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Review

Basic Pathogenic Mechanisms and Epigenetic Players Promoted by Extracellular Vesicles in Vascular Damage

by
Concetta Schiano
1,2,†,
Carolina Balbi
2,†,
Filomena de Nigris
3 and
Claudio Napoli
1,4,*
1
Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania Luigi Vanvitelli, 80138 Naples, Italy
2
Laboratory of Cellular and Molecular Cardiology, Cardiocentro Ticino Institute, 6807 Taverne-Torricella, Switzerland
3
Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
4
Clinical Department of Internal Medicine and Specialistic Units, Division of Clinical Immunology and Immunohematology, Transfusion Medicine and Transplant Immunology (SIMT), Azienda Universitaria Policlinico (AOU), 80138 Naples, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2023, 24(8), 7509; https://doi.org/10.3390/ijms24087509
Submission received: 21 March 2023 / Revised: 14 April 2023 / Accepted: 16 April 2023 / Published: 19 April 2023
(This article belongs to the Special Issue Molecular Research on Epigenetic Modifications)
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Abstract

:
Both progression from the early pathogenic events to clinically manifest cardiovascular diseases (CVD) and cancer impact the integrity of the vascular system. Pathological vascular modifications are affected by interplay between endothelial cells and their microenvironment. Soluble factors, extracellular matrix molecules and extracellular vesicles (EVs) are emerging determinants of this network that trigger specific signals in target cells. EVs have gained attention as package of molecules with epigenetic reversible activity causing functional vascular changes, but their mechanisms are not well understood. Valuable insights have been provided by recent clinical studies, including the investigation of EVs as potential biomarkers of these diseases. In this paper, we review the role and the mechanism of exosomal epigenetic molecules during the vascular remodeling in coronary heart disease as well as in cancer-associated neoangiogenesis.

1. Introduction

The vasculature controls homeostasis and the functional integration of tissues and organ systems [1,2]. Hemodynamic and bioactive stimuli stimulate the vasculature, which responds with multiple structural and phenotypic changes that are well described during the onset and progression both of cardiovascular diseases (CVDs) and cancer [1,2,3]. Starting from fatty streaks, cell components of the vascular wall change their function, contributing to the progression of atheromatous plaques, chronic inflammation and clinical manifestations of coronary heart disease (CHD) [4,5,6,7,8,9]. Endothelial adaptative remodeling also occurs during cancer growth, representing a key event during the transition from local to systemic and metastasis dissemination [10]. Different metabolic and epigenetic signaling between endothelial cells and the microenvironment are crucial to the initiation and progression of pathological vascular modifications [1,2,3,11]. Therefore, investigation of the pathophysiology of the vascular remodeling mechanism both in CVDs and cancer is of great value for finding new disease targets and biomarkers. A central role in vasculature modifications is the crosstalk between several cell types necessary to transfer information from one site to another. An emerging body of evidence implies that extracellular vesicles (EVs), which circulate in biological fluids, are vehicles of a variety of molecules to recipient endothelial cells during CVD and cancer growth [12,13,14,15,16,17,18]. However, the role of EVs and their epigenetic influences in the pathogenesis of vascular damage are poorly explored. Here, we discuss the epigenetic effects exerted by EVs on the vasculature both in coronary heart disease (CHD) and cancer.

2. EVs Biology and Function

According to the International Society for Extracellular Vesicles (ISEV) (https://www.isev.org, accessed on 15 April 2023), vesicles include both small and medium/large particles, also known as exosomes (Exo) and microvesicles (MVs), which differ by size and effect on biogenesis [19,20]. The literature reports that EVs can be isolated from biological fluids, such as serum, plasma, urine and amniotic fluid, as well as from the conditioned medium of cells cultured and treated in vitro [12,13,16]. EVs can provide “circulating information” to promote intercellular communication [20]. However, since their number and molecular composition can differ considerably, depending on the micro-environmental and pathophysiological status of their cellular origin, their purity and the method of preparation are very important [21,22]. The EVs’ cargo is known to include proteins and nucleic acids such as DNA, mRNA and a variety of non-coding RNAs (ncRNAs) that, when released in target cells, differentially regulate gene expression [23,24,25]. Exosomes not only regulate physiological states, such as tissue regeneration, immune surveillance and stem cell plasticity [26,27,28,29], but also participate in the pathophysiology of CVD, neurodegenerative diseases and malignant tumors [30,31,32] and have potential value for precise diagnosis, prognosis assessment and disease treatment. Moreover, given their biological role, EVs can affect the pathogenesis of CVD and tumor progression [33,34,35]. Specific EVs containing microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circRNAs, may recruit DNA methylase (DNAm) or histone deacetylase enzymes to induce epigenetic changes in target cells [5]. Growing evidence indicates that epigenetic mechanisms are closely related to cardiovascular disease development and cancer neoangiogenesis [36,37,38]. Herein, we review recent findings on the interplay between the molecular cargo of EVs that induces epigenetic modifications in vessel during both CVD and cancer vascularization.

3. The Epigenetic Role of EVs in Cardiovascular Damage

3.1. EVs and Peripheral Endothelial Dysfunction

Epigenetic changes contribute to the development of CVDs and begin with progressive alterations of the endothelial tissue [3,7]. Endothelial dysfunction is characterized by impaired vascular function, loss of antithrombotic function, excessive proliferation of vascular smooth muscle cells (VSMCs), platelet activation and macrophage migration [9,39]. In endothelial dysfunctional cells, intercellular and vascular cell adhesion molecule-1 (ICAM-1 and VCAM-1) are overexpressed and promote the leukocytes’ adhesion [40]. Several aberrant epigenetic modifiers, mainly miRNAs and lncRNAs, are transported by EVs on dysfunctional endothelial cells (ECs) that modify gene expression and contribute to the acceleration of vascular disease to advanced atherosclerosis [41,42] (Figure 1).
Ding Yu Lee and colleagues demonstrated that the downregulation of miR-10a in both the circulation (serum) and aortic endothelium is highly associated with atherogenesis. miR-10a reduced leukocyte infiltration through GATA6/VCAM-1 signaling pathway, thereby decreasing plaque formation. Thus, this study showed that miR-10a downregulation is associated with atherosclerosis and its induction could prove to be a novel therapeutic target for this disease [43]. Evidence also demonstrated that several miRNAs regulate the leukocytes’ infiltration into the endothelium vessel. One example is miR-155-EVs from VSMCs that target ECs down-regulate integrin proteins and tight junctions. These EVs generate leaky membranes, favor leukocytes and other immune cells migration into sub-endothelium where macrophages can maturate in the foam cells [3,7,40,44]. Moreover, data showed that miRNA-155- and miRNA-223-EVs may also target mononuclear cells, favoring LDL accumulation and their transformation in damaged endothelium [45,46]. Hall and colleagues outlined the importance of an EV-derived circRNA, named Circ-Lpr6, for vascular pathogenesis in both animal and human models. This novel circRNA acts as a sponge for miR-145, thereby regulating its downstream targets. Molecular studies demonstrated that Circ-Lpr6 impairs miR-145-mediated regulation of VSMCs differentiation, migration and proliferation. Furthermore, its overexpression resulted in a decreased intimal area in mouse aortas. Therefore, Circ-Lrp6 could be required to counterbalance miR-145 into VSMCs, providing further evidence that ncRNAs are an important target in this disease, as the ratio between Circ-Lpr6 bound to miR-145 versus unbound plays a role in vascular pathogenesis [47]. Another feature of endothelial dysfunctional vessels is the alteration of the coagulation pathway due to abnormal platelets activation. EVs released following this stimulus are found in chemokine RANTES (normal activation-regulated, expressed, and presumably secreted T cell), thus promoting the neutrophils’ adhesion and migration, starting inflammation [48].

3.2. EVs in Inflammation and Calcification

Cellular damage plays a critical role in the inflammatory response, delivering a high amount of EVs containing pro- and anti-inflammatory signals to target cells [3,7,43]. Although ncRNAs are not classically considered as direct epigenetic modificators, they might have a role in such events. Protective mechanisms are activated by miRNA-126, miRNA-210 and miRNA-214 promoting angiogenesis and vasculogenesis [48,49,50]. In particular, miRNA126 increased the expression of chemokine 12 ligand (CCL12), reduced macrophage entry into the vascular wall and protected the vascular endothelium [51]. A supportive role for this action mechanism derived from the observation that the silencing of miRNA-126 caused leaky vessels, hemorrhage of blood from arterial vessels and partial embryonic lethality. Silencing also induced a loss of vascular integrity and defects in ECs proliferation and angiogenesis [52]. Although miRNA-214 targeting damaged ECs, it also promoted angiogenesis and thus favored the restoration of vessel integrity [50]. The contribution of EVs to endothelial inflammation has been reported to be due to DC-derived EVs that activated the TNF-α/NF-κβ pathway, contributing to the progression of atherosclerosis in animal model [53]. In response to inflammatory stimuli, ECs transferred EV-miR-92a-3p to VSMC, resulting in cell proliferation, while EV miR-146a inhibited their migration, further exacerbating the inflammatory response [54,55,56]. The RNCR3 ncRNA released from ECs in aortic atherosclerotic lesions showed a protective role, regulating miR-185-5p in VSMC target cells. Specifically, miR-185-5p favored the interaction between RNCR3 and Klf2, promoting ECs vasoprotection [57]. In vivo knockdown of RNCR3 worsens atherosclerosis, hypercholesterolemia and inflammation [57]. Thus, EV-transported ncRNAs have a key role in the onset of CVDs. EVs are also involved in the progression of vascular calcification [58]. Analysis of murine and human vessels showed that macrophage-derived EVs promoted intimal microcalcification [59]. Furthermore, the enrichment of these EVs with the calcium-binding protein S100A9 facilitated the calcification progression together with VSMC-derived EVs [59]. In response to this stimulus, miRNA150-EVs promoted vascular maintenance by activating the endothelial vascular endothelial growth factor (VEGF)-A/VEGFR/PI3K/Akt pathway [60]. Although little data are available on EVs regulating apoptosis during endothelial damage, it was demonstrated that HUVECs treated with macrophage-derived EVs activate NF-κB and TLR4 signaling pathways, causing ECs apoptosis [53].

3.3. EVs and CHD

Inflammation and calcification have interconnected roles in the pathophysiology of CHD and acute coronary syndrome (ACS) [3,7,11]. For the first time, the transcriptomic analysis of EVs from ACS patients revealed the presence of mRNA coding for epigenetic enzymes, such as DNA methyltransferases (DNMTs) [61]. Notably, ACS-derived EVs absorbed on PBMCs from healthy subjects modulated the expression of several genes, presumably via epigenetic mechanism in agreement with previously reported [62,63,64,65,66]. In particular, EVs induced methylome changes promoting a significant activation of Synaptosin (SYP), Cell Adhesion Molecule L1 Like (CHL1) and SH2 Domain Containing Adaptor Protein B (SHB) genes [61]. These findings underlined the epigenetic contribution in the role of EVs in ACS.
In the clinical practice, CHD diagnosis is made by coronary CT scan [7,67] and coronary angiography [7,68]. However, it is still unclear whether EVs could be a tool to improve CHD risk estimation future investigations should be conducted to combine EVs and clinical parameters. Shi and colleagues demonstrated that human blood samples from healthy subjects have 86% more EVs compared to CHD patients [69,70]. Therefore, both EV count and content are of potential interest as disease-specific biomarkers [71,72,73,74,75].
Nowadays, it is known that, in the cardiovascular system, EVs also play important epigenetic-indirect roles in the acute post-myocardial infarction (MI) damage and repair mechanisms inducing myocardial remodeling and cardiac regeneration [76]. Recently, echocardiographic experiments had shown that exosomes derived from the mesenchymal stem cell of adipose tissue (ADSC) could improve left ventricular ejection fraction, whereas their administration could significantly alleviate MI-induced cardiac fibrosis [77]. Additionally, ADSC-exosomes treatment has been shown to reduce cardiomyocyte apoptosis, increasing angiogenesis. Molecular experiments demonstrated that ADSCs-derived exosomes can promote microvascular ECs proliferation and migration and inhibit cardiomyocytes apoptosis through miRNA-205. This assumption was confirmed via the transfection of ADSC-derived exosomes into MI-induced mice and observing a decrease in cardiac fibrosis, an increase in angiogenesis, and an improvement of cardiac function [77]. Cardiac fibroblast-derived EVs modulate cardiac remodeling, favoring intercellular communication between cardiomyocytes (CM) and cardiac fibroblasts [78,79]. Consistently, exosomal miRNA-21 CM-derived, reduced the expression of sarcoplasmic protein sorbin 2 containing SH3 domain (SORBS2) and PDZ and LIM domain 5 (PDLIM5), producing an increase in cell size and stimulating cardiomyocyte hypertrophy [80,81]. Moreover, miRNA-21 promoted the cardiac fibrosis inducing the endothelial-to-mesenchymal cell transition [82] and altered expression of superoxide dismutase (SOD) in HF patients [83,84]. Increasing research has attracted attention to the roles of EVs-ncRNAs as potential diagnostic biomarkers. Other than miRNAs, several studies have indicated that lncRNAs significantly regulate fibrosis, thereby having a direct effect on ECM gene expression, the TGF-β signaling pathway and the proliferation of fibroblasts or transition to myofibroblast [23,85,86,87]. These effects are also proposed to be mediated by paracrine communication of EVs between donor and recipient cells, especially in cardiomyocytes and fibroblasts [23]. Exosomes-containing lncRNA ZFAS1 could induce cardiac fibrosis via the Wnt4/β-catenin signal pathway by sponging miR-4711-5p in cardiac fibroblasts [85]. LncRNA MIAT is up-regulated in serum-derived EVs from atrial fibrillation (AF) patients. MIAT aggravated the atrial remodeling and promoted AF by binding with miR-485-5p [86]. Neat1 is obviously up-regulated by P53 and HIF2A in cardiomyocytes in response to hypoxia and is enriched in cardiomyocyte-derived exosomes. Neat1 is essential for cell survival and fibroblast functions. This finding was confirmed via genetic knockout of Neat1 that impaired cardiac function during MI [87]. Although currently studies aim at the analysis of EVs from human samples in AF, HF and MI repair, large studies need to be performed to determine their utility in the clinical routine [88]. In addition to all the findings on basic mechanisms involving EVs, various clinical studies have been initiated to date. Some of these are still at the recruitment stage, and the few completed studies have not yet published their first results (NCT03660683, NCT04142138, NCT03034265, NCT03984006, NCT02822131, NCT00331331, NCT03837470 and NCT04266639). All studies listed in Table 1 will investigate the general cargo of EVs from different biological fluids and tissues, but none have provided help to investigating specific molecules. Trials are evaluating the role of EVs as carriers of anti-inflammatory signal or drug delivery systems. However, these are still few, and their results are not fully available (Table 1).

4. Basic Mechanisms and Epigenetic Role of EVs in Tumor Vascularization

4.1. EVs in Neoangiogenesis

Initiation of angiogenesis is an important early event in premalignant lesions to supply nutrients and oxygen [1,9] (Figure 2).
EVs such as extracellular organelles elicit signaling between tumor and vascular cells carrying functional and epigenetic modifications to adapt the microenvironment to tumor growth conditions (Figure 2). Tumor hypoxia is the most potent stimulus of EVs biogenesis [89]. EV content may activate the proliferative and migratory status of ECs, favoring neo-vessel formation via different mechanisms, including epigenetic ones [90] (Figure 2). The canonical VEGF (or Notch signaling pathway) was described as being activated by EVs from different tumor types because ECs promoted sprouting and proliferation [91,92,93,94] (Figure 2). Other metabolic programs have also been proven to influence the migration of ECs [16]. We reported that EVs containing EDIL3 activate a mitochondrial and vesicular trafficking program through the purinergic receptor 4 in normal quiescent ECs. This stimulus promotes endothelial cell survival, proliferation, motility and organization into capillary-like structures in vitro and in vivo [16].
EVs may also regulate endothelial function via epigenetic mechanisms. In preclinical and clinical settings, a variety of ncRNAs and long noncoding RNA (lncRNA) transcripts packaged in EVs have been shown to be capable of modifying gene expression without altering the DNA sequence [95]. Generally, EVs-miRNAs are transferred into ECs, where they are post-transcriptionally downregulating antiangiogenic genes, promoting growth and vessel sprouting. However, the role of individual exosomal miRNAs is dependent on tumor histology and stage. In squamous cell carcinoma (ESCC), miR-181b-5p predicts a poorer overall survival. It was also shown to be involved in vessel formation by promoting endothelial growth via AKT targeting endothelial transcript for PTEN and PHLPP2 [96]. In multiple myeloma, the number of EVs carrying miR-135b is significantly increased compared to normal individuals. Transfer of this miRNA in ECs downregulates the inhibitor of hypoxia-inducible factor 1 (HIF-1), resulting in the formation of endothelial tubes through the HIF signaling pathway [97]. MiR-9-EVs from glioma play a pivotal role in both pathogenesis and vascularization. When miR-9 is absorbed by ECs, the increased neoangiogenesis activates multiple pathways, among them COL18A1, Thrombospondin-2 (THBS2), Protein patched homolog 1 (PTCH1) and prolyl hydroxylase 3 (PHD3) via MYC and OCT4 [98]. One of the most common miRNAs associated with poor prognosis of several cancer types is miR-210 [99,100]. Exosomal miR-210 uptake from ECs promotes angiogenesis by targeting specific processes depending on the tumor microenvironment [100]. The chromatin epigenetic regulation of proangiogenic genes has also been attributed to different lncRNA packaged in EVs, although the mechanism is not fully elucidated [101,102,103] (Figure 2). LncRNAs can work as molecular scaffold, assembling several chromatin regulator proteins and reshaping the DNA structure in the nucleus and thus favoring the transcription or silencing of target genes [104]. In other cases, lncRNAs can act as ceRNAs or sponges, sequestering endogenous miRNAs and inhibiting their action on target. For example, gastric cancer exosomal lncRNA PVT1 was reported to have the capacity to activate proliferation of ECs by forming a complex with polycomb repressive complex 2 (PRC2), the major histone methyltransferase on the STAT3 promoter, activating the transcription of the VEGFAs [105]. Several exosomal lncRNAs and proteins have been identified that originate from non-small cells lung cancer (NSCLC), some of which have a role in neoangiogenesis, e.g., lncRNA-p21 and Ubiquitin-fold modifier conjugating enzyme 1 (UFC1) protein [105,106,107]. The mechanism identified for UFC1 revealed the binding to the enhancer of Zeste 2 (EZH2) protein in the polycomb repressor complex 2 (PRC2) and their accumulation at the promoter region of the PTEN gene. This complex catalyzes the trimethylation of H3K27, the inhibition of PTEN expression and the activation of angiogenesis via AKT. UFC1 knockdown inhibited NSCLC growth in a mouse xenograft tumor model [107]. Another pro-angiogenic mechanism is downstream Angiopoietin 2/Tyrosin kinase endothelial receptor 2 (Ang2/Tie2). This pathway is activated by lncRNA EPIC1 in NSCLC and promotes channel formation and the proliferation of ECs [108]. Furthermore, the switch of ECs towards the proliferative phenotype was attributed to exosomal MANTIS. This lncRNA influenced the epigenetic regulation of angiogenic sprouting and alignment of ECs, modifying the chromatin complex, SWI/SNF (Switch/Sucrose non-fermentable), to facilitate the access to RNA polymerase II machinery and gene transcription [109].
Different mechanisms have been attributed to metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1), which may promote angiogenesis in endothelial ovarian carcinoma and in lung cancer [110,111]. Studies have demonstrated the influence of MALAT-1 and other lncRNAs in the complex interplay among lncRNA-miRNA-mRNA governing the sequestration and inactivation of miRNAs. For example, lncNKX2–1 from gastric cancer was reported to increase tumor growth and angiogenesis in both in vitro and in vivo models to direct sponge miR-145–5p, which upregulates Serpin Family E member 1 (SERPINE1) and vascular endothelial growth factor receptor (VEGFR) 2 signaling pathways [112]. A similar mechanism was also defined for receptor activity-modifying protein 2 (RAMP2-AS1) from chondrosarcoma, Urothelial cancer associated (UCA1) for pancreatic cancer, Small nucleolar RNA host gene 1 (SNHG1) from breast [112,113,114], RNA CCAT2 in exosomes from gliomas [115,116] and LINC00707 from cervical or bladder cancer [117,118]. Taken together, these data indicated that EVs have a role in tumor neoangiogenesis through epigenetic mechanisms. Emerging research is evaluating exosomes and their content as potential cancer biomarkers in clinical setting (Table 2). A survey on ClinicalTrials.gov (https://clinicaltrials.gov/, accessed on 15 April 2023) shows a total of 88 trials, of which 60 (68%) EVs’ cargo from different source are used as biomarkers of disease or response to therapy applications. In the case of exosome therapy, as a drug-delivery system, seven trials (8%) have been registered and one clinical trial (1.72%) is related to exosome as vaccine study. Although no definitive data are available, a manufacturing practice (GMP) as exosome production method and purification methods is present in the current trial. Furthermore, the European Medicines Agency (https://www.ema.europa.eu/en, accessed on 15 April 2023) has released scientific recommendations on classification of advanced therapy medicinal products. This nascent field of biomedicine offers new opportunities for the treatment of diseases and dysfunctions of the human body. In addition, it provides guidelines, recommendations, for researchers. However, the transition of EVs from basic research to clinical application is still premature.

4.2. EVs and Vascular Alterations in Tumor Progression

The disruption of vascular integrity and the consequent increase in vascular permeability allows tumor cells to penetrate the vasculature and metastasize. EVs secreted by cancer cells during tumor growth play an important role in vascular leakage (Figure 2). Studies have demonstrated that EVs from metastatic cancer cells may modify ECs’ permeability by altering cytoskeletal-associated proteins or downregulating the RhoA/ROCK pathway [119]. EVs containing miRNAs (including miR-200c, miR-141 and miR-429), which correlated with a poor prognosis of colon cancer, were demonstrated to downregulate ZEB protein and modify the membrane permeability of ECs [120]. Similarly, EVs carrying miR-25-3p, more frequent in patients with metastasis than in those without, were demonstrated to induce vascular leakage and enhance colon cancer metastasis [121]. The same is true for EVs miR-105 in breast cancer [122]. Furthermore, EVs miR-939 correlated with poor prognosis of gastric cancer and increased the permeability of ECs by downregulating the transcription of VE-cadherin [123]. A similar mechanism was reported for LncX26 in gastric cancer [124]. Additionally, the loosening of endothelial integrity and ultimately inducing colon cancer metastasis were attributed to post-transcriptional down regulation of p120-catenin (p120) mediated by transferring of exosomal miR-27b-3p from colon cancer [125] or miR-638 from HCC [126]. In NSCL cancer patients, exosomal miR-375-3p positively correlated with patient TNM stages. In vivo, miR-375-3p-enriched exosomes destroyed the endothelial structure of lung, liver and brain tissues of mice, leading to increased blood vessel permeability. Exosomal miR-375-3p internalized by breaking the tight junction of ECs through negative regulation of claudin-1 expression [127]. Another important pathway of EVs systemic activity is the degradation of extracellular matrix (ECM), favoring tumor growth and preparation of the metastasis niche. In particular, MMP-1 in EVs derived from cancer cells is a representative indicator of ECM degradation [128] (Figure 2). Evidence shows that the pharmacological reduction of EVs decreases the secretion of MMPs, resulting in an inhibition of tumor growth and metastasis [128,129]. This pathway is epigenetically regulated by exosomal lnc-MMP2-2 released by NSLC. The lncRNA internalized into ECs competed with miR-1207-5p to downregulate EPB41L5 and increased vascular permeability, promoting brain metastasis [130]. These data indicate a key role of EVs in damaging the endothelium and promoting intravasation of tumor cells and extravasation at distal sites (Figure 2). Moreover, considering the epigenetic roles of some ncRNAs and their capacity to control gene expression, the development of epigenetic-related drugs with higher specificity and fewer side effects would be a possible future approach.

4.3. EVs in Metastatic Niche: And Other Types of Vessels

Tumor vasculatures increase the tumor capability to metastasize by acquiring mesenchymal characteristics [131,132]. Both normal and tumor endothelial ECs are capable of acquiring a mesenchymal phenotype, increasing the tumor’s ability to metastasize. TECs comparing to ECs exhibiting cytogenetic abnormalities, such as aneuploid chromosomes, are differ metabolically, more resistant to starvation and release more angiocrine molecules and EVs [133,134]. The presence of TEC is associated with conversion of indolent tumor to more aggressive phenotype, and their presence was correlated with reactivation of dormant CD44v6+ tumor stem cells [135,136]. ECs and TECs within the vasculature gain a mesenchymal phenotype (vimentin alfa-smooth muscle actin positive), in some tumor types, shed from the endothelial lining layer of neoplastic vasculature into peripheral blood to the colonizing distal organ [135,136,137,138]. The mechanism is not fully understood. Exosomal Annexin A1 is one of the triggers inducing endothelial-to-mesenchymal transition (EndEMT) and activating RAC1/PAK2 in the gastric cancer model, whereas TGF-β on the surface of EVs triggers the same phenotypic switch in melanoma [139,140,141]. Moreover, data from EVs containing miR-92a-3p, derived from colon cancer cells, showed upregulation of mesenchymal markers, such as snail and vimentin, and downregulated the tight junction marker ZO-1 in HUVECs referred as “partial-EndoMT” [142]. EVs released from tumor cells during hypoxia participate in the EndMT switch of TECs, particularly EVs loaded with lysyl oxidase-like 2 protein (LOXL2) [143]. LOXL2 is a member of the LOX family and regulates extracellular matrix (ECM) remodeling, angiogenesis and premetastatic niche formation. LOXL2 acts as deaminase enzyme into the nucleus contributing to transcription, alternative splicing and miRNA regulation. All these pathways contribute to EndoEMT transition, proliferation and migration of ECs and TECs to distant organs and vasculogenic mimicry mechanism (Figure 2) [143]. Exosomal lncRNA antisense transcript of GATA6 (GATA6-AS) has also been reported to bind LOXL2, which regulates endothelial gene expression underlying EndoEMT transition [144]. The authors demonstrated that GATA6-AS associated with LOXL2 activates H3K4me3 marks and positively regulates the angiogenesis-related genes periostin and cyclooxygenase-1 in ECs. [144]. According to recent studies a multitude of other forms of neovascularization have been observed in cancer settings, including vascular looping and splitting (intussusception), vasculogenic mimicry and remodeling of larger ‘feeding’ vessels (arterio/venogenesis). An epigenetic mechanism mediated by EVs was also involved in vascular mimicry (Figure 2). Here, tumor cells undergoing epithelial-mesenchymal transition (EMT) form microvascular channels contributing to tumor vascularization [145]. These vessel types are negative to CD31 antigen and insensitive to anti angiogenic therapy. The mechanism involved the transferring of EVs containing lncRNAs into target cells, where they act as sponge of selective miRNAs or as scaffold for chromatin remodeling [145,146,147,148,149,150,151]. These mechanisms have been described for HULC in glioblastoma MALAT-1 in gastric cancer and in lung cancer Linc0155 [152,153,154]. Vasculogenic cooption (VCO) is another way by which tumor cells incorporate vessels from normal tissue to gain access to blood supply and growth locally (Figure 2). It is reported that tumor cells can migrate along blood vessels beyond the advancing front of the tumor and may spread to distant metastases [143]. Vessel cooption was initially described in gliomas and lung metastasis [155,156]. Then, VCO was reported in breast cancer metastasis and gastric metastasis from colon [143]. The mechanism of VCO is mediated by VEGF, but it is reasonable to think that EVs rich in VEGF are also involved [155].

5. Conclusions and Perspectives

Some pathogenic aspects of cancer and CHD are defined by the pathophysiology of vascular damage induced by key events in which EVs might play a role. EV counts, types and contents tend to vary, depending on collection methods. By analyzing literature data, we found that only three ncRNAs, specifically, miR-92a-3p, miR-145 and miR-210, were involved in vascular damage, both in the context of CVDs and in tumor neoangiogenesis, although with different mechanisms, underling the possible common pathway. Epigenetic tissue-specific reversible changes induced by exosomal cargo could play a role in the initiation and progression of disease complications. In terms of biomarkers, exosomal ncRNAs could be superior compared to non-exosomal ncRNAs for their specify in methods preparation, the protection from degradation and stability. Moreover, exosomal ncRNAs exist in considerable amounts in different body fluids that can be non-invasively sampled. Considering the epigenetic reversible roles of some ncRNAs, the establishment of novel approaches for modulating their expression or counteract their action could be a future goal [18]. To this end, in the cardiovascular field, 28 clinical studies were started which include exosome analyses (Table 1). In the field of oncology, 88 trials have begun in order to investigate the potential prognostic role of EVs. The most promising application appears to be biomarkers for gastrointestinal cancers (Table 2). However, larger, randomized, prospectively enrolling multicenter trials are necessary to identify EVs as potential clinical biomarkers to better guide clinical treatments.

Author Contributions

Conceptualization, C.N., F.d.N., C.S. and C.B.; resources, C.S., C.B. and F.d.N.; writing-original draft preparation, C.S., C.B. and F.d.N.; supervision and final approval of the intellectual content, C.N.; funding acquisition, C.N., C.S., C.B. and F.d.N. All authors have read and agreed to the published version of the manuscript.

Funding

This study was funded by: PRIN2017F8ZB89 from the Italian Ministry of University and Research (MIUR) (Claudio Napoli) and Ricerca Corrente (RC) 2019 from the Italian Ministry of Health (Claudio Napoli); Internal University Research Grant “VALERE: Vanvitelli Project 2020” (Concetta Schiano) from the Italian Ministry of University and Research (MUR); Internal competitive Research Grant “V:ALERE 2020” (Filomena de Nigris) from the Italian Ministry of University and Research (MUR); Swiss Heart Foundation no. FF21017 (Carolina Balbi).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We thank Annapaola Coppola, post-graduate student of the Patologia Clinica and Biochimica Clinica certification Board Program, for her collaboration in drafting Table 1 and Table 2. We thank Sabrina Conte for administrative support to the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Extracellular vesicles and vascular damage. Schematic representation of atherosclerotic EVs. They are produced by the different cell types involved in the mechanism of plaque formation. Harmful EVs can promote atherogenesis by altering vascular integrity, increasing inflammatory response and promoting thrombus formation. On the other hand, beneficial EVs, containing specific ncRNAs, can play athero-protective roles by promoting the repair of damaged endothelium and repressing the activation of inflammatory cells. The EVs interact with target cells via direct fusion, endocytosis or the binding of surface proteins. After this invagination, cytosolic proteins or RNA content-EVs transfer to the extracellular space. In the target cells, ncRNAs (such as lncRNAs, miRNAs, circRNAs) can (A) control nuclear gene expression via epigenetic changes and/or (B) affect protein function.
Figure 1. Extracellular vesicles and vascular damage. Schematic representation of atherosclerotic EVs. They are produced by the different cell types involved in the mechanism of plaque formation. Harmful EVs can promote atherogenesis by altering vascular integrity, increasing inflammatory response and promoting thrombus formation. On the other hand, beneficial EVs, containing specific ncRNAs, can play athero-protective roles by promoting the repair of damaged endothelium and repressing the activation of inflammatory cells. The EVs interact with target cells via direct fusion, endocytosis or the binding of surface proteins. After this invagination, cytosolic proteins or RNA content-EVs transfer to the extracellular space. In the target cells, ncRNAs (such as lncRNAs, miRNAs, circRNAs) can (A) control nuclear gene expression via epigenetic changes and/or (B) affect protein function.
Ijms 24 07509 g001
Ijms 24 07509 g002 550
Figure 2. Schematic representation of EVs involved in different mechanisms of tumor angiogenesis. Tumor cell-derived exosomes carrying biological molecules are involved in various angiogenic mechanisms: (A) sprouting angiogenesis, vessel enlargement, arteriogenesis, vascular mimicry and vessel-cooption favoring tumor growth and pre-metastasis niche formation; (B) Exosomes from malignant cells released locally or at distant sites can induce vessel modifications, with endothelial damage favoring intravasation. Triggering endothelial-mesenchymal transition, which favors endothelial migration at the distal site. Stimulation of extravasation at distant pre-metastatic niche; and (C) Schematic representation of epigenetic mechanisms: 1 DNA methylation; 2 Histone modifications; 3 non-coding RNA targets intracellular mRNA.
Figure 2. Schematic representation of EVs involved in different mechanisms of tumor angiogenesis. Tumor cell-derived exosomes carrying biological molecules are involved in various angiogenic mechanisms: (A) sprouting angiogenesis, vessel enlargement, arteriogenesis, vascular mimicry and vessel-cooption favoring tumor growth and pre-metastasis niche formation; (B) Exosomes from malignant cells released locally or at distant sites can induce vessel modifications, with endothelial damage favoring intravasation. Triggering endothelial-mesenchymal transition, which favors endothelial migration at the distal site. Stimulation of extravasation at distant pre-metastatic niche; and (C) Schematic representation of epigenetic mechanisms: 1 DNA methylation; 2 Histone modifications; 3 non-coding RNA targets intracellular mRNA.
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Table
Table 1. Clinical studies of EVs’ evaluation as diagnostic biomarker for CVD treatment.
Table 1. Clinical studies of EVs’ evaluation as diagnostic biomarker for CVD treatment.
NumberNCT NumberStatusConditionsStudy TypePopulation (Participants Number)Outcome
1NCT03660683TerminatedDiabetes Mellitus, Type 2
Cardiovascular Diseases		Interventional
(Dapagliflozin 10 mg)		15Evaluation of exosomes released from kidney podocyte after treatment, as indicator of kidney podocyte health, via urine assay
2NCT04142138CompletedPrehypertensionInterventional
(DASH)		9Characterization of urine exosome protein abundance pattern during nutritional changes, shifting from a “westernized diet” to a DASH diet
3NCT03478410RecruitingAFInterventional
(Epicardial fat biopsy)		35Quantification of epicardial fat-derived exosomes in patients with and without AF
4NCT04356300Not yet recruitingMODS after surgical repaired for ATAADInterventional
(MSC-exosome administration intravenously to patients once a day for two weeks)		60Intravenously treatment with MSC-derived exosomes immediately after ascending aortic replacement combined with open placement of triple branched stent graft
5NCT05669144RecruitingMI
Myocardial Ischemia
Myocardial Stunning		Interventional
(Intracoronary and intramyocardial injection of exosomes)		20Mitochondria and MSC-derived exosomes evaluation
6NCT03034265CompletedHypertensionObservational24Quantification of urinary exosomal sodium channels
7NCT03384433Unknown statusCerebrovascular DisordersInterventional
(Intravenous administration of allogenic MSC-generated exosomes transfected by miR-124 post-stroke)		5Intravenous administration of allogenic MSC-generated exosomes transfected by miR-124 post-stroke
Evaluation of disability improvement of patients with acute ischemic stroke after exosome administration
8NCT03984006CompletedAutoimmune thyroid disease
Heart Failure		Observational5Urinary exosomal NT-proBNP detection to find earlier predicting biomarkers for heart dysfunction
9NCT02822131CompletedHypertensionInterventional
(High phosphate diet)		10Urine exosome evaluation after high phosphate intake
10NCT05490173Not yet recruitingPremature Birth
Extreme Prematurity
Preterm Intraventricular Hemorrhage
Hypoxia-Ischemia, Cerebral
Neurodevelopmental Disorders		Interventional
(MSC-derived exosomes intranasal administration)		10EVs effect investigation through analysis of perinatal brain injury biomarkers (S-100, NSE, EPO) and mRNA
11NCT05035134RecruitingIntracerebral
Hemorrhage Circulating Exosomes		Observational300Circulating exosomes evaluation by RNA and proteome sequencing
12NCT04127591Unknown statusMIObservational10Peripheral plasma exosome miRNA evaluation
13NCT05326724RecruitingPost-stroke Dementia
Acupuncture		Interventional
(Acupuncture)		30Quantification of acupuncture-induced exosomes
14NCT00331331CompletedUveitis
Vasculitis
Ocular Inflammatory Disease		Observational147Vitreus exosome evaluation
15NCT05243368Not yet recruitingCCUInterventional
(MSC-derived exosome treatment)		30Evaluation of microenvironment favoring tissue regeneration after MSC-derived exosome treatment
16NCT03837470CompletedHFpEFInterventional
(Sodium Chloride; Furosemide administration)		14Urine exosome evaluation after treatment
17NCT05370105RecruitingStroke
Rehabilitation		Observational100Characterization of blood EVs
18NCT03264976Not yet recruitingDRObservational200miRNA sequencing of serum exosomes
19NCT04334603RecruitingHFInterventional
(Exercise training program)		120Plasma exosomes concentration evaluation
20NCT03227055Unknown statusChildhood Chronic Kidney DiseaseObservational155Urine exosome miRNAs evaluation
21NCT04184076Unknown statusAcute ischemic strokeInterventional
(Time-restricted feeding)		40Characterization of plasma exosome markers (phospho-IRS1, phospho-Tau, Abeta1–42, phospho-IRS1)
22NCT04641585Not yet recruitingBrugada Syndrome 1Interventional
(Brugada Syndrome diagnosti test)		144Evaluation of exosome coding and noncoding RNAs
23NCT05155358RecruitingHeat Stroke
Early Waking
MODS
Proteinosis
Liver Injury
Kidney Injury		Observational150Plasma exosome miRNAs evaluation
24NCT04235023Unknown statusSleep Apnea
Inflammation
Atherosclerosis		Interventional
(apnea hypopnea index ≥ 15 per hour)		60Plasma exosome evaluation
25NCT03275363Unknown statusNeurocognitive Disorder
Mild Cognitive Impairment
Alzheimer Dementia
Vascular Dementia
Age-related Cognitive Decline		Observational500Blood microvesicles and exosome analysis
26NCT04266639CompletedStroke,
Acute Ischemic Stroke
Cerebrovascular Disorders
Central Nervous System Diseases		Interventional
(Remote ischemic conditioning)		45Characterization of EVs surface markers and content after treatment
27NCT05624203Not yet recruitingMyocardial Reperfusion Injury
Treatment Outcome
Prognosis
ST Elevation Myocardial Infarction		Interventional
(Exercise training)		100Blood microvesicles analysis
28NCT04250493RecruitingMultiple System AtrophyInterventional
(HOMA)		124Evaluation of neural-derived plasma exosomes after HOMA
Abbreviations: ATAAD: Acute type A aortic dissection; AF: Atrial Fibrillation; CCU: Chronic skin ulcers; DASH: Dietary approaches to stop hypertension diet; DR: Diabetic retinopathy; EVs: Extracellular vesicles; HF: Heart Failure; HFpEF: Heart failure with preserved ejection fraction; HOMA: Homeostasis model assessment of insulin resistance fasting; MI: Myocardial infarction; MODS: Multiple organ dysfunction syndrome; MSC: Mesenchymal Stromal Cells; NCT: National Clinical Trial.
Table
Table 2. Clinical studies of EV evaluation as diagnostic biomarkers for cancer treatment.
Table 2. Clinical studies of EV evaluation as diagnostic biomarkers for cancer treatment.
NumberNCT NumberStatusConditionsStudy TypePopulation (Participants Number)Outcome
1NCT02702856CompletedProstate CancerObservational
Multi center		2000Validation of the association between exosome urine gene signature with high Gleason grade/score (GS ≥ 7)
2NCT04529915Active, not recruitingLung CancerObservational
Multi center		470Analysis of blood exosomes signature as an early marker of lung cancer
3NCT04394572CompletedColorectal CancerObservational80Quantification of serum exosomes using specific exosomes markers as CD63 and CD81
4NCT04939324RecruitingLung Cancer
NSCL Cancer		Interventional
exosome will be collected from tumor drain vein during surgery		30Analysis of molecular profiling of exosome with a sample in tumor-draining vein in order to identify prognostic molecular characteristics associated with cancer recurrence after surgery
5NCT02393703RecruitingPancreatic Cancer Benign Pancreatic DiseaseObservational
diagnostic		111Differential gene expression in exosomes from cancer and healthy subjects to connect disease recurrence and outcomes with peculiar gene expression
6NCT01294072RecruitingColon CancerInterventional
Curcumin delivery		35Curcumin delivery by using plant exosomes to target the drug to colon tumors and normal colon tissue
7NCT01159288CompletedNSCL CancerInterventional
cyclophosphamide (mCTX) followed by vaccinations with tumor antigen-loaded dendritic cell-derived exosomes (Dex).		41Evaluation of tumor antigen-loaded in dendritic cell-derived exosomes
8NCT01668849CompletedHead and Neck Cancer
Oral Mucositis		Interventional
Chemoradiation Lortab, Fentanyl patch.		60Investigate the ability of plant (grape) exosomes to prevent oral mucositis associated with chemoradiation
9NCT04288141RecruitingHER2-positive Breast CancerObservational
diagnostic		40Evaluation of peripheral blood exosomes containing HER2 and HER3 dimers to predict tumor positivity
10NCT05587114RecruitingLung CancerObservational
diagnostic		150Exosome markers derived from peripheral blood and pulmonary venous blood from patients who underwent lung cancer surgery as early tumor markers
11NCT03608631RecruitingMetastatic Pancreatic Adenocarcinoma
Pancreatic Ductal Adenocarcinoma		Interventional Drug: Mesenchymal Stromal Cells-derived Exosomes with KRAS G12D siRNA28Evaluation of Exosomes with KRAS G12D siRNA in blood
12NCT04653740RecruitingAdvanced Breast CancerInterventional
changes in the profile of tumor, associated with resistance to palbociclib at the individual level 		25Exosome characterization associated with palbociclib resistance
13NCT03830619CompletedLung CancerObservational
diagnostic		1000Serum exosomal lncRNAs characterization
14NCT04155359RecruitingBladder CancerObservational
diagnostic		3000Evaluation of urine exosomes miR Sentinel™ BCa Test, a urine exosome-based diagnostic test, as an aid in diagnosing bladder cancer
15NCT05427227RecruitingAdvanced or Late Stage Gastrointestinal CancerObservational
diagnostic		500Plasma derived exosomes to explore the efficacy and mechanism of anti-HER2, immunotherapy and anti-CLDN18.2 of gastrointestinal cancer
16NCT04167722RecruitingProstate CancerObservational
Robotic Radical Prostatectomy		100Evaluation of exosomal small RNAs
in lean vs. obese patients
(array)
17NCT04258735RecruitingMetastatic Breast CancerInterventional
First line of treatment		300Peripheral blood exosome nucleic acid content evaluation after first line of treatment
18NCT03109873CompletedLarynx, Lip, Oral Cavity, Pharynx CancerInterventional
Drug: Metformin Hydrochloride		9Characterization of exosome profile
19NCT04629079RecruitingLung CancerObservational
Diagnostic		800Characterization of exosomal pre-microRNA early detection in hypoxia tumor
20NCT04556916RecruitingProstate CancerObservational
Diagnostic		320Molecular characterization of circulating blood exosomes as diagnostic markers
21NCT03895216CompletedBone MetastasesObservational
Diagnostic		34Evaluation of miRNA content of circulating tumor exosomes after surgery of bone metastasis
22NCT02147418RecruitingOropharyngeal CancerObservational
Case control		30Exosome testing as a screening modality for human papillomavirus-positive oropharyngeal squamous cell carcinoma
23NCT04530890RecruitingBreast Cancer Digestive Cancer Gynecologic Cancer Interventional
Diagnostic		1000Evaluation of the exosomes diagnostic value
24NCT03032913CompletedPDACObservational
Diagnostic		52Evaluation of onco-exosome quantification in the diagnosis of pancreatic cancer
25NCT03488134Active, not recruitingThyroid CancerObservational
Diagnostic		74Predicting prognosis and recurrence of thyroid cancer via new biomarkers, urinary exosomal Thyroglobulin and Galectin-3
26NCT04453046TerminatedSquamous Cell Carcinoma of the Head and NeckInterventional
Drug: Hemopurifier,
Pembrolizumab		2Kinetics of exosome depletion and reactivation in individual patient during the treatment
27NCT02662621CompletedCancerInterventional hormone therapy71Evaluation of HSP70-exosomes in blood and urine prognostic marker
28NCT05424029RecruitingNSCL CancerObservational
Diagnostic		200Extracellular vesicles and particles (EVP) number as biomarkers of recurrence in non-small cell lung cancer
29NCT04960956TerminatedProstate Cancer
Urothelial Carcinoma		Observational
Diagnostic		13Evaluation of urine glycosylate exosomes
30NCT04781062Active, not recruitingBreast CancerInterventional367MiRNA exosome sequencing
As signature of early diagnosis
31NCT04100811RecruitingProstate CancerObservational
Diagnostic		4000SncRNAs urine exosome validation platform
32NCT04720599CompletedUrologic CancerObservational
Diagnostic		120ExoDx Prostate (IntelliScore) in men presenting for initial prostate biopsy
33NCT03811600CompletedSleep Apnea Syndromes
Obstructive Cancer		Observational
Diagnostic		90Evaluation of exosomal PD-1/PD-L1 expression
34NCT03432806RecruitingColon Cancer
Liver Tumors		Observational
Diagnostic		80Characterization of exosomal proteins
as biomarkers to monitor the liver pre-metastatic niche
35NCT04357717TerminatedProstate CancerObservational
Diagnostic early marker		150Clinical performance of the ExoDx prostate cancer
36NCT05559177RecruitingChimeric exosomal tumor vaccinesInterventional
Chimeric exosomal tumor vaccines		9Dose evaluation of chimeric exosome vaccine
37NCT04852653RecruitingRectal Cancer, Liquid BiopsyObservational40Evaluating extracellular vesicles obtained via liquid biopsy for neoadjuvant treatment response assessment in rectal cancer (RECC-EV)
38NCT02977468RecruitingTriple Negative Breast CancerInterventional
Drug: Pembrolizumab		15Evaluation of serum exosomes as marker in response to therapy
39NCT03824275Active, not recruitingProstatic NeoplasmsInterventional
Drug: 18F-DCFPyL PET/CT		129Characterization of circulating exosomes
40NCT03911999CompletedProstate CancerObservational180Identification of potential exosomal microRNAs in urine as marker of diagnosis
41NCT05572099RecruitingProstate CancerObservational750Evaluation of the ExoDx prostate test
42NCT03711890RecruitingPancreatic Carcinoma Pancreatic Intraductal Papillary Mucinous NeoplasmInterventional
procedure: Optical Coherence Tomography		75Evaluation of blood cancer-derived exosomes
43NCT03031418CompletedCancer of ProstateObservational
Validation diagnostic tool		532Clinical Evaluation of the ‘ExoDx Prostate IntelliScore’
44NCT03317080Active, not recruitingLung CancerObservational
Early diagnosis		400Clinical evaluation of tumor exosome liquid biopsy
45NCT05397548RecruitingGastric CancerObservational
Early diagnosis		700Evaluation of predictive value of circulating exosomal lncRNA-GC1
46NCT02862470CompletedThyroid CancerObservational
Early diagnosis		22Evaluation of urine exosomes as biological markers
47NCT03791073RecruitingOncologyObservational200Evaluation of interstitial tissue fluid as source of exosomes
48NCT03235687Active, not recruitingCancer of the ProstateInterventional
Surgery		1000Evaluation of the ExoDx Prostate (IntelliScore)
49NCT02063464CompletedOvarian Cancer
Cancer of the Ovary
Ovarian Neoplasms		Observational85Evaluation of blood exosomes as prognostic and outcome
50NCT05375604RecruitingAdvanced HCC
Gastric Cancer Metastatic to Liver
Colorectal Cancer Metastatic to Liver		Interventional
Drug: CDK-004		30Evaluation of CDK-004 as marker of cell-derived exosomes efficiency
51NCT05101655CompletedOsteosarcoma
Pulmonary Metastases		Observational
Diagnosis		60Development of microfluidic chip technology to capture exosome subgroups
52NCT03108677Active, not recruitingLung Metastases OsteosarcomaObservational
Diagnosis		90Identification of RNA profile from circulating exosomes
53NCT02439008TerminatedCarcinoma
Hepatocellular
Colorectal Neoplasms
Melanoma
Kidney Neoplasms		Interventional
Radiotherapy		28Quantification of secreted exosomes
before and after radiotherapy
54NCT05334849CompletedAdvanced Gastric
Carcinoma
Immunotherapy		Observational80Identification of identified circulating exosomal lncRNA-GC1 as marker of efficacy of immunotherapy
55NCT03250078RecruitingPancreatic NeoplasmsObservational100Evaluation of serum exosomes carrying gene mutation associate with high risk of hereditary gastric cancer
56NCT03109847CompletedThyroid CancerInterventional
Drug: Metformin Hydrochloride
Radioactive iodine		13Characterization of serum and salivary exosome profile
57NCT02921854CompletedNSCL CancerInterventional
Immunotherapy		60Detection of circulating markers of immunogenic cell death
58NCT05192694RecruitingProstate CancerInterventional
Procedure: Tomography		40Extracellular vesicles (exosomes) isolated and markers of reactive stroma
59NCT02507583CompletedMalignant Glioma
Neoplasms		Interventional
Drug: Exosomal IGF-1R/AS		33Evaluation of blood IGF-1R/AS
as dose escalation
60NCT04948437RecruitingSarcomaObservational
Diagnosis		103Urinary exosomal thyroglobulin, galectin-3, calprotectin A9, transketolase, keratin 19, angiopoietin-1, tissue inhibitor of metalloproteinas, keratin 8, calprotectin A8, annexin II.
61NCT03800121RecruitingGlioblastoma MultiformeObservational
Diagnosis		30Evaluation of blood exosomes
62NCT02071719TerminatedRenal Cell CancerObservational6Evaluation of serum and urine exosomes
63NCT01550523CompletedMalignant Glioma of BrainInterventional
Drug: exosomal IGF-1R/AS ODN		13Evaluation of exosomal IGF-1R/AS ODN-induced tumor cell
64NCT02892734TerminatedHER2/Neu Negative, Recurrent Inflammatory Breast Carcinoma
Breast Cancer
Breast Carcinoma		Interventional
Drug: Ipililumab
Nivolumab		3Evaluation of blood exosomes as response to therapy
65NCT04053855RecruitingClear Cell Renal Cell CarcinomaObservational
Diagnosis		100Evaluation of urinary exosomes
66NCT05705583RecruitingRenal Cell CarcinomaObservational100Evaluation of circulating exosomes blood and urine as marker of response to immunotherapy
67NCT02928432CompletedProstate CancerInterventional
Drug: Rednisone to dexamethasone change in mCRPC patients treated with abiraterone		26Evaluation of blood exosomes
as marker of therapy switch
68NCT04499794RecruitingUntreated Advanced NSCL cancer Patients
FISH Identified ALK Fusion Positive or Negative		Interventional
Drug: ULK inhibitor		75Study of exosomal EML4-ALK fusion
69NCT03228277CompletedNSCL CancerInterventional
Drug: Olmutinib		25Evaluation of DNA T790M mutation from bronchoalveolar lavage fluid EVs
70NCT03334708RecruitingPancreatic Cancer, Pancreatic Diseases, Pancreatitis, Pancreatic CystObservational
Diagnosis		700Evaluation of blood exosome profile
71NCT03985696RecruitingLymphoma, B-cell, Aggressive Non-Hodgkin (B-NHL)Interventional
Drug: anti-CD20 and Nivolumab 		90Evaluation of exosomal CD20 and PD-L1 exosomes and resistance to immunotherapy
72NCT04340245Active, not recruitingProstate CancerObservational
Diagnosis		60Evaluation of blood and urine exosomes to discriminate progressors from non-progressors
73NCT05575622RecruitingHepatocellular CarcinomaObservational
Diagnosis		200Clinical analysis of CTC and exosome combination and efficacy of immunotherapy in patients with hepatocellular carcinoma
74NCT03854032Active, not recruitingLip, Oral Cavity Squamous Cell Carcinoma, Pharynx, Larynx, Squamous Cell CarcinomaInterventional
Drug: Nivolumab		45Evaluation of blood exosome abundance and composition and treating patients with stage II-IV squamous cell cancer
75NCT03236675Active, not recruitingCarcinoma, Non-Small-Cell LungObservational
Diagnosis		60Evaluation of exosomal EML4-ALK fusion transcripts and T790M EGFR mutation
76NCT01629498RecruitingRecurrent Lung Non-Small Cell CarcinomaInterventional
Image-Guided		100Evaluation of blood exosomes and treatment of regionally metastatic head and neck squamous cell cancer
77NCT05110781RecruitingCutaneous Squamous Cell Carcinoma of the Head and NeckInterventional
Drug: Atezolizumab		18Evaluation of plasma exosomal levels
78NCT05441189CompletedStage I–II PDACObservational
Diagnosis		70Evaluation of specific exosome signature
and gene signature for predicting
79NCT05166616RecruitingAdvanced NSCL CarcinomaInterventional
Drug: Minnelide and Osimertinib		30Evaluation of exosomal pattern
and treatment of advanced EGFR mutated non-small cell lung cancer
80NCT03096340TerminatedCancerObservational
Drug: IT-141		10Evaluation of exosomes presence
and monotherapy in patients with advanced cancer
81NCT00578240Active, not recruitingProstate CancerObservational
Diagnosis		5290Evaluation of exosome presence into peripheral blood, bone marrow, urine and other bodily fluids
82NCT02051101CompletedPort-Wine StainInterventional19Characterization of exosome profile and pathogenic mechanisms of port wine stain
83NCT02535247TerminatedLymphoma
T-Cell, Peripheral		Interventional
Drug: MK-3475		17Circulating exosome analysis and study of MK-3475 R/R NK and T-cell non-Hodgkin Lymphoma
84NCT03410030CompletedPancreatic Adenocarcinoma Resectable and MetastasesInterventional
Drug: AA NABPLAGEM		27Evaluation of potential exosome pattern as biomarker and AA NABPLAGEM
85NCT03083678Active, not recruitingChordomaInterventional
Drug: Afatinib		43Evaluation of circulating exosomes
and Afatinib in locally advanced and metastatic chordoma
86NCT03217266Active, not recruitingSoft Tissue SarcomaInterventional
Drug: Navtemadlin		46Evaluation of tumor genetic mutations in deoxyribonucleic acid ribonucleic acid isolated from exosomes and Navtemadlin and radiation therapy in treating patients with soft tissue sarcoma
87NCT03537599CompletedRecurrent Acute Myeloid Leukemia with MyelodysplasiaInterventional
Drug: Daratumumab		4Evaluation of exosome pattern and Daratumumab and donor lymphocyte infusion in treating participants with relapsed acute myeloid leukemia after stem cell transplant
88NCT04483219RecruitingMetastatic Colorectal AdenocarcinomaInterventional
Drug: Tyrosine Kinase Inhibitor (TKI) + Anti-PD-1 Antibody		53Evaluation of circulating exosome pattern in metastatic colorectal adenocarcinoma
Abbreviations: NSCL: Non-Small Cell Lung; lncRNAs: long noncoding RNAs; sncRNAs: small noncoding RNAs; HCC: Hepatocellular Carcinoma; PDAC: pancreatic ductal adenocarcinoma; miRNA: micro RNA; NCT: National Clinical Trial.
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MDPI and ACS Style

Schiano, C.; Balbi, C.; de Nigris, F.; Napoli, C. Basic Pathogenic Mechanisms and Epigenetic Players Promoted by Extracellular Vesicles in Vascular Damage. Int. J. Mol. Sci. 2023, 24, 7509. https://doi.org/10.3390/ijms24087509

AMA Style

Schiano C, Balbi C, de Nigris F, Napoli C. Basic Pathogenic Mechanisms and Epigenetic Players Promoted by Extracellular Vesicles in Vascular Damage. International Journal of Molecular Sciences. 2023; 24(8):7509. https://doi.org/10.3390/ijms24087509

Chicago/Turabian Style

Schiano, Concetta, Carolina Balbi, Filomena de Nigris, and Claudio Napoli. 2023. "Basic Pathogenic Mechanisms and Epigenetic Players Promoted by Extracellular Vesicles in Vascular Damage" International Journal of Molecular Sciences 24, no. 8: 7509. https://doi.org/10.3390/ijms24087509

APA Style

Schiano, C., Balbi, C., de Nigris, F., & Napoli, C. (2023). Basic Pathogenic Mechanisms and Epigenetic Players Promoted by Extracellular Vesicles in Vascular Damage. International Journal of Molecular Sciences, 24(8), 7509. https://doi.org/10.3390/ijms24087509

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