomes have been shown to arise due to shedding/budding of the cell membrane in a manner similar to that of MVs and both these EVs have been shown to exhibit the presence of the cytoskeletal remodeling controller protein ARF6, thereby indicating towards a common or at least a similar mode of biogenesis [33, 34, 35]. A visual representation of the different types of EVs has been provided in Figure 1.

Figure 1.

Major types of EVs generated by majority of cells with the exception of large oncosomes which are generated exclusively by cancer cells. MVE, multivesicular endosomes.

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2. EMT and cancer metastasis

Epithelial-mesenchymal transition (EMT) is a naturally occurring cellular phenomena that was originally described in the context of cell differentiation during embryonic development [36]. At the most fundamental level, it involves the conversion or trans-differentiation of epithelial cells to their mesenchymal counterparts. Epithelial cells exhibit cell-cell junctions and apical-basal polarity while mesenchymal cells lack such structural distinctions and as a result exhibit far greater motility [37]. During the process of EMT several different signaling pathways that control cell shape and motility are activated which results in the alteration of gene expression programs and the ultimate restructuring of the cytoskeleton to produce the characteristic undifferentiated/poorly differentiated morphology of mesenchymal cells [38, 39]. Through many years of investigation EMT has been shown to be an integral part of several developmental stages of organisms and has also been shown to be reactivated during later phases of the organism’s lifespan such as during the activation of tissue repair and during certain diseases such as cancer [40, 41].

As EMT confers greater invasive/migration properties to cancer cells through the acquisition of mesenchymal traits, the process serves as a preparatory stage for metastasis for most solid state cancers. The National Institute of Cancer defines metastasis as the spread of cancer cells from the place where they first formed to another part of the body [42]. Through the study of animal tumor models and cultured human carcinoma cells, it has been realized that the activation of EMT gradually causes carcinoma cells to lose their cell-cell junctions, and to degrade the surrounding extracellular matrix (ECM) or basement membrane through the expression of ECM degrading enzymes known as matrix metalloproteinases (MMPs) [43, 44, 45]. This effectually leads to dissemination of cancer cells as either single cells or as collective migratory masses, which can now invade neighboring tissue sites or metastasize to distant sites of the body to form secondary tumors [46, 47, 48]. During this transitionary process, cancer cells exhibit a gradual down regulation of proteins that are representative of epithelial state or epithelial markers, predominantly E-cadherin, and a concomitant increase in mesenchymal markers such as N-cadherin, fibronectin and vitronectin [38].

It is to be noted that along with conferring of greater invasive properties, EMT also grants increased survivability to transitioning cells. Generally, the detachment of anchorage-dependent cells from the surrounding ECM, which is key for metastasis to take place, is associated with a type of programmed cell death known as anoikis [49]. This is due to the fact that under normal conditions, interaction of cell surface integrins with the ECM leads to the activation of a phosphorylation cascade that eventually leads to the activation of AKT, which in turn promotes cell survival. When the integrin-ECM connection is lost, the cell survival signals cease and proapoptotic proteins such as BAD can function unhindered to initiate cell death. However, gene expression changes associated with EMT such as the down-regulation of E-cadherin and the up-regulation of N-cadherin have been shown to increase resistance to anoikis [50]. Thus, EMT is an essential precondition that must be completed for cancer cells to be able to metastasize. These intracellular and extracellular changes are brought about due to the hyper-activation of various oncogenic signaling pathways which ultimately leads to the upregulation or activation of certain EMT transcription factors, mainly belonging to the SNAIL (SNAIL1 and SNAIL2), ZEB (ZEB1 and ZEB2) and bHLH (TWIST1 and TWIST2) family of transcription factors. These transcription factors are the major drivers of the transitionary process [39, 51].

Another precondition that is necessary for the successful completion of metastasis is the mesenchymal-epithelial transition (MET). Cancer cells must undergo EMT in order to disseminate from the primary tumor mass, invade neighboring tissues or blood vessels and migrate to distant sites within the body. However, in order for these metastasized cancer cells to anchor themselves to the new tissues, and form secondary tumors they must regain their epithelial characteristics and proliferative abilities which were drastically down-regulated during the transition to mesenchymal phenotype [52, 53]. A generalized overview of the events involved in EMT and metastasis has been depicted in Figure 2.

Figure 2.

General overview of the events involved in cancer metastasis. ECM, extracellular matrix; CTC, circulating tumor cell.

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3. Role of extracellular vesicles in cancer metastasis

An ever-increasing amount of evidence suggests that tumor-secreted EVs have distinct roles to play in the establishment of a metastasis conducive environment. Several key steps have been identified that eventually lead up to secondary tumor development. These include but are not restricted to remodeling of the ECM, induction of angiogenesis, induction of EMT, promotion of vascular leakiness/permeability and establishment of pre-metastatic niche (PMN) [54]. In this section we will be discussing how tumor-secreted EVs influence these steps as according to existing preclinical data. A summarization of the major pro-metastatic factors isolated from different EVs have been provided in Table 1.

MoleculeTypeIsolated fromReferences
FibronectinProteinExosomes[55]
α3 integrinsProteinExosomes[55, 56]
ADAM10ProteinExosomes[56]
MMP14ProteinExosomes[57, 58, 59]
ARF6ProteinOncosomes[34]
MMP2ProteinOncosomes[34]
MMP9ProteinOncosomes[34]
EMMPRINProteinMicrovesicles[60]
HSP90ProteinExosomes[61]
VimentinProteinExosomes[62]
N-cadherinProteinExosomes[63]
miR142-3PRNAExosomes[64]
miR-23aRNAExosomes[65]
miR-494RNAExosomes[66]
miR-542pRNAExosomes[66]
miR-122RNAMicrovesicles[67]
MIFProteinExosomes[68]
Y RNA hY4RNAExosomes[69]
PDL1ProteinExosomes[70]
ARG1ProteinExosomes[71]

Table 1.

Major cell migration and metastasis promoting factors isolated from different EV types.

3.1 Role of extracellular vesicles in ECM remodeling

ECM remodeling during cancer progression is generally regarded as an essential step for increasing the invasiveness of tumors. As mentioned before cancer cells can modulate the state and composition of the ECM by altering their surface proteins and by secreting ECM degrading enzymes. However, new evidence suggests that tumor-secreted EVs may serve as an additional means of ECM modulation. Proteomic profiling of tumor-secreted exosomes has revealed that these EVs are enriched with ECM modifying molecules such as fibronectin, α3 integrins, ADAM10 and MMP14, and have been correlated with increased stromal tissue invasion and cell migration [55, 56, 57, 58, 59]. Similarly, large oncosomes were shown to harbor a variety of biomolecules with ECM remodeling activity such as ARF6, MMP2 and MMP9, and their increased abundance in these EVs has been correlated with increased tissue invasion [34]. Microvesicles shed by tumors were demonstrated to transfer the tumor derived factor EMMPRIN to stromal fibroblasts, thereby stimulating the production of MMPs [60].

3.2 Role of extracellular vesicles in induction of angiogenesis

Hypoxia induced angiogenesis plays an essential role in the metastatic pathways as the new blood vessels formed serve as potential routes by which tumor cells from the primary tumor site enter in to the circulation. In case of many solid tumors, the density of blood vessels surrounding and infiltrating the tumor can serve as a reliable indicator of metastatic potential, with highly vascular primary tumors exhibiting higher incidence of metastasis than less vascular primary tumors [72]. In case of breast cancer cells, the onset of hypoxia has been shown to enhance exosome release [73]. Exosomes derived from glioblastoma multiforme (GBM) cells exposed to hypoxic conditions have been shown to induce angiogenesis by stimulating the production and release of pro-angiogenic cytokines and growth factors from stromal endothelial cells [74].

3.3 Role of extracellular vesicles in induction of EMT

Among the different types of EVs, tumor-derived exosomes have been reported to considerably enhance the induction of EMT in recipient cells. When exosomes derived from breast cancer cell lines of varying degrees of metastatic potential were applied to recipient cells in a wound healing assay, the exosomes derived from cell lines with greater metastatic potential were able to induce much greater cell migration and wound closure than those derived from cell lines with lesser metastatic potential [75]. These cancer-derived exosomes were reported to exhibit the presence of EMT promoting factors such as HSP90 and vimentin [61, 62]. Exosomes derived from highly metastatic lung cancer cell lines were shown to greatly increase the expression of mesenchymal markers such as N-cadherin and vimentin, and at the same time reducing the expression of epithelial markers such as E-cadherin in recipient epithelial cells [63]. An association was reported between exosomes derived from H-Ras over-expressing Madin-Darby canine kidney epithelial cells and the induction of EMT in recipient epithelial cells, however this report lacks functional validation [64].

Apart from tumor cells, mesenchymal stem cells (MSCs) located within pro-tumorigenic environments also secrete EVs that have been demonstrated to play key roles in regulating cancer stem cell (CSC) homeostasis, chemoresistance and metastasis. Exosomes derived from bone marrow derived MSCs (BM-MSCs) have been shown to carry the oncogenic miRNA - miR142-3p. Uptake of such exosomal miR142-3P promotes NOTCH1 signaling in colon cancer cancer cells through the suppression of NUMB protein generation, and in turn stimulates EMT in these cells [76]. Again, BM-MSC derived exosomes have been shown to be carriers of pro-oncogenic proteins such as UBR2. BM-MSC derived exosomes abundant in UBR2 were shown capable of promoting stemness properties and migration in gastric cancer cells both at the in vitroand in vivolevels [77].

3.4 Role of extracellular vesicles in promoting vascular permeability

Vascular leakiness/permeability is a pre-requisite for PMN formation as it allows for the extravasation of circulating tumor cells (CTCs) with far greater ease compared to normal vasculature [78]. Exosomes derived from breast cancer cells have been shown to promote vascular permeability in the lungs through the upregulation of proinflammatory S100 gene expression and the activation of Src kinase signaling [79]. Metastatic breast cancer-derived exosomes showing abundance of miR-105 have been linked to the downregulation of the tight junction protein ZO1 in recipient vascular endothelial cells, thereby greatly increasing vascular permeability and susceptibility for extravasation of CTCs [80]. In a similar manner, hypoxic lung cancer-derived exosomes containing miR-23a was shown to increase angiogenesis and vascular permeability by suppressing prolyl hydroxylase and ZO1 expression respectively, in recipient vascular endothelial cells [65].

3.5 Role of extracellular vesicles in PMN establishment

The PMN refers to an environment or site which is distant from the primary tumor site and which is suitable for the survival and propagation of inbound CTCs. The concept first came in to consideration through the observations made in 1989 that clearly showed that different tumor types show a tendency to metastasize to different and distinct sites in the body [81]. These observations hinted towards a direct role of the microenvironment in controlling metastatic incursion. Since then, several factors have been identified that play critical roles in PMN formation [82]. Renal cancer stem cell-derived CD105 positive microvesicles were shown to promote angiogenesis and PMN formation in the lungs through a defined set of pro-angiogenic mRNAs and miRNAs [83]. Tumor-derived exosomes containing miR-494 and miR-542p were demonstrated to induce downregulation of cadherin-17 and upregulation of MMP2, MMP3 and MMP14 in lymph node stromal cells and lung fibroblasts [66]. Breast cancer cell-derived microvesicles containing miR-122 were shown to suppress glucose metabolism in stromal cells by inhibiting pyruvate kinase action. This resulted in the development of a PMN having greater availability of glucose for breast cancer cells to utilize [67]. In addition to these, tumor-derived exosomes were shown to be responsible for TLR3 activation in lung epithelial cells [84]. This activation of TLR3 was mediated by a defined set of small nuclear RNAs (snRNAs) which were found to be enriched in the exosomal population. TLR3 activation leads to the secretion of chemokines which in turn recruit neutrophils as well as macrophages and monocytes, thereby promoting PMN formation.

In one notable study, pancreatic ductal adenocarcinoma (PDAC)-derived exosomes were demonstrated to orchestrate a stepwise progression of PMN formation [68]. Uptake of PDAC-derived exosomes loaded with macrophage inhibitory factors (MIFs) by Kupffer cells caused TGF-β secretion and upregulation of fibronectin expression in hepatic stellate cells. This in turn resulted in the recruitment of bone marrow-derived macrophages to the microenvironment, thereby aiding in the establishment of a PMN and considerably increasing the probability of metastatic growth at the site.

3.6 Role of extracellular vesicles in host immunomodulation

Immune evasion or the ability to escape detection or triggering of the host’s immune system is considered a hallmark of cancer and is necessary for tumors to survive and progress to metastasis. For this purpose, cancer cells have evolved a variety of ways of debilitating the host immune system [85]. Tumor-derived EVs have recently been shown to carry a varied arsenal of immunomodulatory molecules and so have turned out to be one of the major mediators of host immunosuppression. One of the key mechanisms deployed by tumor-derived EVs to modulate host immune responses is regulation of PD1-PDL1 interactions. Chronic lymphocytic leukemia derived EVs have been shown to carry the non-coding Y RNA hY4 which increases expression of the programmed death-ligand PDL1 in circulating monocytes [69]. PD1-PDL1 interaction stimulates down-regulation of T cell receptor (TCR) activation in CD8+ T cells thereby preventing an auto-immune response [86]. EVs isolated from metastatic melanomas and glioblastomas have displayed expression of PDL1 on their membrane surfaces and are capable of directly binding PD1 receptors on T cells and suppressing T cell response [70].

Arginase-1 (ARG1) is another T cell response modulatory protein that has been found to be present in tumor-derived EVs [71]. ARG1 mediated depletion of L-Arginine leads to down-regulation of the TCR subunit CD3ζ, thereby suppressing T cell activation [87]. Additionally, L-Arginine depletion also causes cell cycle arrest at the G1 phase of the cell cycle through the activation of RICTOR/mTORC2 complex [88].

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4. Diagnostic and prognostic value of extracellular vesicles

The key factors that define an ideal diagnostic and prognostic marker can be summed up as follows: the ability to provide accurate information about the physiological state of the organism, bioavailability, and finally ease of isolation. EVs have lately gathered substantial importance as both diagnostic and prognostic tools in cancer as they qualify all the above-mentioned criteria [4, 89, 90]. The molecular content of EVs is often representative of both their cellular origins and the physiological condition of their originator cells. EVs are also readily detectable and isolated from body fluids such as serum, plasma, urine and saliva. With all these characteristics, EVs show massive potential as a non-invasive means of disease monitoring [91, 92, 93, 94]. An example of this is found in the case of the prostate cancer where the metalloreductase STEAP1 is upregulated and shows stage wise elevation in expression levels. It was shown that there was a significant increase in the presence of STEAP1 positive EVs in the plasma of males diagnosed with prostate cancer (PCa) compared to control males [95]. In addition, proteomic profiling of serum derived EVs of PCa patients revealed differential expression of prognostic protein markers such as PD-L1, ERG, Integrin-β5, Survivin, TGF-β, phosphorylated-TSC2 as well as partners of the MAP-kinase and mTOR pathways compared to control patient serum derived EVs [96]. Similarly in the case of gall bladder cancer (GBC), the oncogenic miRNA – miR-1246 was shown to be upregulated in patient serum derived EVs compared to controls. The reverse scenario was observed in the case of the tumor suppressive miR-451a [97]. The oncogenic glioma-specific growth factor receptor EGFRvIII, a variant form of EGFR has been shown to be present in EVs secreted by glioma cells and cells transfected with with the EGFRvIII mutant construct [98]. These EVs were later on found to be present in the sera of GBM patients [99]. Certain EV-associated biomarkers can allow for differentiation between cancers with low or high metastatic potential. These biomarkers include but are not restricted to miR-122, miR181c and miR-105 (breast cancer metastasis); MET, TYRP2 and HSP70 (high stage melanoma); integrin β4 (lung metastasis); MIF4 (pancreatic cancer metastasis to liver); integrins α3 and β1 (metastatic prostate cancer) [68, 80, 100, 101, 102, 103, 104]. Taken together these findings strongly support the utility of EVs in disease monitoring and so should be exploited as a resource for improving current cancer diagnostic procedure while at the same time serving as an additional variable for accurate assessment of cancer prognosis.

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5. Future applications of extracellular vesicles in cancer therapy

Nanotechnology-based techniques are increasingly being utilized in the fields of medical imaging and targeted delivery of therapeutic molecules. A significant amount of work has gone in to the development of various nanotechnology-assisted drug delivery systems and the results have been fairly promising [105, 106, 107, 108, 109]. However, the artificial nature of these nano-drug delivery platforms present considerable issues relating to toxicity within the body [110]. For this reason, there exists a demand for efficient nano-drug delivery systems exhibiting significantly lesser toxicity. EVs seem set to meet this demand as they exhibit several useful features such as their small size for penetrating deep in to target tissues, high stability in host circulation and their ability to evade the host immune system as in the case of EVs generated from host’s own cells [111, 112, 113, 114]. Additionally, EVs have already proven themselves to be efficient carriers of functional cellular proteins and RNA species. As a result, EVs have garnered considerable attention as potential delivery systems for therapeutic molecules such as coding and non-coding RNAs, peptides and inhibitors [115]. So far both active and passive means of loading of therapeutic agents in to EVs have been developed. For example, drug molecules can be loaded in to EVs by simply incubating them with the isolated EV population as seen in the case of paclitaxel, doxorubicin and curcumin [116, 117, 118]. Alternatively, therapeutic agents may be actively loaded in to EVs through electroporation [119]. In addition, EVs may be isolated from cells that have been modified to overexpress proteins or RNA species of therapeutic value as this would lead to the enrichment of these molecules in generated EV populations [120, 121]. Overall, EVs represent an attractive alternative to artificially generated nano-drug delivery systems. However, the full-fledged adoption of EVs over conventional nanoparticles still requires more time, investigation and majority approval of the scientific community.

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Acknowledgments

We would like to acknowledge Department of Science and Technology (NanoMission: DST/NM/NT/2018/105(G); SERB: EMR/2017/000992) and Focused Basic Research (FBR): 31-2(274)2020-21/Bud-II, HCT, CSIR, Govt. of India.

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Conflict of interest

Authors declare no conflict of interest.

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Bhaskar Basu and Subhajit Karmakar (December 29th 2021). The Role of Extracellular Vesicles in the Progression of Tumors towards Metastasis [Online First], IntechOpen, DOI: 10.5772/intechopen.101635. Available from:

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