Abstract
Current research has demonstrated that extracellular vesicles (EVs) and circulating tumor cells (CTCs) are very closely related in the process of distant tumor metastasis. Primary tumors are shed and released into the bloodstream to form CTCs that are referred to as seeds to colonize and grow in soil-like distant target organs, while EVs of tumor and nontumor origin act as fertilizers in the process of tumor metastasis. There is no previous text that provides a comprehensive review of the role of EVs on CTCs during tumor metastasis. In this paper, we reviewed the mechanisms of EVs on CTCs during tumor metastasis, including the ability of EVs to enhance the shedding of CTCs, protect CTCs in circulation and determine the direction of CTC metastasis, thus affecting the distant metastasis of tumors.
Similar content being viewed by others
Introduction
Liquid biopsy is an emerging tumor diagnostic technique for tumor detection and monitoring that detects tumor-associated molecular markers in specimens by collecting body fluid samples for mainly analysis of circulating tumor DNA (ctDNA), CTCs and EVs [1, 2]. Among several markers of liquid biopsy, CTCs and EVs have good stability and detection sensitivity that can reflect the aggressiveness, metastatic potential, and prognosis of tumor cells [3,4,5,6]. In recent advances in liquid biopsy, EVs and CTCs have been commonly used as markers for liquid biopsies in tumor diagnosis [7], surveillance [8], prognosis [9], tumor classification and subtype discrimination [10]. CTC mRNA profiles are diverse and common, reflecting spatial tumor heterogeneity, and EV signals fluctuate greatly during treatment, thus reflecting temporal heterogeneity [11].
EVs are a general term for particles that are naturally released by cells [12]. EVs are secreted via the endosomal pathway. First, the cell membrane is recessed inward to form early sorting endosomes. Then, late sorting endosomes are formed, and intraluminal vesicles (ILVs) are produced, further forming multivesicular vesicles (MVBs), which are partly degraded by lysosomes and partly released extracellularly to form EVs [13, 14]. According to the biogenesis pathway, EVs can be broadly classified into three categories: exosomes, microvesicles, and apoptotic bodies [15], which in this review we collectively refer to as EVs. In terms of structure, EVs contain proteins, nucleic acids and lipids (Fig. 1), which play an important role in tumor formation, metastasis, and invasion [1, 14, 16,17,18]. Tumor-derived EVs in the blood are mainly secreted from primary tumor cells or released from burst CTCs [19]. Nontumor-derived EVs mainly refer to EVs from immune cells, platelets, and stem cells [20]. Here, we summarize tumor- and nontumor-derived EV cargoes that influence tumor progression (Table 1).
CTCs are tumor cells that are shed from the primary tumor and enter the hematologic system with the potential to seed secondary tumors at newly metastatic sites [70]. CTC morphology may be different depending on the type, stage, and status of the tumor [71, 72]. CTCs can be released as a single cell or in homotypic or heterotypic clusters [73] (Fig. 2). Cluster formation is produced in part by contact between a cell‒cell ligand‒protein or cytokine receptor and another cell [74]. An aggregate of more than one cancer cell is a homotypic CTC cluster; in combination with other cell types, such as immune cells or stromal cells, are heterotypic CTC clusters [75]. Compared to the single cells present in the circulation, these CTC clusters have an intercellular adhesion component that can promote tumor metastasis [76]. Data obtained from mouse models indicate that CTC clusters have a higher propensity to metastasize than CTCs [76]. With tumor growth, cancer cells, as single CTCs or CTC clusters, tend to break through the extracellular matrix (ECM) and infiltrate the circulation or transform into EpCAM CTCs, thereby reducing cell adhesion and promoting polarization and metastasis [77].
Tumor metastasis is important for disease progression and prognosis. The metastasis of tumors through circulation includes several stages: invasion, intravasation, intravascular survival, extravasation, and secondary site colonization (Fig. 2). Studies [78,79,80] suggest that EVs protect CTCs during tumor metastasis. CTCs can be considered as seeds and the cargoes carried by EVs as fertilizer, where EVs can affect CTC colonization and growth in soil-like distant target organs. In other words, CTCs are a form of tumor cell presence that can reach distant organs and colonize through circulation, while various cellular sources of EVs can carry related molecules such as nucleic acids and proteins [81] that influence cell behavior and promote CTC-mediated metastasis.
This review summarizes the multiple mechanisms by which EVs regulate CTC-mediated distant tumor metastasis to better inform the early diagnosis, treatment, and prognosis of cancer.
EVs enhance the shedding ability of CTCs
EVs promote epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) remodeling
During the invasion phase, EMT leads to a decrease in tumor cell adhesion and can improve migration and invasion [82], facilitating tumor shedding to form CTCs. EVs play a vital role in EMT [83] and can regulate EMT through a variety of mechanisms. Specifically, EVs can promote EMT by carrying pro-EMT signaling factors, regulating key genes in the EMT pathway, activating the Wnt pathway and PTEN pathway, and promoting macrophage M2 polarization to enhance the shedding ability of CTCs (Table 2).
EVs can carry many EMT-promoting factors, such as transforming growth factor-beta (TGF-β), which can activate the EMT pathway directly or indirectly [84, 85]. Moreover, EVs are rich in miRNAs that can regulate key genes in the EMT pathway through the downregulation of E-cadherin and upregulation of N-cadherin, thereby promoting EMT [86, 87]. Additionally, Fang et al. [88] reported that the long noncoding RNA (lncRNA) PCAT1 derived from colorectal cancer (CRC) EVs was found to regulate the activity of the Netrin-1-CD146 complex in CTCs, promoting EMT and liver metastasis in CRC. The Wnt pathway plays an important role in tumorigenesis and progression and can promote tumor progression through the activation of EMT [89]. Accumulating evidence [90] demonstrates that EVs are involved in the transfer of functional proteins and noncoding RNAs that trigger Wnt/β-catenin signaling to promote EMT. A more detailed study [91] has shown that EVs may also promote intercellular signaling of the Wnt pathway to prolong EMT in the tumor microenvironment (TME) [92]. PTEN overexpression promotes apoptosis and inhibits cell migration and invasion [93], and EVs can carry miRNAs to regulate EMT by affecting the PI3K/Akt and PTEN signaling pathways to promote CTC shedding [93, 94]. In addition to the mechanisms mentioned above, EVs can also promote EMT by promoting macrophage polarization to the M2 phenotype [95]. For example, according to a study [28], tumor-derived EV PKM2 induces M2 macrophage polarization via the AMPK pathway, leading to a decrease in E-cadherin and enhancement of N-cadherin and vimentin, thereby enhancing EMT in lung cancer. In another study [96], glioma cells selectively released tumor suppressive miR-3591-3p through EVs by targeting CBLB and activating the JAK2/PI3K/Akt/mTOR and STAT3 pathways to promote macrophage M2 polarization, and macrophages treated with miR-3591-3p mimics were enriched in TGFβ receptor signaling in EMT.
The TME includes immune cells, such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), tumor-associated macrophages (TAMs), dendritic cells, and B cells, as well as nonimmune cells and ECM, which play an important role in tumor recurrence and metastasis [97]. The ECM consists of proteins and carbohydrates that support basic cellular life activities, and diseases involving tumor invasion are attributed to the shift from homeostasis to remodeling of the ECM [98]. ECM is a prerequisite for tumor cell invasion and metastasis [99]. Within the hypoxic TME, EV levels increase and can mediate intercellular signaling [100,101,102,103,104]. EVs could enhance the remodeling of ECM and promote the invasion of tumor cells into the stroma, thereby promoting the detachment of CTCs from the primary site.
EVs can promote ECM remodeling directly by carrying ECM remodeling-related enzymes or indirectly by regulating stromal cells (Table 2). A study [105] has shown that matrix metalloproteinases (MMPs) in EVs can degrade ECM proteins, leading to remodeling of the ECM. Fibroblasts are a major component of the tumor stroma and have been shown to play an important role in tumor progression [106]. EVs can trigger fibroblast differentiation into cancer-associated fibroblasts (CAFs) [107,108,109,110], thereby remodeling the ECM and facilitating the spread of tumor cells [99, 111, 112]. Mesenchymal stem cells (MSCs) are also important tumor stromal cells, and tumor cell-derived EVs activate pro-oncogenic pathways in MSCs and promote their conversion to CAFs [26], which is also beneficial for promoting ECM remodeling and thus facilitating CTC shedding.
EVs promote angiogenesis and increase vascular permeability
Tumor-derived EVs can promote angiogenesis directly or indirectly by stimulating macrophages to release proangiogenic factors [113], which play an important role in the formation of CTCs from primary tumor shedding (Table 2). In recent research [114], EV lncRNA ATB derived from ovarian cancer cells was shown to promote angiogenesis by regulating the miR-204-3p/TGFβR2 axis. A study [115] reported that hypoxic pancreatic ductal adenocarcinoma cell-derived EV miR-30b-5p promotes angiogenesis by inhibiting GJA1. Another study [116] found that EVs secreted by cervical cancer cells can deliver miR-663b to human umbilical vein endothelial cells (HUVECs) and inhibit the expression of adhesion protein (vinculin), thereby promoting angiogenesis and tumor growth. A previous study [117] found that EV miR-221-3p secreted by cervical cancer cells promotes angiogenesis by downregulating MAPK10 expression. EVs can also indirectly induce angiogenesis by stimulating VEGF release from macrophages. For example, lung cancer cell-derived EV miR-103a confers immunosuppressive and tumor-promoting phenotypes on macrophages, causing them to express high levels of the proangiogenic factors VEGF and angiopoietin-1, thereby promoting angiogenesis [118]. Recent studies have shown that tumor angiogenesis can be mediated not only by tumor cells but also by tumor stromal cells. For instance, Shi et al. [119] found that CAF-derived EVs can regulate CRC angiogenesis and progression by delivering VEGFA. CAF-derived EVs also upregulate miR-135b-5p, which promotes CRC cell growth and angiogenesis by inhibiting thioredoxin-interacting protein (TXNIP) [120].
Through endo-vascular penetration, tumor cells can be shed and enter circulation as CTCs [121]. Vascular barrier disruption is a critical step in CTC-mediated metastasis, which requires disruption of vascular tight junctions [122], and disruption of vascular endothelial cell integrity as well as consequent vascular permeability promotes subsequent metastasis of tumor cells [123], including the process of CTC extravasation [124]. Tumor-derived EVs can facilitate the production and metastasis of CTCs by transferring contents to endothelial cells to enhance vascular permeability (Table 2). Mechanistically, EVs can be delivered into endothelial cells and then attenuate endothelial junction integrity by directly inhibiting the expression of vascular endothelial cadherin (VE-Cad), p120-catenin (p120) and zonula occludens-1 (ZO-1), which increase vascular permeability and promote tumor metastasis [125]. EV of EMT-CRC cell origin, miR-27b-3p, is transferred to endothelial cells and enhances vascular permeability by targeting VE-Cad and p120, which promote the production of CTCs [123]. A study [126] found that gastric cancer-derived EVs X26nt increase vascular permeability by directly binding VE-Cad in HUVECs. Researchers [127] found that breast cancer (BC)-derived EV miR-939-5p metastasizes from tumor cells to endothelial cells and directly targets VE-Cad, leading to disruption of tight junctions, thereby facilitating tumor cell entry into blood vessels to form CTCs by disrupting endothelial junctional integrity. In addition, EV miRNAs can target the tightly linked component protein ZO-1 [128]. A recent study [129] found that nasopharyngeal carcinoma-derived EV miR-455 increases vascular permeability by targeting ZO-1. Liu et al. [130] revealed that triple-negative breast cancer (TNBC)-derived EVs could transfer EphA2 protein to endothelial cells to enhance vascular permeability by downregulating ZO-1 and activating the RhoA pathway in endothelial cells, thus promoting tumor cell metastasis. In addition, EV-mediated miR-182-5p inhibits the tight junction-associated protein ZO-1, thereby enhancing vascular permeability and transendothelial migration of tumors [131]. A research project [132] reported that EV miR-25-3p in CRC promotes vascular permeability and tumor metastasis by targeting the ZO-1 protein. Hsu et al. indicated that hypoxic lung tumor cell-derived EV miR-23a upregulates the inhibition of the tight junction protein ZO-1 to increase vascular permeability [133], which suggests a potential association between EVs and CTCs. Moreover, a previous study [134] showed that EV-associated miR-105 in BC disrupts tight junctions by directly targeting the protein ZO-1. On the other hand, EV miR-375-3p could also promote small cell lung cancer metastasis by directly binding to the 3’UTR of the tight junction protein claudin-1 in vascular endothelial cells and negatively regulating its expression to disrupt the tight junctions in vascular endothelial cells [135]. Research [136] has shown that NSCLC-derived EV miR-3157-3p can translocate into vascular endothelial cells to target TIMP2/KLF2, promote angiogenesis and increase vascular permeability, thereby promoting tumor metastasis.
In addition to promoting angiogenesis, EVs can also promote tumor metastasis by promoting lymphangiogenesis. EVs circ_0026611 inhibit PROX1 acetylation and ubiquitination to promote lymphangiogenesis in esophageal squamous carcinoma [137]. EVs derived from gastric cancer cells deliver miR-1246 to lymphatic endothelial cells and promote lymphangiogenesis and lymphatic remodeling [138].
EVs promote tumor metastasis by protecting CTCs
EVs activate platelets to protect CTCs
It has been shown that platelets can interact with tumor cells and influence tumor metastasis [141,142,143]. One mechanism is that tumor-derived EVs activate platelets to form tumor cell-induced platelet aggregates (TCIPA), and CTCs can become entangled in the thrombus formed by aggregated platelets [144], thus protecting CTCs from the deleterious effects of shear and giving them the advantage of evading immune surveillance by forming a physical barrier around them [145,146,147,148].
Specifically, tumor-derived EVs can directly activate platelets, thereby promoting thrombosis. Tumor cells express a procoagulant protein, tissue factor (TF), which can be released as TF-positive EVs [149, 150]. Previous studies [151, 152] have shown that TF on the surface of tumor-derived EVs is associated with platelet-activated aggregation and thrombosis and that EV-activated platelets can also be driven by TF-independent pathways, illustrating the complexity of the mechanism of tumor EV-induced platelet activation. For example, studies [152] have reported that BC-derived EVs induce platelet activation and aggregation through both independent and dependent mechanisms of TF, which may lead to cancer-associated thrombosis. Moreover, recent studies [153] have found that tumor-derived EVs deliver cancer markers in a CD63-dependent manner to activate platelets and promote thrombosis (Fig. 2). Activated platelets form cell-fibrin-platelet aggregates around CTCs or stagnant tumor cells, providing mechanical protection and transferring MHC class I proteins to CTCs, interfering with the recognition of cancer cells by NK cells [154]. We predict that EVs may function in the activation of platelets to protect CTCs. Furthermore, recent study [155] showed that CTCs can uptake platelets, thus mediating immune escape, and more research is needed to explore whether this is also related to EVs.
Tumor-derived EVs not only protect CTCs by activating platelets to promote thrombosis but also enhance the adhesion of CTCs and promote metastasis. In a study [156], it was observed that EVs of hepatocellular carcinoma (HCC) origin induced ROS in HCC cells through SMAD3 signaling and regulated CTC adhesion, thereby promoting metastasis. In addition, during platelet activation or apoptosis, platelet extracellular vesicles can form [157], and they are associated with tumor progression [158]. Research [159] suggests that platelet-derived microparticles promote tumor cell invasiveness by stimulating the synthesis and secretion of MMP-2. Another study [160] showed that the characterization of the expression of promalignant genes and prothrombotic phenotypes in cancer cells by the crosstalk with platelet mEVs could provide prognostic information on cancer.
EVs induce immunosuppression to protect CTCs from attack
While immune cells can recognize and attack CTCs under normal conditions, EVs can carry molecules that interact with circulating immune cells (T cells, NK cells, and B cells) to keep CTCs from attacking. Specifically, tumor-derived EVs carry immunosuppressive cargo, deliver molecular signals to immune cells, and participate in various immunosuppressive or immunostimulatory signaling pathways [161].
In particular, EVs mediate the immune escape of tumor cells by expressing programmed death ligand 1 (PD-L1) in the circulation [162]. PD-L1 is a type I transmembrane protein that binds to its receptor PD-1 to inhibit T-cell activation and thus maintain immune homeostasis [163]. PD-L1 can be expressed on tumor-derived EVs and induce immunosuppression by binding to PD-1 on T cells [164,165,166], and PD-L1 on EVs is significantly upregulated in patients with distant tumor metastasis [167, 168], which indicates that EVs may potentially mediate the immune escape of CTCs. Based on this principle, anti-PD-1/PD-L1 immune checkpoint therapies have recently blocked PD-1/PD-L1 binding, allowing T cells to work and inhibiting tumor growth [163]. Referring to some existing studies [169, 170], we consider that targeting the secretion of EVs may be a way to counteract EVs. In addition, research has found that PD-L1 can also be detected on the surface of CTCs in many cancer types [171]. Moreover, EVs with FasL expression are able to cause apoptosis of antitumor CD8+ T cells [172], probably due to the interaction between MHC class I of EVs and CD8+ receptors of T cells, which leads to apoptosis of T cells by activating the Fas/FasL signaling pathway [161, 173], thereby producing an immunosuppressive effect.
NK cells are a subset of lymphocytes that can participate in antitumor immune responses [174]. In terms of EVs helping CTCs evade immune surveillance, NKG2D plays an important role in the cytotoxicity of NK cells [175], and EVs expressing ligands of NKG2D lead to impaired toxic function of NK cells [176], which may also mediate immune escape of CTCs. The BCR pathway controls B-cell survival, proliferation and activation and is a key player in the B-cell signaling mechanism [177]. A recent study [178] suggests that EVs may inhibit B-cell proliferation and survival through the expression levels of coreceptors involved in the negative regulation of BCR signaling.
EVs determine the direction of metastasis and colonization of CTCs
During the whole transfer process, each type of cancer has a specific metastatic pathway, and cancer metastasis usually follows the target distribution of CTCs to preferred organs, which is called “organotropism” or “organ-specific metastasis“ [179]. EVs can provide metastatic organotropism, meaning that EVs can help determine the direction of CTC metastasis and promote CTC distant metastasis and colonization by participating in the formation of a pre-metastatic niche (PMN).
Tumor-derived EV integrins determine organotropism
The amount of specific integrins in EVs seems to be responsible for the increased expression of the S100 gene in target cells and ultimately for the effect on organs [121]. Hoshino et al. [180] showed that EV proteomics reveals different integrin expression patterns and fusion to target cells in a tissue-specific manner to direct organ-specific colonization with EV integrins α6β4 and α6β1 associated with lung metastasis and EV integrin αvβ5 associated with liver metastasis. EVs expressing integrins α6β1 and α6β4 are directed to lung epithelial cells and lung fibroblasts, and integrin α6β4 also promotes lung metastasis by promoting S100 gene expression and the Src signaling pathway; EVs expressing integrin αvβ5 promote liver metastasis by binding to resident macrophages (Kupffer cells) in the liver and upregulating cell migration genes and S100 production genes [180, 181]. In addition, Huang et al. [182] found that EVs with low levels of miR-34c-3p can accelerate non-small cell lung cancer (NSCLC) invasion and migration by upregulating integrin α2β1. In a further study [183], tumor-derived αvβ3 integrin was associated with prostate cancer bone metastasis. Moreover, αv integrins are highly expressed in brain metastases [184, 185], where αvβ3, αvβ5 and αvβ6 integrins are associated with lung cancer brain metastases [186] (Fig. 2).
EVs are involved in the formation of the pre-metastatic niche (PMN)
The primary tumor establishes a microenvironment conducive to tumor growth through tumor-derived factors before CTCs reach the predetermined secondary sites of metastatic disease, referred to as the PMN [187, 188]. The marker of PMN formation is the recruitment of immune cells to establish an immunosuppressive microenvironment [189].
Tumor-derived EVs induce the recruitment of suppressive immune cells such as TAMs, tumor-associated neutrophils, Tregs, and MDSCs to distant secondary sites, thereby suppressing the antitumor immune response [190], promoting PMN formation and facilitating the colonization of CTCs. Tregs are the primary immunosuppressive cells in tumor immunity. They efficiently infiltrate and adapt to the TME and suppress antitumor immune responses, and inhibition of Treg infiltration in the TME increases tumor immune responses [191]. A study [192] found that tumor-derived EVs play a key role in the induction of Treg infiltration into pulmonary PMN by upregulating fibroblast-derived CCL1 production. Recently, a study [193] also revealed a novel mechanism of LC3-EV-enhanced lung PMN formation.
EVs can also participate in PMN formation by carrying loadings that affect the phenotype or function of the recipient cells. Specifically, tumor-derived EVs produced in the hypoxic microenvironment of tumor cells can polarize macrophages to the M2 phenotype in a HIF-1α- or HIF-2α-dependent manner, which facilitates the establishment of an immunosuppressive microenvironment, thus contributing to PMN formation [194, 195]. It was recently found that under hypoxic conditions, epithelial ovarian cancer cell-derived EVs deliver miR-21-3p, miR-125b-5p, and miR-181d-5p to macrophages and induce polarization of M2 macrophages, promoting tumor cell proliferation and migration [196]. Hypoxic glioma-derived EVs deliver miR-10b-5p through the NEDD2L/PIK4CA/PI3K/AKT axis to accelerate macrophage M2 polarization and promote glioma progression [197]. Moreover, EVs can affect receptor cell function, and dormant cancer cell-derived EVs promote PMN formation and cancer cell survival in the bone marrow by reprogramming the metabolic processes of bone marrow mesenchymal cells through the transfer of EVs IGF-2 and IGFBP2 [198].
EVs promote distant tumor metastasis
Organotropic metastasis is the tendency of certain primary tumors to spawn and dominate secondary tumors at distant metastatic sites in specific organs [199]. Additionally, EVs can promote lymphangiogenesis [137, 200] and lymph node metastasis of primary tumor cells [201,202,203,204,205,206,207]. We next summarize some of the mechanisms by which EVs determine CTCs colonization in different distant metastatic sites (Fig. 3). Prostate cancer is most likely to develop bone metastases, and prostate cancer-derived miR-378a-3p-containing EVs promote osteolysis by activating the Dyrk1a/Nfatc1/Angptl2 axis in bone marrow macrophages during tumor bone metastasis [208]. Another study [209] found that primary prostate cancer cells educate the bone marrow to promote bone metastasis through primary prostate cancer EV-mediated transfer of PKM2 into bone marrow mesenchymal cells and subsequent upregulation of CXCL12. Tumor-derived EV miR-375 directly targets DIP2C and upregulates the Wnt signaling pathway to promote prostate cancer bone metastasis [210]. In another study [211], EV lncRNA-SOX2OT promotes bone metastasis of NSCLC by targeting the miRNA-194-5p/RAC1 signaling axis in osteoclasts. Bone metastases are also the preferred site of metastasis for BC. EVs with high CDH11 and ITGA5 expression (CDH11high/ITGA5high EVs) produced by BC cells contribute to the formation of an osteogenic PMN in bone, further facilitating RUNX2high cancer cell colonization and metastasis to bone [212].
In brain metastases from BC, BC-derived EV miR-1290 activates astrocytes in the brain metastasis microenvironment via the FOXA2→CNTF signaling axis and promotes tumor brain metastasis [213]. In another study [214], the loss of X-inactive-specific transcript (XIST) augment the secretion of EV miRNA-503, which promote brain metastasis in BC by affecting tumor cells and the tumor microenvironment. Furthermore, EV lnc-MMP2-2 upregulates EPB41L5 expression by sponging miR-1207-5p, and then EPB41L5 directly promotes endothelial-to-mesenchymal transition and destroys tight junctions, which ultimately promotes brain metastasis in NSCLC [215]. Another study [216] also reported that EVs transmit LINC00482 to regulate the miR-142-3p/TGF-β1 axis, induce microglial M2 polarization and affect the PMN, thus enhancing brain metastasis of NSCLC. Tiong et al. [217] reported that lung cancer-derived EVs expressing miR-21 promote lung cancer brain metastasis by inhibiting DGKB activation of the ERK/STAT3 signaling pathway.
The lung is rich in blood supply and is a metastatic site for many tumors. For instance, EVs carrying miR-200 promote BC cell colonization in the lung [218]. BC cells transmit sEV-miR-106b-5p and sEV-miR-18a-5p to macrophages and induce PD-L1 expression through the PTEN/AKT and PIAS3/STAT3 signaling pathways, which also leads to macrophage polarization and the development of BC lung metastasis [219]. Xia et al. [220] found that BC-derived EVs promote BC lung metastasis by carrying the lncRNA SNHG16 through the miR-892b/PPAPDC1A axis. In another study [221], tumor-derived EVs carrying miR-1247-3p promote lung metastasis of HCC by downregulating B4GALT3 to convert fibroblasts into CAFs and activating the β1-integrin-NF-κB signaling pathway. In a mouse experiment [222], EVs were found to carry the Rab22a-NeoF1 fusion protein to promote osteosarcoma cell metastasis to the lung via PYK2 activation of RhoA in donor cells in osteosarcoma. Furthermore, recent studies [193] have demonstrated new mechanisms by which EVs promote lung metastasis: tumor-derived LC3 EVs activate lung fibroblasts to produce CCL2 via the HSP60-TLR2‐MyD88‐NF‐κB pathway, which can recruit Mos to the lungs, contribute to the formation of pulmonary PMN and ultimately promote metastasis.
EVs also play an important role in CTC-mediated liver metastasis of CRC. Tumor-derived EV miR-934 can promote CRC liver metastasis by regulating the crosstalk between CRC cells and TAMs [223]. Wei et al. [224] found that CRC-EVs with a high cargo of CDC42 could activate NOD1 to promote tumor liver metastasis. CRC-derived EV miR‐181a‐5p activates hepatic stellate cells (HSCs) via regulation of IL6/STAT3 signaling, which promotes secretion of CCL20 from α‐HSCs and further activation of the ERK1/2/Elk‐1 pathway via CCR6 and upregulation of miR‐181a‐5p in CRC cells, ultimately resulting in liver metastases [225]. CRC-derived EVs carrying ADAM17 promote E-cadherin cleavage and enhance the migratory properties of CRC cells, which in turn facilitate liver metastasis in vivo [226]. Additional mechanisms involve the formation of an immunosuppressive microenvironment. CRC-derived EVs carrying TGF-β1 induce the formation of immunosuppressive ecological sites in the liver prior to metastasis and promote tumor metastasis [227]. Furthermore, recent studies [228] have shown that hepatocyte-derived EVs in fatty liver enhance the progression of CRC liver metastases by promoting oncogenic Yes-associated protein signaling and an immunosuppressive microenvironment. Recently, Chang et al. [229] found that pancreatic cancer-derived EV-EZR regulates the STAT3 and YAP-1 signaling pathways and promotes fibroblast activation for pancreatic cancer liver metastasis. In addition, another study [230] found that gastric cancer-derived EV miR-519a-3p activates the MAPK/ERK pathway by targeting DUSP2, which leads to M2-like polarization of macrophages, ultimately leading to gastric cancer liver metastasis.
Conclusions and perspectives
This paper reviews the mechanisms by which EVs affect CTCs during their detachment from the primary tumor, their survival in the circulation and eventual colonization to distant sites in recent years. The process is complex, and although a large number of mechanisms have been described, many still remain to be researched. Learning more about these mechanisms can inspire us to gain a deeper understanding of tumor metastasis and facilitate our thinking about tumor prevention, diagnosis, and therapeutic strategies.
We conclude that EVs promote CTC-mediated metastasis and progression through a variety of mechanisms, including (i) EVs promote EMT by carrying pro-EMT signaling factors, regulating key genes and pathways in EMT, and promoting macrophage M2 polarization; EVs promote ECM remodeling by carrying ECM remodeling-related enzymes and regulating stromal cells; and EVs promote angiogenesis by directly or indirectly releasing proangiogenic factors and promote vascular permeability by targeting proteins, such as VE-Cad and ZO-1, which enhance the detachment of CTCs; (ii) EVs protect CTCs by activating platelets to form thrombus, and by carrying molecules that interact with circulating immune cells such as T cells, NK cells and B cells in the circulatory system; and (iii) EVs determine tumor organotropism by carrying integrins, as well as carrying cargoes such as proteins and nucleic acids to regulate relevant pathways and thus participate in PMN formation, ultimately facilitating the colonization of CTCs at distant sites.
By reading the relevant literature, we also found that there are still some mechanisms to be investigated for the role of EVs on CTCs. In circulation, CTCs can internalize platelets to express specific antigens to bind to NK cells, but the exact mechanism by which CTCs uptake platelets is currently unknown. It may be that EVs from the primary tumor domesticate platelets and thus lead to uptake, which is a direction that needs to be researched in the future. Whether the binding of CTCs to immune cells is a direct contact or EVs from primary tumor sources are first released into the bloodstream to interact with immune cells before inducing immunosuppression is a process that also needs to be investigated. In addition, there are many mechanisms involved in the process of EV-induced immunosuppression in tumors, but which one plays the dominant role and its specific causes need to be further investigated. Furthermore, there are more EV integrins that determine the shedding of CTCs from the primary tumor to specific distant metastatic sites that need to be discovered, and it is also necessary to think about whether there are other mechanisms of EV origin influencing organotropism in addition to EV integrins, and all these need to be researched further. We believe that further research on the role of EVs on CTCs during metastasis will also help to identify new biomarkers in liquid biopsies, which will contribute to the development of more innovative and precise oncology therapies to provide greater assistance to cancer patients.
Data Availability
Not applicable.
Abbreviations
- EVs:
-
Extracellular vesicles
- CTCs:
-
Circulating tumor cells
- EMT:
-
Epithelial-mesenchymal transition
- ECM:
-
Extracellular matrix
- PMN:
-
Pre-metastatic niche
- CRC:
-
Colorectal cancer
- HCC:
-
Hepatocellular carcinoma
- NSCLC:
-
Non-small cell lung cancer
- TNBC:
-
Triple-negative breast cancer
- CAFs:
-
Cancer-associated fibroblasts
- MSCs:
-
Mesenchymal stem cells
- BMSCs:
-
Bone marrow mesenchymal cells
- TGF-β:
-
Transforming growth factor-beta
- miRNA:
-
MicroRNA
- lncRNA:
-
Long noncoding RNA
- TME:
-
Tumor microenvironment
- MDSCs:
-
Myeloid-derived suppressor cells
- Tregs:
-
Regulatory T cells
- TAM:
-
Tumor-associated macrophages
- MMP:
-
Matrix metalloproteinase
- HUVECs:
-
Human umbilical vein endothelial cells
- VE-Cad:
-
Vascular endothelial cadherin
- ZO-1:
-
Zonula occludens-1
- TF:
-
Tissue factor
- BC:
-
Breast cancer
- PD-L1:
-
Programmed death ligand 1
References
Zhou H, Zhu L, Song J, Wang G, Li P, Li W, Luo P, Sun X, Wu J, Liu Y, et al. Liquid biopsy at the frontier of detection, prognosis and progression monitoring in Colorectal cancer. Mol Cancer. 2022;21:86.
Zhu Z, Hu E, Shen H, Tan J, Zeng S. The functional and clinical roles of liquid biopsy in patient-derived models. J Hematol Oncol. 2023;16:36.
Wang Z, Chen JQ, Liu JL, Tian L. Exosomes in Tumor microenvironment: novel transporters and biomarkers. J Transl Med. 2016;14:297.
Ma S, Zhou M, Xu Y, Gu X, Zou M, Abudushalamu G, Yao Y, Fan X, Wu G. Clinical application and detection techniques of liquid biopsy in gastric cancer. Mol Cancer. 2023;22:7.
Wei Y, Yang W, Huang Q, Chen Y, Zeng K, Chen J, Chen J. Clinical significance of circulating Tumor cell (CTC)-specific microRNA (miRNA) in Breast cancer. Prog Biophys Mol Biol. 2023;177:229–34.
Jin F, Zhu L, Shao J, Yakoub M, Schmitt L, Reißfelder C, Loges S, Benner A, Schölch S. Circulating tumour cells in patients with Lung cancer universally indicate poor prognosis. Eur Respir Rev 2022, 31.
Słomka A, Wang B, Mocan T, Horhat A, Willms AG, Schmidt-Wolf IGH, Strassburg CP, Gonzalez-Carmona MA, Lukacs-Kornek V, Kornek MT. Extracellular vesicles and circulating Tumour cells - complementary liquid biopsies or standalone concepts? Theranostics. 2022;12:5836–55.
Li W, Wang H, Zhao Z, Gao H, Liu C, Zhu L, Wang C, Yang Y. Emerging nanotechnologies for Liquid Biopsy: the detection of circulating Tumor cells and extracellular vesicles. Adv Mater. 2019;31:e1805344.
Nanou A, Miao J, Coumans FAW, Dolce EM, Darga E, Barlow W, Smerage JB, Paoletti C, Godwin AK, Pusztai L, et al. Tumor-derived extracellular vesicles as complementary prognostic factors to circulating Tumor cells in metastatic Breast Cancer. JCO Precis Oncol. 2023;7:e2200372.
He S, Ding L, Yuan H, Zhao G, Yang X, Wu Y. A review of sensors for classification and subtype discrimination of cancer: insights into circulating Tumor cells and tumor-derived extracellular vesicles. Anal Chim Acta. 2023;1244:340703.
Keup C, Suryaprakash V, Storbeck M, Hoffmann O, Kimmig R, Kasimir-Bauer S. Longitudinal Multi-Parametric Liquid Biopsy Approach Identifies Unique Features of Circulating Tumor Cell, Extracellular Vesicle, and Cell-Free DNA Characterization for Disease Monitoring in Metastatic Breast Cancer Patients. Cells 2021, 10.
Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7:1535750.
Ye Z, Chen W, Li G, Huang J, Lei J. Tissue-derived extracellular vesicles in cancer progression: mechanisms, roles, and potential applications. Cancer Metastasis Rev 2023.
Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science 2020, 367.
Ramirez-Garrastacho M, Bajo-Santos C, Line A, Martens-Uzunova ES, de la Fuente JM, Moros M, Soekmadji C, Tasken KA, Llorente A. Extracellular vesicles as a source of Prostate cancer biomarkers in liquid biopsies: a decade of research. Br J Cancer. 2022;126:331–50.
Muhsin-Sharafaldine MR, McLellan AD. Tumor-derived apoptotic vesicles: with death they do part. Front Immunol. 2018;9:957.
Wang Y, Lu Y, Wan R, Wang Y, Zhang C, Li M, Deng P, Cao L, Hu C. Profilin 1 induces Tumor Metastasis by promoting Microvesicle Secretion through the ROCK 1/p-MLC pathway in Non-small Cell Lung Cancer. Front Pharmacol. 2022;13:890891.
Clancy JW, D’Souza-Schorey C. Tumor-derived extracellular vesicles: multifunctional entities in the Tumor Microenvironment. Annu Rev Pathol. 2023;18:205–29.
Wan Y, Xia YQ, Zheng SY. Extruded small extracellular vesicles: splinters of circulating tumour cells may promote cancer Metastasis? Br J Cancer. 2022;127:1180–3.
Beltraminelli T, Perez CR, De Palma M. Disentangling the complexity of tumor-derived extracellular vesicles. Cell Rep. 2021;35:108960.
Wu L, Xue M, Lai S, Chen J, Lin Y, Ding N, Zhong J, Chen S, Wang L. Hypoxia derived exosomes promote the proliferation and Metastasis of Colorectal cancer through the regulation of HIF-1α/miR-4299/ZBTB4. Life Sci. 2023;329:121872.
Wu F, Yang J, Shang G, Zhang Z, Niu S, Liu Y, Liu H, Jing J, Fang Y. Exosomal miR-224-5p from Colorectal Cancer Cells Promotes Malignant Transformation of Human Normal Colon Epithelial Cells by Promoting Cell Proliferation through Downregulation of CMTM4. Oxid Med Cell Longev 2022, 2022:5983629.
Li J, Yang P, Chen F, Tan Y, Huang C, Shen H, Peng C, Feng Y, Sun Y. Hypoxic colorectal cancer-derived extracellular vesicles deliver microRNA-361-3p to facilitate cell proliferation by targeting TRAF3 via the noncanonical NF-κB pathways. Clin Transl Med. 2021;11:e349.
Shang A, Gu C, Wang W, Wang X, Sun J, Zeng B, Chen C, Chang W, Ping Y, Ji P, et al. Exosomal circPACRGL promotes progression of Colorectal cancer via the miR-142-3p/miR-506-3p- TGF-β1 axis. Mol Cancer. 2020;19:117.
Li B, Chen Y, Liang L, Wang Y, Huang W, Zhao K, Liu S, Deng G, Chen J. Tumor-derived extracellular vesicles shuttle c-Myc to promote gastric cancer growth and Metastasis via the KCNQ1OT1/miR-556-3p/CLIC1 axis. Cell Death Dis. 2022;13:217.
Gu J, Qian H, Shen L, Zhang X, Zhu W, Huang L, Yan Y, Mao F, Zhao C, Shi Y, Xu W. Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through TGF-β/Smad pathway. PLoS ONE. 2012;7:e52465.
Xu Y, Luan G, Li Z, Liu Z, Qin G, Chu Y. Tumour-derived exosomal lncRNA SNHG16 induces telocytes to promote Metastasis of hepatocellular carcinoma via the miR-942-3p/MMP9 axis. Cell Oncol (Dordr). 2023;46:251–64.
Zhou S, Lan Y, Li Y, Li Z, Pu J, Wei L. Hypoxic tumor-derived exosomes induce M2 macrophage polarization via PKM2/AMPK to promote Lung Cancer Progression. Cell Transpl. 2022;31:9636897221106998.
Zhou H, Huang X, Yang X, Jiang F, Shao F, Shi W, Huang K, Pan J, Zhang Y, Chen J, Wang Y. CircRAPGEF5 promotes the proliferation and Metastasis of Lung Adenocarcinoma through the miR-1236-3p/ZEB1 Axis and serves as a potential biomarker. Int J Biol Sci. 2022;18:2116–31.
Yu F, Liang M, Huang Y, Wu W, Zheng B, Chen C. Hypoxic tumor-derived exosomal mir-31-5p promotes lung adenocarcinoma Metastasis by negatively regulating SATB2-reversed EMT and activating MEK/ERK signaling. J Exp Clin Cancer Res. 2021;40:179.
Liu X, Li Y, Chen C, Dong J, Zhou J, Tong D, Wang L, Gao X, Kang X. Exosomal EphA2 promotes Tumor Metastasis of triple-negative Breast cancer by damaging endothelial barrier. Clin Exp Metastasis. 2023;40:105–16.
Jin C, Shi L, Li K, Liu W, Qiu Y, Zhao Y, Zhao B, Li Z, Li Y, Zhu Q. Mechanism of Tumor–derived extracellular vesicles in regulating renal cell carcinoma progression by the delivery of MALAT1. Oncol Rep 2021, 46.
Tsutsui T, Kawahara H, Kimura R, Dong Y, Jiapaer S, Sabit H, Zhang J, Yoshida T, Nakada M, Hanayama R. Glioma-derived extracellular vesicles promote Tumor progression by conveying WT1. Carcinogenesis. 2020;41:1238–45.
Xu H, Li M, Pan Z, Zhang Z, Gao Z, Zhao R, Li B, Qi Y, Qiu W, Guo Q, et al. Mir-3184-3p enriched in cerebrospinal fluid exosomes contributes to progression of glioma and promotes M2-like macrophage polarization. Cancer Sci. 2022;113:2668–80.
Chen H, Chen X, Zhang Z, Bao W, Gao Z, Li D, Xie X, Zhou P, Yang C, Zhou Z, et al. Extracellular vesicles-transferred SBSN drives glioma aggressiveness by activating NF-κB via ANXA1-dependent ubiquitination of NEMO. Oncogene. 2022;41:5253–65.
Zhao C, Wang H, Xiong C, Liu Y. Hypoxic glioblastoma release exosomal VEGF-A induce the permeability of blood-brain barrier. Biochem Biophys Res Commun. 2018;502:324–31.
He Z, Wang J, Zhu C, Xu J, Chen P, Jiang X, Chen Y, Jiang J, Sun C. Exosome-derived FGD5-AS1 promotes tumor-associated macrophage M2 polarization-mediated Pancreatic cancer cell proliferation and Metastasis. Cancer Lett. 2022;548:215751.
Lin J, Wang X, Zhai S, Shi M, Peng C, Deng X, Fu D, Wang J, Shen B. Hypoxia-induced exosomal circPDK1 promotes Pancreatic cancer glycolysis via c-myc activation by modulating miR-628-3p/BPTF axis and degrading BIN1. J Hematol Oncol. 2022;15:128.
Wang B, Mao JH, Wang BY, Wang LX, Wen HY, Xu LJ, Fu JX, Yang H. Exosomal mir-1910-3p promotes proliferation, Metastasis, and autophagy of Breast cancer cells by targeting MTMR3 and activating the NF-κB signaling pathway. Cancer Lett. 2020;489:87–99.
Huang S, Zhao J, Yu H, Chen G. Mechanism of tumor-derived extracellular vesicles in prostatic cancer progression through the circFMN2/KLF2/RNF128 axis. Apoptosis 2023.
Zheng Y, Zhu K, Wang G. miR-106a-5p carried by tumor-derived extracellular vesicles promotes the invasion and Metastasis of Ovarian cancer by targeting KLF6. Clin Exp Metastasis. 2022;39:603–21.
Wang L, Zhao F, Xiao Z, Yao L. Exosomal microRNA-205 is involved in proliferation, migration, invasion, and apoptosis of Ovarian cancer cells via regulating VEGFA. Cancer Cell Int. 2019;19:281.
Yan X, Zhang S, Jia J, Yang J, Song Y, Duan H. Exosomal MiR-423-3p inhibits macrophage M2 polarization to suppress the malignant progression of Cervical cancer. Pathol Res Pract. 2022;235:153882.
Song Y, Wang M, Tong H, Tan Y, Hu X, Wang K, Wan X. Plasma exosomes from endometrial cancer patients contain LGALS3BP to promote endometrial cancer progression. Oncogene. 2021;40:633–46.
Jiang Y, Qiu Q, Jing X, Song Z, Zhang Y, Wang C, Liu K, Ye F, Ji X, Luo F, Zhao R. Cancer-associated fibroblast-derived exosome miR-181b-3p promotes the occurrence and development of Colorectal cancer by regulating SNX2 expression. Biochem Biophys Res Commun. 2023;641:177–85.
Zhang Y, Yin C, Wei C, Xia S, Qiao Z, Zhang XW, Yu B, Zhou J, Wang R. Exosomal mir-625-3p secreted by cancer-associated fibroblasts in Colorectal cancer promotes EMT and chemotherapeutic resistance by blocking the CELF2/WWOX pathway. Pharmacol Res. 2022;186:106534.
Wang S, Du P, Cao Y, Ma J, Yang X, Yu Z, Yang Y. Cancer associated fibroblasts secreted exosomal miR-1290 contributes to Prostate cancer cell growth and Metastasis via targeting GSK3β. Cell Death Discov. 2022;8:371.
Yan Z, Sheng Z, Zheng Y, Feng R, Xiao Q, Shi L, Li H, Yin C, Luo H, Hao C, et al. Cancer-associated fibroblast-derived exosomal miR-18b promotes Breast cancer invasion and Metastasis by regulating TCEAL7. Cell Death Dis. 2021;12:1120.
Yang K, Zhang J, Bao C. Exosomal circEIF3K from cancer-associated fibroblast promotes Colorectal cancer (CRC) progression via miR-214/PD-L1 axis. BMC Cancer. 2021;21:933.
Zhou L, Li J, Tang Y, Yang M. Exosomal LncRNA LINC00659 transferred from cancer-associated fibroblasts promotes Colorectal cancer cell progression via miR-342-3p/ANXA2 axis. J Transl Med. 2021;19:8.
Li X, Wu F. Mesenchymal stem cell-derived extracellular vesicles transfer miR-598 to inhibit the growth and Metastasis of non-small-cell Lung cancer by targeting THBS2. Cell Death Discov. 2023;9:3.
Jahangiri B, Khalaj-Kondori M, Asadollahi E, Purrafee Dizaj L, Sadeghizadeh M. MSC-Derived exosomes suppress Colorectal cancer cell proliferation and Metastasis via miR-100/mTOR/miR-143 pathway. Int J Pharm. 2022;627:122214.
Liu L, Cheng M, Zhang T, Chen Y, Wu Y, Wang Q. Mesenchymal stem cell-derived extracellular vesicles prevent glioma by blocking M2 polarization of macrophages through a miR-744-5p/TGFB1-dependent mechanism. Cell Biol Toxicol. 2022;38:649–65.
Pan Y, Wang X, Li Y, Yan P, Zhang H. Human umbilical cord blood mesenchymal stem cells-derived exosomal microRNA-503-3p inhibits progression of human endometrial cancer cells through downregulating MEST. Cancer Gene Ther. 2022;29:1130–9.
Yu L, Gui S, Liu Y, Qiu X, Zhang G, Zhang X, Pan J, Fan J, Qi S, Qiu B. Exosomes derived from microRNA-199a-overexpressing mesenchymal stem cells inhibit glioma progression by down-regulating AGAP2. Aging. 2019;11:5300–18.
Figueroa J, Phillips LM, Shahar T, Hossain A, Gumin J, Kim H, Bean AJ, Calin GA, Fueyo J, Walters ET, et al. Exosomes from Glioma-Associated Mesenchymal stem cells increase the tumorigenicity of glioma stem-like cells via transfer of miR-1587. Cancer Res. 2017;77:5808–19.
Zhu G, Xia Y, Zhao Z, Li A, Li H, Xiao T. LncRNA XIST from the bone marrow mesenchymal stem cell derived exosome promotes osteosarcoma growth and Metastasis through miR-655/ACLY signal. Cancer Cell Int. 2022;22:330.
Yang Y, Ma S, Ye Z, Zheng Y, Zheng Z, Liu X, Zhou X. NEAT1 in bone marrow mesenchymal stem cell-derived extracellular vesicles promotes Melanoma by inducing M2 macrophage polarization. Cancer Gene Ther. 2022;29:1228–39.
Liu Q, Zhang J, Liu Y, Peng H, Wu Y. Extracellular vesicles extracted from bone marrow mesenchymal stem cells carrying MicroRNA-342-3p inhibit the INHBA/IL13Rα2 axis to suppress the growth and Metastasis of Breast cancer. Transl Oncol. 2022;18:101333.
Liu X, Jiang F, Wang Z, Tang L, Zou B, Xu P, Yu T. Hypoxic bone marrow mesenchymal cell-extracellular vesicles containing mir-328-3p promote Lung cancer progression via the NF2-mediated Hippo axis. J Cell Mol Med. 2021;25:96–109.
Liang Y, Zhang D, Li L, Xin T, Zhao Y, Ma R, Du J. Exosomal microRNA-144 from bone marrow-derived mesenchymal stem cells inhibits the progression of non-small cell Lung cancer by targeting CCNE1 and CCNE2. Stem Cell Res Ther. 2020;11:87.
Jiang S, Mo C, Guo S, Zhuang J, Huang B, Mao X. Human bone marrow mesenchymal stem cells-derived microRNA-205-containing exosomes impede the progression of Prostate cancer through suppression of RHPN2. J Exp Clin Cancer Res. 2019;38:495.
Guan H, Peng R, Fang F, Mao L, Chen Z, Yang S, Dai C, Wu H, Wang C, Feng N, et al. Tumor-associated macrophages promote Prostate cancer progression via exosome-mediated miR-95 transfer. J Cell Physiol. 2020;235:9729–42.
Li F, Xu T, Chen P, Sun R, Li C, Zhao X, Ou J, Li J, Liu T, Zeng M, et al. Platelet-derived extracellular vesicles inhibit ferroptosis and promote distant Metastasis of nasopharyngeal carcinoma by upregulating ITGB3. Int J Biol Sci. 2022;18:5858–72.
Michael JV, Wurtzel JGT, Mao GF, Rao AK, Kolpakov MA, Sabri A, Hoffman NE, Rajan S, Tomar D, Madesh M, et al. Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress Tumor growth. Blood. 2017;130:567–80.
Liang H, Yan X, Pan Y, Wang Y, Wang N, Li L, Liu Y, Chen X, Zhang CY, Gu H, Zen K. MicroRNA-223 delivered by platelet-derived microvesicles promotes Lung cancer cell invasion via targeting Tumor suppressor EPB41L3. Mol Cancer. 2015;14:58.
Di Pace AL, Pelosi A, Fiore PF, Tumino N, Besi F, Quatrini L, Santopolo S, Vacca P, Moretta L. MicroRNA analysis of natural killer cell-derived exosomes: the microRNA let-7b-5p is enriched in exosomes and participates in their anti-tumor effects against Pancreatic cancer cells. Oncoimmunology. 2023;12:2221081.
Neviani P, Wise PM, Murtadha M, Liu CW, Wu CH, Jong AY, Seeger RC, Fabbri M. Natural killer-derived exosomal miR-186 inhibits Neuroblastoma Growth and Immune Escape mechanisms. Cancer Res. 2019;79:1151–64.
Zhou WJ, Zhang J, Xie F, Wu JN, Ye JF, Wang J, Wu K, Li MQ. CD45RO(-)CD8(+) T cell-derived exosomes restrict estrogen-driven endometrial cancer development via the ERβ/miR-765/PLP2/Notch axis. Theranostics. 2021;11:5330–45.
Lin D, Shen L, Luo M, Zhang K, Li J, Yang Q, Zhu F, Zhou D, Zheng S, Chen Y, Zhou J. Circulating Tumor cells: biology and clinical significance. Signal Transduct Target Ther. 2021;6:404.
Parkinson DR, Dracopoli N, Petty BG, Compton C, Cristofanilli M, Deisseroth A, Hayes DF, Kapke G, Kumar P, Lee J, et al. Considerations in the development of circulating Tumor cell technology for clinical use. J Transl Med. 2012;10:138.
Lone SN, Nisar S, Masoodi T, Singh M, Rizwan A, Hashem S, El-Rifai W, Bedognetti D, Batra SK, Haris M, et al. Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments. Mol Cancer. 2022;21:79.
Müller Bark J, Kulasinghe A, Chua B, Day BW, Punyadeera C. Circulating biomarkers in patients with glioblastoma. Br J Cancer. 2020;122:295–305.
Charles Jacob HK, Charles Richard JL, Signorelli R, Kashuv T, Lavania S, Vaish U, Boopathy R, Middleton A, Boone MM, Sundaram R et al. Modulation of early Neutrophil Granulation: the circulating Tumor Cell-Extravesicular connection in pancreatic ductal adenocarcinoma. Cancers (Basel) 2021, 13.
Ozimski LL, Gremmelspacher D, Aceto N. A fatal affair: circulating Tumor cell relationships that shape Metastasis. iScience. 2021;24:103073.
Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, et al. Circulating Tumor cell clusters are oligoclonal precursors of Breast cancer Metastasis. Cell. 2014;158:1110–22.
Qiu J, Xu J, Zhang K, Gu W, Nie L, Wang G, Luo Y. Refining Cancer Management using Integrated Liquid Biopsy. Theranostics. 2020;10:2374–84.
Ludwig S, Floros T, Theodoraki MN, Hong CS, Jackson EK, Lang S, Whiteside TL. Suppression of lymphocyte functions by plasma exosomes correlates with Disease Activity in patients with Head and Neck Cancer. Clin Cancer Res. 2017;23:4843–54.
Ye L, Zhang F, Li H, Yang L, Lv T, Gu W, Song Y. Circulating Tumor Cells Were Associated with the number of T lymphocyte subsets and NK Cells in Peripheral blood in Advanced Non-small-cell Lung Cancer. Dis Markers. 2017;2017:5727815.
Fu Q, Zhang Q, Lou Y, Yang J, Nie G, Chen Q, Chen Y, Zhang J, Wang J, Wei T, et al. Primary tumor-derived exosomes facilitate Metastasis by regulating adhesion of circulating Tumor cells via SMAD3 in Liver cancer. Oncogene. 2018;37:6105–18.
Adriani RR, Gargari SLM. Comparative application of microfluidic systems in circulating Tumor cells and extracellular vesicles isolation; a review. Biomed Microdevices. 2022;25:4.
Joseph JP, Harishankar MK, Pillai AA, Devi A. Hypoxia induced EMT: a review on the mechanism of Tumor progression and Metastasis in OSCC. Oral Oncol. 2018;80:23–32.
Bigagli E, Cinci L, D’Ambrosio M, Luceri C. Transcriptomic Characterization, Chemosensitivity and Regulatory effects of exosomes in spontaneous EMT/MET transitions of Breast Cancer cells. Cancer Genomics Proteomics. 2019;16:163–73.
Rodrigues-Junior DM, Tsirigoti C, Lim SK, Heldin CH, Moustakas A. Extracellular vesicles and transforming growth factor β signaling in Cancer. Front Cell Dev Biol. 2022;10:849938.
Drabsch Y, ten Dijke P. TGF-β signalling and its role in cancer progression and Metastasis. Cancer Metastasis Rev. 2012;31:553–68.
Xue M, Chen W, Xiang A, Wang R, Chen H, Pan J, Pang H, An H, Wang X, Hou H, Li X. Hypoxic exosomes facilitate bladder Tumor growth and development through transferring long non-coding RNA-UCA1. Mol Cancer. 2017;16:143.
Wang L, Yang G, Zhao D, Wang J, Bai Y, Peng Q, Wang H, Fang R, Chen G, Wang Z, et al. CD103-positive CSC exosome promotes EMT of clear cell renal cell carcinoma: role of remote MiR-19b-3p. Mol Cancer. 2019;18:86.
Fang X, Xu Y, Li K, Liu P, Zhang H, Jiang Y, Tang J, Li Y. Exosomal lncRNA PCAT1 Promotes Tumor Circulating Cell-Mediated Colorectal Cancer Liver Metastasis by Regulating the Activity of the miR-329-3p/Netrin-1-CD146 Complex. J Immunol Res 2022, 2022:9916228.
Hu W, Wang Z, Zhang S, Lu X, Wu J, Yu K, Ji A, Lu W, Wang Z, Wu J, Jiang C. IQGAP1 promotes Pancreatic cancer progression and epithelial-mesenchymal transition (EMT) through Wnt/β-catenin signaling. Sci Rep. 2019;9:7539.
Xiao Z, Feng X, Zhou Y, Li P, Luo J, Zhang W, Zhou J, Zhao J, Wang D, Wang Y, et al. Exosomal mir-10527-5p inhibits Migration, Invasion, Lymphangiogenesis and Lymphatic Metastasis by affecting Wnt/β-Catenin signaling via Rab10 in esophageal squamous cell carcinoma. Int J Nanomedicine. 2023;18:95–114.
Liu Y, Tang T, Yang X, Qin P, Wang P, Zhang H, Bai M, Wu R, Li F. Tumor-derived exosomal long noncoding RNA LINC01133, regulated by Periostin, contributes to pancreatic ductal adenocarcinoma epithelial-mesenchymal transition through the Wnt/β-catenin pathway by silencing AXIN2. Oncogene. 2021;40:3164–79.
Balaji S, Kim U, Muthukkaruppan V, Vanniarajan A. Emerging role of Tumor microenvironment derived exosomes in therapeutic resistance and Metastasis through epithelial-to-mesenchymal transition. Life Sci. 2021;280:119750.
Zeng Q, Zhu Z, Song L, He Z. Transferred by exosomes-derived MiR-19b-3p targets PTEN to regulate Esophageal cancer cell apoptosis, migration and invasion. Biosci Rep 2020, 40.
Yang B, Feng X, Liu H, Tong R, Wu J, Li C, Yu H, Chen Y, Cheng Q, Chen J, et al. High-metastatic cancer cells derived exosomal miR92a-3p promotes epithelial-mesenchymal transition and Metastasis of low-metastatic cancer cells by regulating PTEN/Akt pathway in hepatocellular carcinoma. Oncogene. 2020;39:6529–43.
Yang C, Dou R, Wei C, Liu K, Shi D, Zhang C, Liu Q, Wang S, Xiong B. Tumor-derived exosomal microRNA-106b-5p activates EMT-cancer cell and M2-subtype TAM interaction to facilitate CRC Metastasis. Mol Ther. 2021;29:2088–107.
Li M, Xu H, Qi Y, Pan Z, Li B, Gao Z, Zhao R, Xue H, Li G. Tumor-derived exosomes deliver the Tumor suppressor mir-3591-3p to induce M2 macrophage polarization and promote glioma progression. Oncogene. 2022;41:4618–32.
Qin Y, Zheng X, Gao W, Wang B, Wu Y. Tumor microenvironment and immune-related therapies of head and neck squamous cell carcinoma. Mol Ther Oncolytics. 2021;20:342–51.
Salarian M, Ibhagui OY, Yang JJ. Molecular imaging of extracellular matrix proteins with targeted probes using magnetic resonance imaging. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2020;12:e1622.
Tan S, Xia L, Yi P, Han Y, Tang L, Pan Q, Tian Y, Rao S, Oyang L, Liang J, et al. Exosomal miRNAs in Tumor microenvironment. J Exp Clin Cancer Res. 2020;39:67.
To KKW, Cho WCS. Exosome secretion from hypoxic cancer cells reshapes the Tumor microenvironment and mediates drug resistance. Cancer Drug Resist. 2022;5:577–94.
You L, Wu W, Wang X, Fang L, Adam V, Nepovimova E, Wu Q, Kuca K. The role of hypoxia-inducible factor 1 in Tumor immune evasion. Med Res Rev. 2021;41:1622–43.
Zhang W, Zhou X, Yao Q, Liu Y, Zhang H, Dong Z. HIF-1-mediated production of exosomes during hypoxia is protective in renal tubular cells. Am J Physiol Renal Physiol. 2017;313:F906–f913.
Shao C, Yang F, Miao S, Liu W, Wang C, Shu Y, Shen H. Role of hypoxia-induced exosomes in Tumor biology. Mol Cancer. 2018;17:120.
Meng W, Hao Y, He C, Li L, Zhu G. Exosome-orchestrated hypoxic Tumor microenvironment. Mol Cancer. 2019;18:57.
Tauro BJ, Mathias RA, Greening DW, Gopal SK, Ji H, Kapp EA, Coleman BM, Hill AF, Kusebauch U, Hallows JL, et al. Oncogenic H-ras reprograms Madin-Darby canine kidney (MDCK) cell-derived exosomal proteins following epithelial-mesenchymal transition. Mol Cell Proteomics. 2013;12:2148–59.
Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, Fearon D, Greten FR, Hingorani SR, Hunter T, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020;20:174–86.
Zhu Y, Dou H, Liu Y, Yu P, Li F, Wang Y, Xiao M. Breast Cancer Exosome-Derived miR-425-5p Induces Cancer-Associated Fibroblast-Like Properties in Human Mammary Fibroblasts by TGFβ1/ROS Signaling Pathway. Oxid Med Cell Longev 2022, 2022:5266627.
Hu T, Hu J. Melanoma-derived exosomes induce reprogramming fibroblasts into cancer-associated fibroblasts via Gm26809 delivery. Cell Cycle. 2019;18:3085–94.
Cui Y, Wang D, Xie M. Tumor-derived extracellular vesicles promote activation of Carcinoma-Associated fibroblasts and facilitate Invasion and Metastasis of Ovarian Cancer by carrying miR-630. Front Cell Dev Biol. 2021;9:652322.
Ye B, Duan Y, Zhou M, Wang Y, Lai Q, Yue K, Cao J, Wu Y, Wang X, Jing C. Hypoxic tumor-derived exosomal miR-21 induces cancer-associated fibroblast activation to promote head and neck squamous cell carcinoma Metastasis. Cell Signal. 2023;108:110725.
Paggetti J, Haderk F, Seiffert M, Janji B, Distler U, Ammerlaan W, Kim YJ, Adam J, Lichter P, Solary E, et al. Exosomes released by chronic lymphocytic Leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts. Blood. 2015;126:1106–17.
Ringuette Goulet C, Bernard G, Tremblay S, Chabaud S, Bolduc S, Pouliot F. Exosomes induce fibroblast differentiation into Cancer-Associated fibroblasts through TGFβ signaling. Mol Cancer Res. 2018;16:1196–204.
Bai S, Wang Z, Wang M, Li J, Wei Y, Xu R, Du J. Tumor-derived exosomes modulate primary site Tumor Metastasis. Front Cell Dev Biol. 2022;10:752818.
Yuan D, Guo T, Zhu D, Ge H, Zhao Y, Huang A, Wang X, Cao X, He C, Qian H, Yu H. Exosomal lncRNA ATB derived from Ovarian Cancer cells promotes Angiogenesis via regulating miR-204-3p/TGFβR2 Axis. Cancer Manag Res. 2022;14:327–37.
Chen K, Wang Q, Liu X, Wang F, Yang Y, Tian X. Hypoxic Pancreatic cancer derived exosomal miR-30b-5p promotes Tumor angiogenesis by inhibiting GJA1 expression. Int J Biol Sci. 2022;18:1220–37.
You X, Sun W, Wang Y, Liu X, Wang A, Liu L, Han S, Sun Y, Zhang J, Guo L, Zhang Y. Cervical cancer-derived exosomal miR-663b promotes angiogenesis by inhibiting vinculin expression in vascular endothelial cells. Cancer Cell Int. 2021;21:684.
Zhang L, Li H, Yuan M, Li M, Zhang S. Cervical Cancer cells-secreted exosomal microRNA-221-3p promotes Invasion, Migration and Angiogenesis of Microvascular endothelial cells in Cervical Cancer by Down-regulating MAPK10 expression. Cancer Manag Res. 2019;11:10307–19.
Hsu YL, Hung JY, Chang WA, Jian SF, Lin YS, Pan YC, Wu CY, Kuo PL. Hypoxic lung-Cancer-derived extracellular vesicle MicroRNA-103a increases the Oncogenic effects of macrophages by Targeting PTEN. Mol Ther. 2018;26:568–81.
Shi Y, Zhu H, Jiang H, Yue H, Yuan F, Wang F. Cancer-associated fibroblasts-derived exosomes from chemoresistant patients regulate cisplatin resistance and angiogenesis by delivering VEGFA in Colorectal cancer. Anticancer Drugs. 2023;34:422–30.
Yin H, Yu S, Xie Y, Dai X, Dong M, Sheng C, Hu J. Cancer-associated fibroblasts-derived exosomes upregulate microRNA-135b-5p to promote Colorectal cancer cell growth and angiogenesis by inhibiting thioredoxin-interacting protein. Cell Signal. 2021;84:110029.
Terceiro LEL, Edechi CA, Ikeogu NM, Nickel BE, Hombach-Klonisch S, Sharif T, Leygue E, Myal Y. The breast Tumor Microenvironment: a key player in metastatic spread. Cancers (Basel) 2021, 13.
Reymond N, d’Água BB, Ridley AJ. Crossing the endothelial barrier during Metastasis. Nat Rev Cancer. 2013;13:858–70.
Dou R, Liu K, Yang C, Zheng J, Shi D, Lin X, Wei C, Zhang C, Fang Y, Huang S, et al. EMT-cancer cells-derived exosomal miR-27b-3p promotes circulating tumour cells-mediated Metastasis by modulating vascular permeability in Colorectal cancer. Clin Transl Med. 2021;11:e595.
Becker A, Thakur BK, Weiss JM, Kim HS, Peinado H, Lyden D. Extracellular vesicles in Cancer: cell-to-cell mediators of Metastasis. Cancer Cell. 2016;30:836–48.
Fang JH, Zhang ZJ, Shang LR, Luo YW, Lin YF, Yuan Y, Zhuang SM. Hepatoma cell-secreted exosomal microRNA-103 increases vascular permeability and promotes Metastasis by targeting junction proteins. Hepatology. 2018;68:1459–75.
Chen X, Zhang S, Du K, Zheng N, Liu Y, Chen H, Xie G, Ma Y, Zhou Y, Zheng Y, et al. Gastric cancer-secreted exosomal X26nt increases angiogenesis and vascular permeability by targeting VE-cadherin. Cancer Sci. 2021;112:1839–52.
Di Modica M, Regondi V, Sandri M, Iorio MV, Zanetti A, Tagliabue E, Casalini P, Triulzi T. Breast cancer-secreted miR-939 downregulates VE-cadherin and destroys the barrier function of endothelial monolayers. Cancer Lett. 2017;384:94–100.
Solé C, Lawrie CH. MicroRNAs in Metastasis and the Tumour Microenvironment. Int J Mol Sci 2021, 22.
Xie L, Zhang K, You B, Yin H, Zhang P, Shan Y, Gu Z, Zhang Q. Hypoxic nasopharyngeal carcinoma-derived exosomal miR-455 increases vascular permeability by targeting ZO-1 to promote Metastasis. Mol Carcinog. 2023;62:803–19.
Liu X, Li Y, Chen C, Dong J, Zhou J, Tong D, Wang L, Gao X, Kang X. Exosomal EphA2 promotes Tumor Metastasis of triple-negative Breast cancer by damaging endothelial barrier. Clin Exp Metastasis 2022.
Li J, Yuan H, Xu H, Zhao H, Xiong N. Hypoxic Cancer-secreted exosomal mir-182-5p promotes Glioblastoma Angiogenesis by Targeting Kruppel-like factor 2 and 4. Mol Cancer Res. 2020;18:1218–31.
Zeng Z, Li Y, Pan Y, Lan X, Song F, Sun J, Zhou K, Liu X, Ren X, Wang F, et al. Cancer-derived exosomal mir-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat Commun. 2018;9:5395.
Hsu YL, Hung JY, Chang WA, Lin YS, Pan YC, Tsai PH, Wu CY, Kuo PL. Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene. 2017;36:4929–42.
Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, Yu Y, Chow A, O’Connor ST, Chin AR, et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote Metastasis. Cancer Cell. 2014;25:501–15.
Mao S, Zheng S, Lu Z, Wang X, Wang Y, Zhang G, Xu H, Huang J, Lei Y, Liu C, et al. Exosomal mir-375-3p breaks vascular barrier and promotes small cell Lung cancer Metastasis by targeting claudin-1. Transl Lung Cancer Res. 2021;10:3155–72.
Ma Z, Wei K, Yang F, Guo Z, Pan C, He Y, Wang J, Li Z, Chen L, Chen Y, Xia Y. Tumor-derived exosomal mir-3157-3p promotes angiogenesis, vascular permeability and Metastasis by targeting TIMP/KLF2 in non-small cell Lung cancer. Cell Death Dis. 2021;12:840.
Yao W, Jia X, Zhu L, Xu L, Zhang Q, Xia T, Wei L. Exosomal circ_0026611 contributes to lymphangiogenesis by reducing PROX1 acetylation and ubiquitination in human lymphatic endothelial cells (HLECs). Cell Mol Biol Lett. 2023;28:13.
Lu C, Xie L, Qiu S, Jiang T, Wang L, Chen Z, Xia Y, Lv J, Li Y, Li B et al. Small extracellular vesicles derived from Helicobacter Pylori-infected gastric Cancer cells induce lymphangiogenesis and lymphatic remodeling via transfer of miR-1246. Small 2023:e2308688.
Yin Y, Shelke GV, Lässer C, Brismar H, Lötvall J. Extracellular vesicles from mast cells induce mesenchymal transition in airway epithelial cells. Respir Res. 2020;21:101.
Shang A, Wang X, Gu C, Liu W, Sun J, Zeng B, Chen C, Ji P, Wu J, Quan W, et al. Exosomal mir-183-5p promotes angiogenesis in Colorectal cancer by regulation of FOXO1. Aging. 2020;12:8352–71.
McAllister SS, Weinberg RA. The tumour-induced systemic environment as a critical regulator of cancer progression and Metastasis. Nat Cell Biol. 2014;16:717–27.
Leslie M. Cell biology. Beyond clotting: the powers of platelets. Science. 2010;328:562–4.
Labelle M, Hynes RO. The initial hours of Metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination. Cancer Discov. 2012;2:1091–9.
Kanikarla-Marie P, Lam M, Menter DG, Kopetz S. Platelets, circulating Tumor cells, and the circulome. Cancer Metastasis Rev. 2017;36:235–48.
Schlesinger M. Role of platelets and platelet receptors in cancer Metastasis. J Hematol Oncol. 2018;11:125.
Nieswandt B, Hafner M, Echtenacher B, Männel DN. Lysis of Tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res. 1999;59:1295–300.
Rickles FR, Falanga A. Molecular basis for the relationship between Thrombosis and cancer. Thromb Res. 2001;102:V215–224.
Strasenburg W, Jóźwicki J, Durślewicz J, Kuffel B, Kulczyk MP, Kowalewski A, Grzanka D, Drewa T, Adamowicz J. Tumor Cell-Induced platelet aggregation as an emerging therapeutic target for Cancer Therapy. Front Oncol. 2022;12:909767.
Hisada Y, Mackman N. Tissue factor and extracellular vesicles: activation of Coagulation and Impact on Survival in Cancer. Cancers (Basel) 2021, 13.
Hisada Y, Sachetto ATA, Mackman N. Circulating tissue factor-positive extracellular vesicles and their association with Thrombosis in different Diseases. Immunol Rev. 2022;312:61–75.
Geddings JE, Hisada Y, Boulaftali Y, Getz TM, Whelihan M, Fuentes R, Dee R, Cooley BC, Key NS, Wolberg AS, et al. Tissue factor-positive Tumor microvesicles activate platelets and enhance Thrombosis in mice. J Thromb Haemost. 2016;14:153–66.
Gomes FG, Sandim V, Almeida VH, Rondon AMR, Succar BB, Hottz ED, Leal AC, Verçoza BRF, Rodrigues JCF, Bozza PT, et al. Breast-cancer extracellular vesicles induce platelet activation and aggregation by tissue factor-independent and -dependent mechanisms. Thromb Res. 2017;159:24–32.
Dudiki T, Veleeparambil M, Zhevlakova I, Biswas S, Klein EA, Ford P, Podrez EA, Byzova TV. Mechanism of Tumor-Platelet Communications in Cancer. Circ Res. 2023;132:1447–61.
Placke T, Örgel M, Schaller M, Jung G, Rammensee HG, Kopp HG, Salih HR. Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Res. 2012;72:440–8.
Liu X, Song J, Zhang H, Liu X, Zuo F, Zhao Y, Zhao Y, Yin X, Guo X, Wu X, et al. Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating Tumor cells from NK cell surveillance. Cancer Cell. 2023;41:272–287e279.
Fu Q, Zhang Q, Lou Y, Yang J, Nie G, Chen Q, Chen Y, Zhang J, Wang J, Wei T, et al. Correction: primary tumor-derived exosomes facilitate Metastasis by regulating adhesion of circulating Tumor cells via SMAD3 in Liver cancer. Oncogene. 2019;38:5740–1.
Żmigrodzka M, Witkowska-Piłaszewicz O, Winnicka A. Platelets extracellular vesicles as regulators of Cancer Progression-An updated perspective. Int J Mol Sci 2020, 21.
Lazar S, Goldfinger LE. Platelets and extracellular vesicles and their cross talk with cancer. Blood. 2021;137:3192–200.
Dashevsky O, Varon D, Brill A. Platelet-derived microparticles promote invasiveness of Prostate cancer cells via upregulation of MMP-2 production. Int J Cancer. 2009;124:1773–7.
Contursi A, Fullone R, Szklanna-Koszalinska P, Marcone S, Lanuti P, Taus F, Meneguzzi A, Turri G, Dovizio M, Bruno A et al. Tumor-educated platelet extracellular vesicles: proteomic profiling and crosstalk with Colorectal Cancer cells. Cancers (Basel) 2023, 15.
Olejarz W, Dominiak A, Żołnierzak A, Kubiak-Tomaszewska G, Lorenc T. Tumor-Derived Exosomes in Immunosuppression and Immunotherapy. J Immunol Res 2020, 2020:6272498.
Guo Y, Ji X, Liu J, Fan D, Zhou Q, Chen C, Wang W, Wang G, Wang H, Yuan W, et al. Effects of exosomes on pre-metastatic niche formation in tumors. Mol Cancer. 2019;18:39.
Xie F, Xu M, Lu J, Mao L, Wang S. The role of exosomal PD-L1 in Tumor progression and immunotherapy. Mol Cancer. 2019;18:146.
Del Re M, van Schaik RHN, Fogli S, Mathijssen RHJ, Cucchiara F, Capuano A, Scavone C, Jenster GW, Danesi R. Blood-based PD-L1 analysis in tumor-derived extracellular vesicles: applications for optimal use of anti-PD-1/PD-L1 axis inhibitors. Biochim Biophys Acta Rev Cancer. 2021;1875:188463.
Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, Montabana E, Lang UE, Fu Q, Fong L, Blelloch R. Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory. Cell. 2019;177:414–427e413.
Genova C, Tasso R, Rosa A, Rossi G, Reverberi D, Fontana V, Marconi S, Croce M, Dal Bello MG, Dellepiane C et al. Prognostic Role of Soluble and Extracellular Vesicle-Associated PD-L1, B7-H3 and B7-H4 in Non-Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors. Cells 2023, 12.
Akbar S, Raza A, Mohsin R, Kanbour A, Qadri S, Parray A, Zar Gul AR, Philip A, Vijayakumar S, Merhi M, et al. Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor Tumor response to anti-PD-1/PD-L1 therapy in non-small cell Lung cancer patients. Front Immunol. 2022;13:1097117.
Li C, Li C, Zhi C, Liang W, Wang X, Chen X, Lv T, Shen Q, Song Y, Lin D, Liu H. Clinical significance of PD-L1 expression in serum-derived exosomes in NSCLC patients. J Transl Med. 2019;17:355.
Roma-Rodrigues C, Pereira F, Alves de Matos AP, Fernandes M, Baptista PV, Fernandes AR. Smuggling gold nanoparticles across cell types - a new role for exosomes in gene silencing. Nanomedicine. 2017;13:1389–98.
Messenger SW, Woo SS, Sun Z, Martin TFJ. A ca(2+)-stimulated exosome release pathway in cancer cells is regulated by Munc13-4. J Cell Biol. 2018;217:2877–90.
Cortés-Hernández LE, Eslami SZ, Costa-Silva B, Alix-Panabières C. Current applications and discoveries related to the membrane components of circulating Tumor cells and extracellular vesicles. Cells 2021, 10.
Abusamra AJ, Zhong Z, Zheng X, Li M, Ichim TE, Chin JL, Min WP. Tumor exosomes expressing Fas ligand mediate CD8 + T-cell apoptosis. Blood Cells Mol Dis. 2005;35:169–73.
Contini P, Ghio M, Merlo A, Poggi A, Indiveri F, Puppo F. Apoptosis of antigen-specific T lymphocytes upon the engagement of CD8 by soluble HLA class I molecules is Fas ligand/Fas mediated: evidence for the involvement of p56lck, calcium calmodulin kinase II, and calcium-independent protein kinase C signaling pathways and for NF-kappaB and NF-AT nuclear translocation. J Immunol. 2005;175:7244–54.
Vivier E, Ugolini S, Blaise D, Chabannon C, Brossay L. Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol. 2012;12:239–52.
Garcia-Iglesias T, Del Toro-Arreola A, Albarran-Somoza B, Del Toro-Arreola S, Sanchez-Hernandez PE, Ramirez-Dueñas MG, Balderas-Peña LM, Bravo-Cuellar A, Ortiz-Lazareno PC, Daneri-Navarro A. Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in Cervical cancer and precursor lesions. BMC Cancer. 2009;9:186.
Clayton A, Mitchell JP, Court J, Linnane S, Mason MD, Tabi Z. Human tumor-derived exosomes down-modulate NKG2D expression. J Immunol. 2008;180:7249–58.
Dal Porto JM, Gauld SB, Merrell KT, Mills D, Pugh-Bernard AE, Cambier J. B cell antigen receptor signaling 101. Mol Immunol. 2004;41:599–613.
Schroeder JC, Puntigam L, Hofmann L, Jeske SS, Beccard IJ, Doescher J, Laban S, Hoffmann TK, Brunner C, Theodoraki MN, Schuler PJ. Circulating exosomes inhibit B cell proliferation and activity. Cancers (Basel) 2020, 12.
Xie X, Lian S, Zhou Y, Li B, Lu Y, Yeung I, Jia L. Tumor-derived exosomes can specifically prevent cancer metastatic organotropism. J Control Release. 2021;331:404–15.
Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, et al. Tumour exosome integrins determine organotropic Metastasis. Nature. 2015;527:329–35.
Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, Becker A, Hoshino A, Mark MT, Molina H, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17:816–26.
Huang W, Yan Y, Liu Y, Lin M, Ma J, Zhang W, Dai J, Li J, Guo Q, Chen H, et al. Exosomes with low miR-34c-3p expression promote invasion and migration of non-small cell Lung cancer by upregulating integrin α2β1. Signal Transduct Target Ther. 2020;5:39.
Singh A, Fedele C, Lu H, Nevalainen MT, Keen JH, Languino LR. Exosome-mediated transfer of αvβ3 integrin from Tumorigenic to nontumorigenic cells promotes a migratory phenotype. Mol Cancer Res. 2016;14:1136–46.
Berghoff AS, Rajky O, Winkler F, Bartsch R, Furtner J, Hainfellner JA, Goodman SL, Weller M, Schittenhelm J, Preusser M. Invasion patterns in brain metastases of solid cancers. Neuro Oncol. 2013;15:1664–72.
Vogetseder A, Thies S, Ingold B, Roth P, Weller M, Schraml P, Goodman SL, Moch H. αv-Integrin isoform expression in primary human tumors and brain metastases. Int J Cancer. 2013;133:2362–71.
Berghoff AS, Kovanda AK, Melchardt T, Bartsch R, Hainfellner JA, Sipos B, Schittenhelm J, Zielinski CC, Widhalm G, Dieckmann K, et al. αvβ3, αvβ5 and αvβ6 integrins in brain metastases of Lung cancer. Clin Exp Metastasis. 2014;31:841–51.
Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;438:820–7.
Blavier L, Nakata R, Neviani P, Sharma K, Shimada H, Benedicto A, Matei I, Lyden D, DeClerck YA. The capture of extracellular vesicles endogenously released by xenotransplanted tumours induces an inflammatory reaction in the premetastatic niche. J Extracell Vesicles. 2023;12:e12326.
Peinado H, Zhang H, Matei IR, Costa-Silva B, Hoshino A, Rodrigues G, Psaila B, Kaplan RN, Bromberg JF, Kang Y, et al. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer. 2017;17:302–17.
Zhao L, Ma X, Yu J. Exosomes and organ-specific Metastasis. Mol Ther Methods Clin Dev. 2021;22:133–47.
Nishikawa H, Koyama S. Mechanisms of regulatory T cell infiltration in tumors: implications for innovative immune precision therapies. J Immunother Cancer 2021, 9.
Wang M, Qin Z, Wan J, Yan Y, Duan X, Yao X, Jiang Z, Li W, Qin Z. Tumor-derived exosomes drive pre-metastatic niche formation in lung via modulating CCL1(+) fibroblast and CCR8(+) Treg cell interactions. Cancer Immunol Immunother. 2022;71:2717–30.
Sun X, Wang X, Yan C, Zheng S, Gao R, Huang F, Wei Y, Wen Z, Chen Y, Zhou X, et al. Tumor cell-released LC3-positive EVs promote lung Metastasis of Breast cancer through enhancing premetastatic niche formation. Cancer Sci. 2022;113:3405–16.
Chang LC, Chiu HM, Wu MS, Shen TL. The role of small extracellular vesicles in the progression of Colorectal Cancer and its clinical applications. Int J Mol Sci 2022, 23.
Srivastava A, Rathore S, Munshi A, Ramesh R. Extracellular vesicles in Oncology: from Immune suppression to Immunotherapy. Aaps j. 2021;23:30.
Chen X, Zhou J, Li X, Wang X, Lin Y, Wang X. Exosomes derived from hypoxic epithelial Ovarian cancer cells deliver microRNAs to macrophages and elicit a tumor-promoted phenotype. Cancer Lett. 2018;435:80–91.
Li B, Yang C, Zhu Z, Chen H, Qi B. Hypoxic glioma-derived extracellular vesicles harboring MicroRNA-10b-5p enhance M2 polarization of macrophages to promote the development of glioma. CNS Neurosci Ther. 2022;28:1733–47.
Xu J, Feng X, Yin N, Wang L, Xie Y, Gao Y, Xiang J. Exosomes from cisplatin-induced dormant cancer cells facilitate the formation of premetastatic niche in bone marrow through activating glycolysis of BMSCs. Front Oncol. 2022;12:922465.
Urabe F, Patil K, Ramm GA, Ochiya T, Soekmadji C. Extracellular vesicles in the development of organ-specific Metastasis. J Extracell Vesicles. 2021;10:e12125.
Zhou X, Zhong F, Yan Y, Wu S, Wang H, Liu J, Li F, Cui D, Xu M. Pancreatic Cancer cell-derived exosomes promote lymphangiogenesis by downregulating ABHD11-AS1 expression. Cancers (Basel) 2022, 14.
Chen C, Luo Y, He W, Zhao Y, Kong Y, Liu H, Zhong G, Li Y, Li J, Huang J, et al. Exosomal long noncoding RNA LNMAT2 promotes lymphatic Metastasis in Bladder cancer. J Clin Invest. 2020;130:404–21.
Zheng H, Chen C, Luo Y, Yu M, He W, An M, Gao B, Kong Y, Ya Y, Lin Y, et al. Tumor-derived exosomal BCYRN1 activates WNT5A/VEGF-C/VEGFR3 feedforward loop to drive lymphatic Metastasis of Bladder cancer. Clin Transl Med. 2021;11:e497.
Zhou CF, Ma J, Huang L, Yi HY, Zhang YM, Wu XG, Yan RM, Liang L, Zhong M, Yu YH, et al. Cervical squamous cell carcinoma-secreted exosomal mir-221-3p promotes lymphangiogenesis and lymphatic Metastasis by targeting VASH1. Oncogene. 2019;38:1256–68.
Liu T, Li P, Li J, Qi Q, Sun Z, Shi S, Xie Y, Liu S, Wang Y, Du L, Wang C. Exosomal and intracellular miR-320b promotes lymphatic Metastasis in esophageal squamous cell carcinoma. Mol Ther Oncolytics. 2021;23:163–80.
Ding Z, Yan Y, Guo YL, Wang C. Esophageal carcinoma cell-excreted exosomal uc.189 promotes lymphatic Metastasis. Aging. 2021;13:13846–58.
García-Silva S, Benito-Martín A, Nogués L, Hernández-Barranco A, Mazariegos MS, Santos V, Hergueta-Redondo M, Ximénez-Embún P, Kataru RP, Lopez AA, et al. Melanoma-derived small extracellular vesicles induce lymphangiogenesis and Metastasis through an NGFR-dependent mechanism. Nat Cancer. 2021;2:1387–405.
Huang J, Wang X, Wen J, Zhao X, Wu C, Wang L, Cao X, Dong H, Xu X, Huang F, et al. Gastric cancer cell-originated small extracellular vesicle induces metabolic reprogramming of BM-MSCs through ERK-PPARγ-CPT1A signaling to potentiate lymphatic Metastasis. Cancer Cell Int. 2023;23:87.
Wang J, Du X, Wang X, Xiao H, Jing N, Xue W, Dong B, Gao WQ, Fang YX. Tumor-derived miR-378a-3p-containing extracellular vesicles promote osteolysis by activating the Dyrk1a/Nfatc1/Angptl2 axis for bone Metastasis. Cancer Lett. 2022;526:76–90.
Dai J, Escara-Wilke J, Keller JM, Jung Y, Taichman RS, Pienta KJ, Keller ET. Primary Prostate cancer educates bone stroma through exosomal pyruvate kinase M2 to promote bone Metastasis. J Exp Med. 2019;216:2883–99.
Liu Y, Yang C, Chen S, Liu W, Liang J, He S, Hui J. Cancer-derived exosomal miR-375 targets DIP2C and promotes osteoblastic Metastasis and Prostate cancer progression by regulating the wnt signaling pathway. Cancer Gene Ther. 2023;30:437–49.
Ni J, Zhang X, Li J, Zheng Z, Zhang J, Zhao W, Liu L. Tumour-derived exosomal lncRNA-SOX2OT promotes bone Metastasis of non-small cell Lung cancer by targeting the miRNA-194-5p/RAC1 signalling axis in osteoclasts. Cell Death Dis. 2021;12:662.
Li XQ, Zhang R, Lu H, Yue XM, Huang YF. Extracellular vesicle-packaged CDH11 and ITGA5 induce the Premetastatic Niche for Bone colonization of Breast Cancer cells. Cancer Res. 2022;82:1560–74.
Sirkisoon SR, Wong GL, Aguayo NR, Doheny DL, Zhu D, Regua AT, Arrigo A, Manore SG, Wagner C, Thomas A, et al. Breast cancer extracellular vesicles-derived miR-1290 activates astrocytes in the brain metastatic microenvironment via the FOXA2→CNTF axis to promote progression of brain metastases. Cancer Lett. 2022;540:215726.
Xing F, Liu Y, Wu SY, Wu K, Sharma S, Mo YY, Feng J, Sanders S, Jin G, Singh R, et al. Loss of XIST in Breast Cancer activates MSN-c-Met and reprograms Microglia via Exosomal miRNA to promote Brain Metastasis. Cancer Res. 2018;78:4316–30.
Wu D, Deng S, Li L, Liu T, Zhang T, Li J, Yu Y, Xu Y. TGF-β1-mediated exosomal lnc-MMP2-2 increases blood-brain barrier permeability via the miRNA-1207-5p/EPB41L5 axis to promote non-small cell Lung cancer brain Metastasis. Cell Death Dis. 2021;12:721.
Xu W, Patel N, Deng Y, Ding S, Wang T, Zhang H. Extracellular vesicle-derived LINC00482 induces microglial M2 polarization to facilitate brain Metastasis of NSCLC. Cancer Lett. 2023;561:216146.
Tiong TY, Chan ML, Wang CH, Yadav VK, Pikatan NW, Fong IH, Yeh CT, Kuo KT, Huang WC. Exosomal miR-21 determines lung-to-brain Metastasis specificity through the DGKB/ERK axis within the Tumor microenvironment. Life Sci 2023:121945.
Le MT, Hamar P, Guo C, Basar E, Perdigão-Henriques R, Balaj L, Lieberman J. Mir-200-containing extracellular vesicles promote Breast cancer cell Metastasis. J Clin Invest. 2014;124:5109–28.
Xu D, Chen WQ, Liang MX, Chen X, Liu Z, Fei YJ, Shao XY, Wu Y, Zhang W, Tang JH. Tumor-derived small extracellular vesicles promote Breast cancer progression by upregulating PD-L1 expression in macrophages. Cancer Cell Int. 2023;23:137.
Xia W, Liu Y, Cheng T, Xu T, Dong M, Hu X. Extracellular vesicles carry lncRNA SNHG16 to promote Metastasis of Breast Cancer cells via the miR-892b/PPAPDC1A Axis. Front Cell Dev Biol. 2021;9:628573.
Fang T, Lv H, Lv G, Li T, Wang C, Han Q, Yu L, Su B, Guo L, Huang S, et al. Tumor-derived exosomal mir-1247-3p induces cancer-associated fibroblast activation to foster lung Metastasis of Liver cancer. Nat Commun. 2018;9:191.
Zhong L, Liao D, Li J, Liu W, Wang J, Zeng C, Wang X, Cao Z, Zhang R, Li M, et al. Rab22a-NeoF1 fusion protein promotes osteosarcoma lung Metastasis through its secretion into exosomes. Signal Transduct Target Ther. 2021;6:59.
Zhao S, Mi Y, Guan B, Zheng B, Wei P, Gu Y, Zhang Z, Cai S, Xu Y, Li X, et al. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver Metastasis of Colorectal cancer. J Hematol Oncol. 2020;13:156.
Wei X, Ye J, Pei Y, Wang C, Yang H, Tian J, Si G, Ma Y, Wang K, Liu G. Extracellular vesicles from Colorectal cancer cells promote Metastasis via the NOD1 signalling pathway. J Extracell Vesicles. 2022;11:e12264.
Zhao S, Mi Y, Zheng B, Wei P, Gu Y, Zhang Z, Xu Y, Cai S, Li X, Li D. Highly-metastatic Colorectal cancer cell released miR-181a-5p-rich extracellular vesicles promote liver Metastasis by activating hepatic stellate cells and remodelling the tumour microenvironment. J Extracell Vesicles. 2022;11:e12186.
Sun J, Lu Z, Fu W, Lu K, Gu X, Xu F, Dai J, Yang Y, Jiang J. Exosome-derived ADAM17 promotes Liver Metastasis in Colorectal Cancer. Front Pharmacol. 2021;12:734351.
Yang X, Zhang Y, Zhang Y, Li H, Li L, Wu Y, Chen X, Qiu L, Han J, Wang Z. Colorectal cancer-derived extracellular vesicles induce liver premetastatic immunosuppressive niche formation to promote Tumor early liver Metastasis. Signal Transduct Target Ther. 2023;8:102.
Wang Z, Kim SY, Tu W, Kim J, Xu A, Yang YM, Matsuda M, Reolizo L, Tsuchiya T, Billet S et al. Extracellular vesicles in fatty liver promote a metastatic Tumor microenvironment. Cell Metab 2023.
Chang YT, Peng HY, Hu CM, Tien SC, Chen YI, Jeng YM, Chang MC. Pancreatic cancer-derived small extracellular vesical ezrin activates fibroblasts to exacerbate cancer Metastasis through STAT3 and YAP-1 signaling pathways. Mol Oncol 2023.
Qiu S, Xie L, Lu C, Gu C, Xia Y, Lv J, Xuan Z, Fang L, Yang J, Zhang L, et al. Gastric cancer-derived exosomal miR-519a-3p promotes liver Metastasis by inducing intrahepatic M2-like macrophage-mediated angiogenesis. J Exp Clin Cancer Res. 2022;41:296.
Acknowledgements
Figures 1, 2 and 3 were made using www.BioRender.com.
Funding
This study was supported by grants from the National Natural Science Foundation of China (82173245, 82300881), the Sichuan Science and Technology Program (2023YFS0148, 2023YFS0149), and the Science and Technology Achievement Transformation Project, West China Hospital, Sichuan University (CGZH21004, 21HXFH005).
Author information
Authors and Affiliations
Contributions
Siyin Guo and Jianyong Lei were responsible for the conception and design and study supervision. Siyin Guo, Jing Huang, Genpeng Li, Wenjie Chen, Zhihui Li and Jianyong Lei wrote and revised the manuscript. All the authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Guo, S., Huang, J., Li, G. et al. The role of extracellular vesicles in circulating tumor cell-mediated distant metastasis. Mol Cancer 22, 193 (2023). https://doi.org/10.1186/s12943-023-01909-5
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s12943-023-01909-5