Mesenchymal Stem/Stromal-Cell-Derived Extracellular Vesicles in Cancer Therapy: History
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Contributor:
Andreas Nicodemou
,
Soňa Bernátová
,
Michaela Čeháková
,
Ľuboš Danišovič

Despite the tremendous efforts of many researchers and clinicians, cancer remains the second leading cause of mortality worldwide. Mesenchymal stem/stromal cells (MSCs) are multipotent cells residing in numerous human tissues and presenting unique biological properties, such as low immunogenicity, powerful immunomodulatory and immunosuppressive capabilities, and, in particular, homing abilities. Therapeutic functions of MSCs are mediated mostly by the paracrine effect of released functional molecules and other variable components, and among them the MSC-derived extracellular vesicles (MSC-EVs) seem to be one of the central mediators of the therapeutic functions of MSCs. MSC-EVs are membrane structures secreted by the MSCs, rich in specific proteins, lipids, and nucleic acids. Amongst these, microRNAs have achieved the most attention. Unmodified MSC-EVs can promote or inhibit tumor growth, while modified MSC-EVs are involved in the suppression of cancer progression via the delivery of therapeutic molecules, including miRNAs, specific siRNAs, or suicide RNAs, as well as chemotherapeutic drugs. 

  • mesenchymal cells
  • extracellular vesicles
  • cancer therapy

1. Introduction

Mesenchymal stem/stromal cells (MSCs) are multipotent, nonhematopoietic adult somatic stem cells that are present in multiple human tissues, including bone marrow, adipose tissue, amniotic fluid, dental pulp, umbilical cord blood, Wharton’s jelly, etc. [1]. Moreover, MSCs are an important component of the tumor microenvironment (TME) [2]. Due to their unique properties, such as low immunogenicity and powerful immunomodulatory and immunosuppressive capabilities, in particular homing abilities, as well as their contribution to tissue regeneration and repair capabilities, MSCs have become ideal candidates for cell-based therapies, which is further supported by thousands of patients administered with MSCs in clinical trials for the treatment of various diseases, including graft-versus-host disease, hematologic and solid malignancies, bone/cartilage defects, and cardiovascular, autoimmune, or neurologic diseases [3]. Initially, the therapeutic effects of MSCs’ research were attributed to their engrafting and differentiation capacity [4], but current studies indicate that the main therapeutic effects of MSCs are mediated by paracrine mechanisms, through the secretion of a wide array of growth factors, cytokines, and extracellular vesicles (EVs) that collectively contribute to enhancing tissue repair and mitigating inflammatory and immune responses [5][6]. It has been shown that MSCs are involved in tumor development, including tumorigenesis, tumor growth, and metastasis, as well as fine regulation of the TME. However, the exact mechanism of how MSCs affect tumor development and progression is still controversial [7]. MSCs play a double-faced role in tumorigenesis and progression: on one hand, they provide a framework for anchoring tumor cells in the tumor stroma and promote tumor progression through secreting pro-tumorigenic factors [8], supporting tumor angiogenesis, initiating epithelial–mesenchymal transition (EMT), differentiating into tumor-associated fibroblasts [9], and disrupting immune surveillance [10][11][12]. On the other hand, there are many studies demonstrating that MSCs could suppress tumor growth by silencing angiogenesis and increasing inflammatory cell infiltration, apoptosis, and cell cycle arrest, as well as inhibiting the AKT and Wnt signaling pathways [11].

2. Criteria and Methods for MSC-EV Analysis and Validation in Therapeutic Application

It is crucial to comprehensively characterize isolated MSC-EVs appropriately, primarily in terms of their size, morphology, concentration, presence of EV-enriched or loaded markers, and lack of contaminants. In order for the release of MSC-EV preparations to take place for clinical applications, quality release criteria have to be clearly defined. There are ISEV minimal criteria to appropriately validate EVs preparations. Each preparation should be: (1) defined by quantitative measures of the source EVs (e.g., number of secreting cells, volume of biofluid, and mass of tissue); (2) characterized to the extent possible to determine the abundance of EVs (total particle number and/or protein or lipid content); (3) tested for the presence of components associated with EV subtypes or EVs generically, depending on the specificity one wishes to achieve; (4) tested for the presence of non-vesicular, co-isolated components [13].
Additionally, there are further criteria and recommendations for applying EV-based therapeutics in clinical trials, discussed extensively in the ISEV position paper on clinical application by Lener at al. [14]. For instance, in addition to the basic characterization of EVs mentioned above, sterile EV preparations for pharmaceutical use must be tested for the absence of viral and microbiological contaminants and must not contain endotoxins above defined levels. Furthermore, as therapeutic activities cannot be proposed only by molecular profiling, qualified in vitro potency assays are required to predict the intended therapeutic potential of EV preparations, at best in a quantifiable manner. For example, based on the premise that MSC-EVs exert immunosuppressive functions in vivo, T-cell proliferative assays have to be applied to determine immunomodulatory properties ex vivo [14][15]. In addition, certainly the whole preparation of EV therapeutics should demonstrate a standardized production process. In 2017 the EV-TRACK platform was created (https://evtrack.org (accessed on 24 April 2023))—a crowdsourcing knowledgebase allowing researchers to first deposit their isolation and characterization protocols before publication and consequently receive references and recommendations on potential deficiencies in the experimental design [16][17].
Currently, there are typically two types of analysis, using different methodologies, performed on EV preparations: (a) physical analysis and (b) biochemical/compositional analysis. The physical analysis gives insight into the size and concentration of MSC-EVs and usually is performed by nanoparticle tracking analysis (NTA), electron microscopy, including transmission electron microscopy (TEM) and scanning electron microscopy (SEM), atomic force microscopy (AFM), dynamic light scattering (DLS), and tunable resistive pulse sensing (tRPS). The biochemical/compositional analysis typically gives information regarding the cargo of the isolated EVs. This is based on immunodetection methods (ELISA, Western blot, and flow cytometry), mass spectrometry (MS) proteomic analysis, and RNA and/or DNA sequencing. Detailed comprehensive reviews of methods for EV analysis can be found elsewhere, e.g., by Doyle and Wang [18], Coumans et al. [19], or Szatanek et al. [20].

3. MSC-EVs as Drug Carriers

Specific and targeted delivery of drugs to tumors without harming the surrounding healthy tissues is a hopeful wish of many researchers. Significant advances in the development of smart nanocarriers as drug delivery systems have been achieved in recent decades. In particular, lipid-based nanocarriers are used, and liposomes are the preferred pharmaceutical vehicle for drug delivery, which has led to clinical translations in many applications, such as the delivery of anti-cancer drugs, analgetics, immunomodulators, and anti-fungal or anti-viral drugs. In addition to synthetic nanocarriers, the cell-derived EV-based carrier system has attracted great interest in the last few years. In regenerative medicine and oncology, MSC-EVs are already under clinical assessment as potent vectors for future use intended as “cell-free” therapeutics, due to the following outperforming properties: (1) the tremendous potential to overcome barriers created by the tumor environment; (2) the intrinsic homing ability to target tissues—particularly through strong migrating tropism towards tumor sites; (3) the enhanced ability to cross physical and biological barriers, such as the blood–brain barrier, allowing, e.g., the noninvasive treatment of intracerebral diseases; (4) innate anti-inflammatory and pro-regenerative features; (5) good tolerability in the organism leading to longer circulating times—since they are derived from an organism, they are naturally less immunogenic, and additionally often the presence of the CD47 “do not eat me” marker could prevent EVs from undergoing phagocytosis [21][22][23][24][25].
Although native unmodified MSC-EVs are commonly used in clinical practice, they can be further modified functionally to improve their use as drug carriers. Bioengineered MSC-EVs exhibit higher therapeutic potential since they transfer desired cargo and confer enhanced target specificity. In principle, there are two main strategies regarding how to maximize the therapeutic characteristics of MSC-EVs: cargo engineering (incorporation of therapeutic molecules into EVs) and surface modification engineering (EV mimetics).

3.1. Cargo Engineering

Different therapeutic substances, including drugs, proteins, and nucleic acids, can be load into the MSC-EVs. The loading strategies are divided to two main categories:
(1)
Pre-loading (parental cell engineering)—before MSC-EV isolation.
(2)
Post-loading (direct loading)—after isolation of MSC-EVs.

3.1.1. Pre-Loading

In pre-loading, therapeutic molecules, such as nucleic acids, proteins, and/or small drugs, are loaded into EVs through parental cell engineering (MSCs) during the biogenesis of vesicles, leading to the packaging of the desired molecules into the lumen of newly formed EVs. This approach comprises the loading of functional molecules by increasing their concentration in the cytoplasm of parental MSCs, which can be performed directly by incubating drugs with parental cells (passive loading) or by the genetic manipulation of parental cells via modification of RNA/protein components (active loading).
Transfection and transduction of parental cells via expressing plasmids or retro/lentiviral vectors containing information to create EVs enriched with miRNA precursors, siRNAs, or proteins are currently the most frequently used methods of the active loading strategy [21][26][27]. Lou et al. used plasmid vectors to transfect miRNA miR-122 into ATMSC in order to produce ATMSC-EVs with miR-122 cargo and thereby enhance hepatocellular carcinoma chemosensitivity [28]. The strategy of using expressing plasmids also facilitates the clinical translation of proteins with high molecular weight, e.g., tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL), a potent anti-cancer molecule, which was transfected to MSCs for the production of TRAIL-enriched MSC-EVs displaying high cancer cell killing efficiency [29]. Nevertheless, the overexpression of a specific protein may cause an imbalance in cell proliferation and leads to apoptosis. This subsequently reduces the proliferation rate of MSCs and the production of EVs. In addition, the pre-loading approach is associated with the risk that EVs are loaded with unwanted proteins or nucleic acids with unpredictable effects on the performed therapy [30].
Passive loading is often performed for the incorporation of small-molecular-weight drugs, such as paclitaxel (PTX) or curcumin. PTX is a hydrophobic mitotic inhibitor with a strong anti-cancer effect. Pascucci et al. incubated MSCs with high dosages of PTX, and the released MSC-EVs containing encapsulated PTX displayed stronger antitumor activity against pancreatic adenocarcinoma compared to PTX alone [31].

3.1.2. Post-Loading

Post-loading is performed after EV isolation. Similarly, as for the pre-loading strategy, exogenous cargoes are loaded passively or actively into EVs. Passive loading is a relatively simple method in which purified EVs are incubated with hydrophobic drugs to allow passive incorporation into the membrane of EVs. The hydrophobic nature of the cargo and the concentration gradient of the molecules determine these methods, which usually exhibit excellent performance for hydrophobic compounds, such as curcumin; however, the stability of passively loaded drugs is still not clear [32][33][34][35].
For hydrophilic molecules such as nucleic acids that cannot incorporate spontaneously into the membrane of EVs, active loading strategies work better in order to temporarily permeabilize the hydrophobic lipid barrier, either physically or chemically, to allow simple penetration of compounds into EVs. The most common approaches to temporarily physically permeabilize the EV membrane are electroporation, sonication, freeze–thaw cycles, and extrusion. These methods were shown to be successful for small molecules as well as macromolecules [36][37][38]. Gomari et al. used electroporation for successful loading of doxorubicin (DOX), one of the most effective antitumor drugs against solid tumors, into the MSC-EVs. DOX-loaded MSC-EVs showed a significant reduction in the murine breast cancer model tumor growth rate [39]. However, some studies have indicated changes in the morphology of EVs and the forming of RNA aggregates, which caused the loss of function of loaded RNAs or destabilized the EVs’ function in vivo; therefore, the potential influence on loaded cargo requires careful consideration [40][41]
An alternative active post-loading approach utilizes chemicals (transfectants or permeabilizers), such as saponin or triton, to temporarily permeabilize the EV membrane. Saponins are mild surfactants that induce transient membrane destabilization to facilitate the entrance of drug loading into EVs without destroying their lipid bilayer structure. This approach has been shown to be effective mainly for large proteins. Large enzymes over 200 kDa (catalase) have been successfully loaded using saponin detergent [42][43].

3.2. Surface Engineering

One of the reasons for the poor therapeutic effect of some chemotherapeutic drugs used in the treatment of carcinomas relates to their systemic and non-targeting effects. Furthermore, the different abilities of distinct types of cells in capturing EVs is another challenge to overcome before EVs will be able to be utilized in clinical practice. Increasing the targeting capacity of MSC-EVs to tumor cells rather than other cells could dramatically improve the efficiency of antitumor therapy. Changing the surface of MSC-EVs, especially the protein composition, can alter the tropism of MSC-EV preparations, thus increasing the local concentration of MSC-EVs at desired sites, improving the therapeutic effects of loaded drug cargo on the target area, and reducing the adverse impact on other areas. Numerous studies have been performed in order to improve the targeting of MSC-EVs using different approaches, which could be classified into three major categories: genetic engineering, chemical modification of target molecule engineering, and hybrid membrane engineering [11][44].
Altering the targeting peptide on the surface of MSC-EVs is a highly efficient and direct approach to improving the directing of MSC-EVs. Even if MSC-EVs cross the blood–brain barrier, only systemic administration leads to non-specific accumulation in the lung, liver, spleen, or gastrointestinal track [45]. Therefore, it is necessary to improve the targeting of MSC-EVs directly to the tumor site, e.g., to glioma. Jia et al. coupled the neuropilin-1-targeted peptide to the MSC-EV membrane by click chemistry to improve glioma targeting. Furthermore, they loaded superparamagnetic iron oxide nanoparticles (SPIONSs) and curcumin into MSC-EVs to further enhance the magnetic targeting of MSC-EVs and bioimaging of loaded MSC-EVs.
Utilizing targeting peptides conjugated on the surface of MSC-EVs has been further applied to research on lung cancer, breast cancer, liver cancer, or glioblastoma [44]. Moreover, in combination with metal or gold nanoparticles it is possible to perform imaging (magnetic resonance imaging or computed tomography) to further evaluate the distribution of MSC-EVs in the body in order to better understand pharmacodynamics, targeting, and biodistribution of MSC-EVs. Nevertheless, adding targeting peptides can cause unexpected immunogenicity problems, and the impact of the linking modification is still present. Therefore, it is crucial to well understand the complete attributes of the surface composition, coupling procedures, and the molecular mechanisms of the targeted disease [46][47].

4. Distinct Roles of MSC-EVs in Cancer Biology

A number of studies have pointed out the double-edged properties of MSC-EVs in the tumor environment, confirming that MSC-EVs play a dual role in promoting and inhibiting multiple stages of tumorigenesis. Similarly, as for instance with cancer-cell-derived EVs, MSC-EVs have also been reported to play an important role in mediating tumor proliferation, angiogenesis, apoptosis, tumor invasion, dormancy, or resistance to chemotherapy/radiotherapy [48]. This inconsistency over the dual effect of MSC-EVs on tumorigenesis may be facilitated by many factors, including cell origin, experimental design, culture conditions, method of EV administration, or the tumor microenvironment (TME)–MSC-EV crosstalk. Recently, it seems to be just the crosstalk of MSC-EVs in the TME that is pivotal for cancer progression [49]. Moreover, different physical and chemical factors within the TME, such as hypoxia/anoxia or low/high pH, could strongly affect the behavior of MSCs and thereby alter EVs’ release and content. Depending on the present localization and tumor compartment, MSCs could be heterogeneously activated to receive different chemokine signals for transmitting stimulation or suppression of tumor growth [50]. In addition, controversial findings about the functionality of MSC-EVs may be at least partially attributable to the heterogeneity of the parental MSC populations themselves. MSC-EVs originating from various sources contain different proteins, nucleic acids, and bioactive molecules, both in terms quality and quantity, which can affect not only tumor cells, but also other cells comprising the TME, such as immune cells, tumor-associated macrophages, myeloid-derived suppressor cells, endothelial cells, or cancer-associated fibroblasts [2]. Baglio et al. demonstrated that hBMMSCs and ATMSCs secrete EVs enriched in distinctive miRNA and tRNA species [51]. For instance, in relation to the origin of MSC-EVs, MSC-EVs secreted by hBMMSC-EVs promote the tumor growth and invasion of colorectal cancer or osteosarcoma by the carrying of distinct mi-RNAs or lncRNAs via the upregulation of transforming growth factor-β receptor 3 (TGFBR3) or the elevation of ERB protein expression, respectively [52][53]. In contrast, human-umbilical-cord-derived MSC-EVs (hUCMSC-EVs) carried different types of mi-RNAs, curbing the progression of renal cell carcinoma through T-cell immune response [54]. Analogously, ATMSC-EVs balance the proper differentiation of T helper 17 cells (Th17) and T regulation lymphocytes (Tregs) from naive CD4+ T cell to enhance antitumor ability via miR-10a mi-RNA [55]. A systematic review presented by Christodoulou et al. [56] evaluated that 74% of studies reported a tumor-promotion effect for BMMSCs, 54% for ATMSCs, and only 12% for UCMSCs. These findings suggest that UCMSCs-EVs are the best candidates as drug carriers for further clinical trials. On other hand, almost all studies on tumor-associated MSC-EVs (TAMSC-EVs) reported their strong tumor-promotion effect [2][57].

4.1. Tumor Growth

The discussions about the effects of MSC-EVs in carcinogenesis first appeared when Zhu et al. reported that MSC-EVs could promote tumor growth in vivo, similarly to MSCs. They found that BMMSC-EVs support tumor growth in xenograft models of gastrointestinal cancer; however, BMMSC-EVs did not present the same effect on tumor cells in vivo. BMMSC-EVs enhance the expression of VEGF in tumor cells by activating the ERK1/2 pathway to promote tumor angiogenesis [58]. In general, tumor growth is regulated by a variety of growth factor receptors, such as epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), or transforming growth factor-β receptor (TGFBR). The activation or phosphorylation of the functional domains of these receptors by respective intracellular kinases initiates pro-growth signals through protein kinase B (PKB/ACT), protein kinase C (PKC), or mitogen-activated protein kinase (MAP/ERK) pathways, leading to tumor cell proliferation. Furthermore, it has been presented that tumor-associated miRNAs enriched in MSC-EVs are strongly associated with promoting or blocking cancer cell proliferation. MiRNAs are short (20–25 nucleotides) single-stranded non-coding RNAs that regulate the post-transcriptional gene expression in target cells by binding to the 3´-UTRs of mRNAs [59]. Many studies have shown that in malignant tumors, such as in breast cancer, pancreatic cancer, osteosarcoma, or colorectal cancer, MSC-EVs can exert pro-carcinogenic effects by regulating different signaling pathways or protein expression through specific miRNAs [52][53][60][61]. Dong et al. has shown that the transfer of miR-410 from human-umbilical-cord-derived-EVs (hUCMSC-EVs) promoted adenocarcinoma cell growth through direct inhibition of PTEN expression [62]. A study conducted by Guo et al. demonstrated that MSC-EVs deliver miR-130b-3p to lung cancer cells to promote cancer cell proliferation, migration, and invasion via blocking the TXNRD1 pathway by FOXO3 inhibition [63]. In addition to a higher level of miRNAs, other factors such as increased levels of cytokines or adhesion molecules in MSC-EVs may also be involved in the promotion of tumor growth [64][65].
In contrary to the studies mentioned above, miRNAs, lncRNAs, and proteins enriched in MSC-EVs can also participate in cancer suppression. For example, miR222-3p, which is highly expressed in BMMSC-EVs, suppresses acute myeloid leukemia (AML) cell proliferation and promotes apoptosis by targeting the IRF2/INPP4B signaling pathway [66]. Similarly, ATMSC-EVs inhibit prostate cancer through the delivery of miR-145 to reduce Bcl-xL activity and promote apoptosis via the activation of the caspase-3/7 pathway [67]. BMMSC-EVS also enable the delivery of miR101-3p and suppress oral cancer progression by targeting COL10A1 [68]. MSC-EVs isolated from different sources of MSCs were shown to participate in both promotion and suppression of tumor growth. This depends on the EVs’ content, such as the composition of respective miRNAs or protein cargo that can vary under different conditions. Accordingly, MSC-EVs could transfer opposite signals in the same tumor type associated with distinct subsets of miRNA or distinct protein levels. Nonetheless, more studies are required to elucidate multiple molecular signaling pathways involved in the regulation of tumor growth.

4.2. Metastasis/EMT

Metastasis is a complex process that involves the spread of tumor cells through the bloodstream or lymph vessels from their original site (primary site) to distant parts of the body and the formation of new tumors (metastatic tumors). This process is a vital feature of malignant cells and causes more than 90% of cancer-related deaths [69]. The induction of EMT is a hallmark of aggressive tumors, and cells that submit to EMT are inclined to disseminate and form colonies distant from the original location. Emerging evidence has indicated the fundamental role of EVs in the EMT mediating metastasis [70][71]. Numerous studies have investigated the role of MSC-EVs in metastasis and EMT promotion, whereas their findings are contributing to both stimulating the formation of metastatic tumors as well as provoking dormant cells [72]. For instance, Zhou et al. reported that hUCMSC-EVs promote tumor progression and metastasis in breast cancer via induction of EMT by upregulation of the ERK pathway [60]. Similarly, Li et al. described MSC-EVs transfected with miR-222 promoting tumor invasion and immunosuppression of colorectal tumor cells via ATF3 binding and mediating the AKT pathway [73]. In contrary, there are studies showing the inhibition of the metastatic potential of tumor cells mediated by the cargo of MSC-EVs. It was demonstrated that hBMMSC-EVs loaded with miR-22-3p were able to suppress colorectal cell proliferation, migration, and metastasis invasion by regulation of the RAP2B and PI3K/AKT pathways [74]. Likewise, hUCMSC-EVs inhibit the proliferation and migration of endometrial cancer cells by transferring miRNA-302a and downregulating the AKT signaling pathway and cyclin D1 [75]. The study of Yao et al. identified the key molecule circ_0030167 derived from BMMSCs-EVs, which inhibits the invasion, migration, proliferation, and stemness of pancreatic cancer cells by sponging miR-338-5p and targeting the Wif1/Wnt8/β-catenin axis [76]. Commonly, MSC-EVs play an important role in the establishment of the premetastatic tumor niche, while miRNAs carried by MSC-EVs can regulate tumor invasiveness through multiple mechanisms leading to both stimulatory and inhibitory effects.

4.3. Angiogenesis

Angiogenesis is an essential factor for tumor growth and invasion. This process is distinctly regulated by a delicate equilibrium of pro- and anti-angiogenic factors. MSCs themselves can release a whole collection of growth factors and cytokines, such as vascular endothelial grow factor (VEGF), which may promote neovascularization and thus promote tumor cell proliferation [77]. EVs derived from MSCs have the potential to deliver complex pro- or anti-angiogenic information to endothelial cells that are implicated in the angiogenic signaling. It is especially miRNA cargo that was described by Gong et al. to participate in the induction of angiogenesis via BMMSC-EVs [78]. However, the number of studies investigating the role of MSC-EVs in the angiogenesis of tumorigenic tissues is limited and contradictory. For instance, Rosenberger at al. described that human-menstrual-blood-derived MSC-EVs (hMenMSCs-EVs) could facilitate VEGF suppression and inhibit the growth of oral squamous cell carcinoma [79]. Similarly, hMenMSC-EVs also blocked angiogenesis in prostate cancer by the inhibition of VEGF secretion and NF-κB activity and the induction of generating reactive oxygen species (ROS) [80]. In another study, Pakravan et al. demonstrated that BMMSC-EVs can transfer miR-100 to decrease the expression of VEGF through modulation of the mTOR/HIF-1α pathway, thus inhibiting angiogenesis in breast cancer cells [81]. On the other hand, the previously mentioned study of Zhu et al. reported that BMMSC-EVs are capable of increasing the expression of VEGF in tumor cells by activating the ERK1/2 pathway, thus promoting tumor angiogenesis in xenograft models of gastrointestinal cancer [58]. Collectively, existing evidence indicates that MSC-EVs have an inhibitory effect on tumor angiogenesis, and only a few studies suggest the promoting effect. The dual effects of enhanced angiogenesis of non-tumor tissue in contrast to suppressed angiogenesis of tumor tissues are suggested to be properties of regular MSC-EVs.

4.4. Immune Response Regulation

MSC-EVs originating from MSCs exhibited therapeutic effects similar to their parental cells in terms of modulating both innate and adaptive immune response. The dual effect of MSC-EVs in the regulation of the immune system is primarily dependent from the parental cells and the functional state of both parental and target cells [82]. MSC-EVs possess multiple roles in the modulation of responses to T cells, B cells, dendritic cells (DCs), natural-killer cells (NK), and macrophages, as it is extensively summarized elsewhere [83][84]. In general, the most recent studies demonstrated that MSC-EVs, similar to their parent counterparts, mediate immunosuppression rather than immune stimulation [49]. Special attention has to be devoted to TAMSC-EVs, while the majority of studies on TA-MSCs suggest that they support tumor growth. TAMSC-EVs can modify tumor progression by different pathways affecting the whole plethora of TME-residing cells [2]. Yang et al. reported that TAMSC-EVs control cell migration through the miR155/SMARCA4 pathway in teratoid rhabdoid tumors [85]. In relation to immunomodulation, Biswas et al. demonstrated that TAMSC-EVs transfer TGF-β, C1q, and semaphorins, which promotes the differentiation of myeloid-derived suppressor cells into macrophages, thus promoting the progression of breast cancer [65]. Furthermore, in the study of Ren et al. it was demonstrated that BMMSC-EVs grown in hypoxic conditions carry miR21-5p, which is capable of inducing macrophage M2 polarization, leading to the inhibition of apoptosis and the promotion lung cancer development [86].
Studies that examined EVs derived from non-malignant MSCs have found rather significant immune stimulation effects; for instance, UCMSC-EVs deliver miR-182, leading to the increase in the proliferation rate of T and NK-T cells and thus suppressing the metastatic potential and growth of renal cell carcinoma [54]. Furthermore, Zhou et al. engineered BMMSC-EVs loaded with galectin-9 siRNA and oxaliplatin (iEXO-OXA), which prompted antitumor immunity through tumor-suppressive macrophage polarization, cytotoxic T lymphocyte recruitment, and Treg downregulation, and achieved significant therapeutic efficacy in cancer treatment [87]. When combined, MSC-EVs primarily mediate immunosuppression rather than the immune stimulation effects, especially in the case of TAMSC-EVs. MSC-EVs may act to achieve immunosuppression as a way of preventing excessive inflammatory response, thus protecting the tissue microenvironment. Nevertheless, bioengineered MSC-EVs loaded with distinct substances could prompt antitumor response.
To summarize, MSC-EVs derived from different sources of MSCs could be naturally loaded by different molecular cargo, which causes different effects on specific tumors. The source of MSC-EVs was demonstrated to be important for the final tumor-promoting or tumor-suppressive effects of MSC-EVs. For instance, hUCMSC-EVs have proven to be one of the most promising choices because of their low tumor-promoting potential [88]. Moreover, their lower immunogenicity in comparison to MSC-EVs from other sources makes them more suitable for use in allogenic therapies [75]. Furthermore, Rocarro et al. showed that BMMSC-EVs isolated from multiple myeloma (MM) patients could support MM tumor growth, followed by elevated dissemination to distant bone marrow niches, by transferring of lower or undetectable levels of miR-15a, while BMMSC-EVs isolated from healthy individuals suppress tumor growth by transferring a usual amount of miR-15a. However, in addition to the different miRNA levels, there were also other factors, such as superior amounts of adhesion molecules and cytokines, which might be involved in tumor-promoting effects [89]. In addition, the contradictory results have indicated a need for further research in the development of standardized production conditions, followed by isolation and purification approaches, as the MSC culture conditions and subsequent isolation and purification techniques may significantly affect the overall features of the derived EVs. Furthermore, the main conclusions in some studies are not sufficiently supported by performed experiments, and detailed data are missing to allow their further reproduction. Therefore, it is crucial to describe all the detailed procedures for the reported parameters (as discussed in Section 4), as these can influence the production and relevant content of analyzed MSC-EVs. Finally, these controversial tumor-promoting and tumor-suppressive features of MSC-EVs might be partially caused by the complexity of the TME and the systemic environment of the host, in addition to the origin of tumor malignances.

5. Applications of MSC-EVs in Cancer Therapy

EVs are supposed to be promising natural nanovesicles with a huge potential for use in a variety of therapeutic and diagnostic applications. MSCs are one of the most prominent producers of EVs, displaying large expansion capacity compared to other cell sources, which is beneficial for clinically feasible production [90]. It is obvious that MSCs exert their functions via paracrine secretion, while the MSC-EVs are one of the key players. Meanwhile, preclinical data together with data from the performed clinical trials have proven the safety and scalability of MSC-EV preparation processes for clinical applications. MSC-EVs show excellent biocompatibility and exceptional biodistribution properties, including the capability to cross biological barriers, low toxicity and immunogenicity, and strong tumor tropism. Moreover, they could be further artificially modified in order to enhance tumor targeting specificity, efficiency, and safety, and are a promising drug delivery vehicle. Bioengineered MSC-EVs can encapsulate desired therapeutics, such as miRNAs, proteins, or chemotherapeutic drugs. Targeted delivery can improve the efficacy of the drug on the tumor site and reduce the possible strong side effects of the loaded drugs, compared to if applied systemically. One of the reasons for the poor curative effect of some chemotherapeutic drugs relates to their systemic effects. In addition, the use of MSC-EVs as natural drug delivery nanocarriers has several benefits over artificial ones, such as liposomes, as EVs exhibit superior systemic retention, allowing them to exert their function even at distant sites and with decreased immune clearance when administered systemically [21]. Furthermore, the capacity of MSC-EVs in the prolonged release of a precise quantity of drugs increases their therapeutic effectiveness due to the extended circulation of drugs and their accumulation in recipient tumor cells [91]. Moreover, MSC-EVs loaded with therapeutic agents, such as certain mRNAs, miRNAs, regulatory RNAs, proteins, and specific drugs, e.g., paclitaxel [31], doxorubicin/adriamycin [39], gemcitabine [26], cabazitaxel [92], norcantharidin [93], and honokiol [94], demonstrated potent anti-cancer activity; they are delivered to the target site with higher efficiency and maintain a good drug release curve [46].
Nevertheless, in contrast to therapeutic applications of MSC-EVs in regenerative medicine, or for the treatment of neurodegenerative diseases, sepsis, graft-versus-host disease (GVHD), or autoimmune diseases, in the field of cancer therapy the situation seems to be more complicated [95]. A number of studies have pointed out the double-edged properties of MSC-EVs in the tumor environment, confirming that MSC-EVs play a dual role in promoting and inhibiting multiple stages of tumorigenesis. The complexity of the TME makes utilizing MSC-EVs for the treatment of cancer much more difficult, for instance in comparison to the field of regenerative medicine for the treatment of tissue injuries. This is further highlighted in the number of studies on human MSC-EVs targeting tumors that reached clinical trials. While there are more than 200 current trials involving MSCs, and more than 1000 if evaluating them together with the completed ones, there are only about 12 registered using MSC-EVs as therapeutics and only 1 trial that focuses on cancer treatment via MSC-EVs (listed in www.clinicaltrials.gov (accessed on 26 March 2023), identifier: NCT03608631). As mentioned previously, this phase I clinical trial involves MSC-EVs loaded with KrasG12D siRNA (iExosomes) in treating patients with pancreatic cancer (metastatic pancreatic adenocarcinoma and pancreatic dual adenocarcinoma) with the KrasG12D mutation. It is a dose-escalation study based on previous preclinical testing employing clinical-grade ATMSC-EVs loaded with KrasG12D siRNAs used to treat pancreatic cancer in animal models, showing a robust increase in overall survival without any clear toxicity [25][96]. The clinical trial currently being performed by Kalluri and coworkers from M.D. Anderson Cancer Center should be completed within this year. Hopefully, it will bring positive results and also promote other groups to push their preclinical studies to the clinical phase.

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15051453

References

  1. da Silva Meirelles, L.; Chagastelles, P.C.; Nardi, N.B. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J. Cell Sci. 2006, 119, 2204–2213.
  2. Whiteside, T.L. Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment. Semin. Immunol. 2018, 35, 69–79.
  3. Phinney, D.G.; Pittenger, M.F. Concise Review: MSC-Derived Exosomes for Cell-Free Therapy. Stem Cells 2017, 35, 851–858.
  4. Pittenger, M.F.; Mackay, A.M.; Beck, S.C.; Jaiswal, R.K.; Douglas, R.; Mosca, J.D.; Moorman, M.A.; Simonetti, D.W.; Craig, S.; Marshak, D.R. Multilineage Potential of Adult Human Mesenchymal Stem Cells. Science 1999, 284, 143–147.
  5. Caplan, H.; Olson, S.D.; Kumar, A.; George, M.; Prabhakara, K.S.; Wenzel, P.; Bedi, S.; Toledano-Furman, N.E.; Triolo, F.; Kamhieh-Milz, J.; et al. Mesenchymal Stromal Cell Therapeutic Delivery: Translational Challenges to Clinical Application. Front. Immunol. 2019, 10, 1645.
  6. Vizoso, F.J.; Eiro, N.; Cid, S.; Schneider, J.; Perez-Fernandez, R. Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int. J. Mol. Sci. 2017, 18, 1852.
  7. Ridge, S.M.; Sullivan, F.J.; Glynn, S.A. Mesenchymal stem cells: Key players in cancer progression. Mol. Cancer 2017, 16, 31.
  8. Mognetti, B.; La Montagna, G.; Perrelli, M.G.; Pagliaro, P.; Penna, C. Bone marrow mesenchymal stem cells increase motility of prostate cancer cells via production of stromal cell-derived factor-1α. J. Cell. Mol. Med. 2013, 17, 287–292.
  9. Quante, M.; Tu, S.P.; Tomita, H.; Gonda, T.; Wang, S.S.; Takashi, S.; Baik, G.H.; Shibata, W.; DiPrete, B.; Betz, K.S.; et al. Bone Marrow-Derived Myofibroblasts Contribute to the Mesenchymal Stem Cell Niche and Promote Tumor Growth. Cancer Cell 2011, 19, 257–272.
  10. Timaner, M.; Tsai, K.K.; Shaked, Y. The multifaceted role of mesenchymal stem cells in cancer. Semin. Cancer Biol. 2020, 60, 225–237.
  11. Liang, W.; Chen, X.; Zhang, S.; Fang, J.; Chen, M.; Xu, Y.; Chen, X. Mesenchymal stem cells as a double-edged sword in tumor growth: Focusing on MSC-derived cytokines. Cell. Mol. Biol. Lett. 2021, 26, 3.
  12. Hmadcha, A.; Martin-Montalvo, A.; Gauthier, B.; Soria, B.; Capilla-Gonzalez, V. Therapeutic Potential of Mesenchymal Stem Cells for Cancer Therapy. Front. Bioeng. Biotechnol. 2020, 8, 43.
  13. Théry, C.; Witwer, K.W.; Aikawa, E.; Alcaraz, M.J.; Anderson, J.D.; Andriantsitohaina, R.; Antoniou, A.; Arab, T.; Archer, F.; Atkin-Smith, G.K.; 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.
  14. Lener, T.; Gimona, M.; Aigner, L.; Börger, V.; Buzas, E.; Camussi, G.; Chaput, N.; Chatterjee, D.; Court, F.A.; del Portillo, H.A.; et al. Applying extracellular vesicles based therapeutics in clinical trials—An ISEV position paper. J. Extracell. Vesicles 2015, 4, 30087.
  15. Kordelas, L.; Rebmann, V.; Ludwig, A.-K.; Radtke, S.; Ruesing, J.; Doeppner, T.R.; Epple, M.; Horn, P.A.; Beelen, D.W.; Giebel, B. MSC-derived exosomes: A novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 2014, 28, 970–973.
  16. Welsh, J.A.; Van Der Pol, E.; Bettin, B.A.; Carter, D.R.F.; Hendrix, A.; Lenassi, M.; Langlois, M.-A.; Llorente, A.; Van De Nes, A.S.; Nieuwland, R.; et al. Towards defining reference materials for measuring extracellular vesicle refractive index, epitope abundance, size and concentration. J. Extracell. Vesicles 2020, 9, 1816641.
  17. Van Deun, J.; Mestdagh, P.; Agostinis, P.; Akay, Ö.; Anand, S.; Anckaert, J.; Martinez, Z.A.; Baetens, T.; Beghein, E.; Bertier, L.; et al. EV-TRACK: Transparent reporting and centralizing knowledge in extracellular vesicle research. Nat. Methods 2017, 14, 228–232.
  18. Doyle, L.; Wang, M. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells 2019, 8, 727.
  19. Coumans, F.A.W.; Brisson, A.R.; Buzas, E.I.; Dignat-George, F.; Drees, E.E.E.; El-Andaloussi, S.; Emanueli, C.; Gasecka, A.; Hendrix, A.; Hill, A.F.; et al. Methodological Guidelines to Study Extracellular Vesicles. Circ. Res. 2017, 120, 1632–1648.
  20. Szatanek, R.; Baj-Krzyworzeka, M.; Zimoch, J.; Lekka, M.; Siedlar, M.; Baran, J. The Methods of Choice for Extracellular Vesicles (EVs) Characterization. Int. J. Mol. Sci. 2017, 18, 1153.
  21. Herrmann, I.K.; Wood, M.J.A.; Fuhrmann, G. Extracellular vesicles as a next-generation drug delivery platform. Nat. Nanotechnol. 2021, 16, 748–759.
  22. Cao, Y.; Dong, X.; Chen, X. Polymer-Modified Liposomes for Drug Delivery: From Fundamentals to Applications. Pharmaceutics 2022, 14, 778.
  23. Weng, Z.; Zhang, B.; Wu, C.; Yu, F.; Han, B.; Li, B.; Li, L. Therapeutic roles of mesenchymal stem cell-derived extracellular vesicles in cancer. J. Hematol. Oncol. 2021, 14, 136.
  24. Kaneti, L.; Bronshtein, T.; Dayan, N.M.; Kovregina, I.; Khait, N.L.; Lupu-Haber, Y.; Fliman, M.; Schoen, B.W.; Kaneti, G.; Machluf, M. Nanoghosts as a Novel Natural Nonviral Gene Delivery Platform Safely Targeting Multiple Cancers. Nano Lett. 2016, 16, 1574–1582.
  25. Kamerkar, S.; LeBleu, V.S.; Sugimoto, H.; Yang, S.; Ruivo, C.F.; Melo, S.A.; Lee, J.J.; Kalluri, R. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 2017, 546, 498–503.
  26. Klimova, D.; Jakubechova, J.; Altanerova, U.; Nicodemou, A.; Styk, J.; Szemes, T.; Repiska, V.; Altaner, C. Extracellular vesicles derived from dental mesenchymal stem/stromal cells with gemcitabine as a cargo have an inhibitory effect on the growth of pancreatic carcinoma cell lines in vitro. Mol. Cell. Probes 2023, 67, 101894.
  27. Ursula, A.; Jana, J.; Katarina, B.; Petra, P.; Martin, P.; Pavel, P.; Ondrej, T.; Juraj, K.; Martina, Z.; Vanda, R.; et al. Prodrug suicide gene therapy for cancer targeted intracellular by mesenchymal stem cell exosomes. Int. J. Cancer 2019, 144, 897–908.
  28. Lou, G.; Song, X.; Yang, F.; Wu, S.; Wang, J.; Chen, Z.; Liu, Y. Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J. Hematol. Oncol. 2015, 8, 122.
  29. Yuan, Z.; Kolluri, K.K.; Gowers, K.H.C.; Janes, S.M. TRAIL delivery by MSC-derived extracellular vesicles is an effective anticancer therapy. J. Extracell. Vesicles 2017, 6, 1265291.
  30. Xu, M.; Yang, Q.; Sun, X.; Wang, Y. Recent Advancements in the Loading and Modification of Therapeutic Exosomes. Front. Bioeng. Biotechnol. 2020, 8, 586130.
  31. Pascucci, L.; Coccè, V.; Bonomi, A.; Ami, D.; Ceccarelli, P.; Ciusani, E.; Viganò, L.; Locatelli, A.; Sisto, F.; Doglia, S.M.; et al. Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: A new approach for drug delivery. J. Control. Release 2014, 192, 262–270.
  32. Fuhrmann, G.; Serio, A.; Mazo, M.; Nair, R.; Stevens, M.M. Active loading into extracellular vesicles significantly improves the cellular uptake and photodynamic effect of porphyrins. J. Control. Release 2015, 205, 35–44.
  33. Liang, Y.; Duan, L.; Lu, J.; Xia, J. Engineering exosomes for targeted drug delivery. Theranostics 2021, 11, 3183–3195.
  34. De Jong, O.G.; Kooijmans, S.A.A.; Murphy, D.E.; Jiang, L.; Evers, M.J.W.; Sluijter, J.P.G.; Vader, P.; Schiffelers, R.M. Drug Delivery with Extracellular Vesicles: From Imagination to Innovation. Acc. Chem. Res. 2019, 52, 1761–1770.
  35. Sun, D.; Zhuang, X.; Xiang, X.; Liu, Y.; Zhang, S.; Liu, C.; Barnes, S.; Grizzle, W.; Miller, D.; Zhang, H.-G. A Novel Nanoparticle Drug Delivery System: The Anti-inflammatory Activity of Curcumin Is Enhanced When Encapsulated in Exosomes. Mol. Ther. 2010, 18, 1606–1614.
  36. Walker, S.; Busatto, S.; Pham, A.; Tian, M.; Suh, A.; Carson, K.; Quintero, A.; Lafrence, M.; Malik, H.; Santana, M.X.; et al. Extracellular vesicle-based drug delivery systems for cancer treatment. Theranostics 2019, 9, 8001–8017.
  37. Luan, X.; Sansanaphongpricha, K.; Myers, I.; Chen, H.; Yuan, H.; Sun, D. Engineering exosomes as refined biological nanoplatforms for drug delivery. Acta Pharmacol. Sin. 2017, 38, 754–763.
  38. Alvarez-Erviti, L.; Seow, Y.; Yin, H.; Betts, C.; Lakhal, S.; Wood, M.J.A. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 2011, 29, 341–345.
  39. Gomari, H.; Moghadam, M.F.; Soleimani, M.; Ghavami, M.; Khodashenas, S. Targeted delivery of doxorubicin to HER2 positive tumor models. Int. J. Nanomed. 2019, 14, 5679–5690.
  40. Kooijmans, S.A.A.; Stremersch, S.; Braeckmans, K.; De Smedt, S.C.; Hendrix, A.; Wood, M.J.A.; Schiffelers, R.M.; Raemdonck, K.; Vader, P. Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J. Control. Release 2013, 172, 229–238.
  41. Jeyaram, A.; Lamichhane, T.N.; Wang, S.; Zou, L.; Dahal, E.; Kronstadt, S.M.; Levy, D.; Parajuli, B.; Knudsen, D.R.; Chao, W.; et al. Enhanced Loading of Functional miRNA Cargo via pH Gradient Modification of Extracellular Vesicles. Mol. Ther. 2020, 28, 975–985.
  42. Haney, M.J.; Klyachko, N.L.; Zhao, Y.; Gupta, R.; Plotnikova, E.G.; He, Z.; Patel, T.; Piroyan, A.; Sokolsky, M.; Kabanov, A.V.; et al. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J. Control. Release 2015, 207, 18–30.
  43. Fuhrmann, G.; Chandrawati, R.; Parmar, P.A.; Keane, T.J.; Maynard, S.A.; Bertazzo, S.; Stevens, M.M. Engineering Extracellular Vesicles with the Tools of Enzyme Prodrug Therapy. Adv. Mater. 2018, 30, e1706616.
  44. Salunkhe, S.; Dheeraj; Basak, M.; Chitkara, D.; Mittal, A. Surface functionalization of exosomes for target-specific delivery and in vivo imaging & tracking: Strategies and significance. J. Control. Release 2020, 326, 599–614.
  45. Wiklander, O.P.B.; Nordin, J.Z.; O’Loughlin, A.; Gustafsson, Y.; Corso, G.; Mäger, I.; Vader, P.; Lee, Y.; Sork, H.; Seow, Y.; et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J. Extracell. Vesicles 2015, 4, 26316.
  46. Sun, Y.; Liu, G.; Zhang, K.; Cao, Q.; Liu, T.; Li, J. Mesenchymal stem cells-derived exosomes for drug delivery. Stem Cell Res. Ther. 2021, 12, 561.
  47. Ahmadi, M.; Hassanpour, M.; Rezaie, J. Engineered extracellular vesicles: A novel platform for cancer combination therapy and cancer immunotherapy. Life Sci. 2022, 308, 120935.
  48. Wang, N.; Pei, B.; Yuan, X.; Yi, C.; Ocansey, D.K.W.; Qian, H.; Mao, F. Emerging roles of mesenchymal stem cell-derived exosomes in gastrointestinal cancers. Front. Bioeng. Biotechnol. 2022, 10, 1019459.
  49. Xunian, Z.; Kalluri, R. Biology and therapeutic potential of mesenchymal stem cell-derived exosomes. Cancer Sci. 2020, 111, 3100–3110.
  50. Hass, R. Role of MSC in the Tumor Microenvironment. Cancers 2020, 12, 2107.
  51. Baglio, S.R.; Rooijers, K.; Koppers-Lalic, D.; Verweij, F.J.; Lanzón, M.P.; Zini, N.; Naaijkens, B.; Perut, F.; Niessen, H.W.M.; Baldini, N.; et al. Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res. Ther. 2015, 6, 127.
  52. Zhang, N.; Li, L.; Luo, J.; Tan, J.; Hu, W.; Li, Z.; Wang, X.; Ye, T. Inhibiting microRNA-424 in bone marrow mesenchymal stem cells-derived exosomes suppresses tumor growth in colorectal cancer by upregulating TGFBR3. Arch. Biochem. Biophys. 2021, 709, 108965.
  53. Zhao, W.; Qin, P.; Zhang, D.; Cui, X.; Gao, J.; Yu, Z.; Chai, Y.; Wang, J.; Li, J. Long non-coding RNA PVT1 encapsulated in bone marrow mesenchymal stem cell-derived exosomes promotes osteosarcoma growth and metastasis by stabilizing ERG and sponging miR-183-5p. Aging 2019, 11, 9581–9596.
  54. Li, D.; Lin, F.; Li, G.; Zeng, F. Exosomes derived from mesenchymal stem cells curbs the progression of clear cell renal cell carcinoma through T-cell immune response. Cytotechnology 2021, 73, 593–604.
  55. Bolandi, Z.; Mokhberian, N.; Eftekhary, M.; Sharifi, K.; Soudi, S.; Ghanbarian, H.; Hashemi, S.M. Adipose derived mesenchymal stem cell exosomes loaded with miR-10a promote the differentiation of Th17 and Treg from naive CD4+ T cell. Life Sci. 2020, 259, 118218.
  56. Christodoulou, I.; Goulielmaki, M.; Devetzi, M.; Panagiotidis, M.; Koliakos, G.; Zoumpourlis, V. Mesenchymal stem cells in preclinical cancer cytotherapy: A systematic review. Stem Cell Res. Ther. 2018, 9, 336.
  57. Shi, Y.; Du, L.; Lin, L.; Wang, Y. Tumour-associated mesenchymal stem/stromal cells: Emerging therapeutic targets. Nat. Rev. Drug Discov. 2016, 16, 35–52.
  58. Zhu, W.; Huang, L.; Li, Y.; Zhang, X.; Gu, J.; Yan, Y.; Xu, X.; Wang, M.; Qian, H.; Xu, W. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Lett. 2012, 315, 28–37.
  59. Leavitt, R.J.; Limoli, C.L.; Baulch, J.E. miRNA-based therapeutic potential of stem cell-derived extracellular vesicles: A safe cell-free treatment to ameliorate radiation-induced brain injury. Int. J. Radiat. Biol. 2019, 95, 427–435.
  60. Zhou, X.; Li, T.; Chen, Y.; Zhang, N.; Wang, P.; Liang, Y.; Long, M.; Liu, H.; Mao, J.; Liu, Q.; et al. Mesenchymal stem cell-derived extracellular vesicles promote the in vitro proliferation and migration of breast cancer cells through the activation of the ERK pathway. Int. J. Oncol. 2019, 54, 1843–1852.
  61. Ding, Y.; Mei, W.; Zheng, Z.; Cao, F.; Liang, K.; Jia, Y.; Wang, Y.; Liu, D.; Li, J.; Li, F. Exosomes secreted from human umbilical cord mesenchymal stem cells promote pancreatic ductal adenocarcinoma growth by transferring miR-100-5p. Tissue Cell 2021, 73, 101623.
  62. Dong, L.; Pu, Y.; Zhang, L.; Qi, Q.; Xu, L.; Li, W.; Wei, C.; Wang, X.; Zhou, S.; Zhu, J.; et al. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles promote lung adenocarcinoma growth by transferring miR-410. Cell Death Dis. 2018, 9, 218.
  63. Guo, Q.; Yan, J.; Song, T.; Zhong, C.; Kuang, J.; Mo, Y.; Tan, J.; Li, D.; Sui, Z.; Cai, K.; et al. microRNA-130b-3p contained in MSC-derived EVs promotes lung cancer progression by regulating the FOXO3/NFE2L2/TXNRD1 axis. Mol. Ther. Oncolytics 2020, 20, 132–146.
  64. Chen, B.; Cai, T.; Huang, C.; Zang, X.; Sun, L.; Guo, S.; Wang, Q.; Chen, Z.; Zhao, Y.; Han, Z.; et al. G6PD-NF-κB-HGF Signal in Gastric Cancer-Associated Mesenchymal Stem Cells Promotes the Proliferation and Metastasis of Gastric Cancer Cells by Upregulating the Expression of HK2. Front. Oncol. 2021, 11, 648706.
  65. Biswas, S.; Mandal, G.; Chowdhury, S.R.; Purohit, S.; Payne, K.K.; Anadon, C.; Gupta, A.; Swanson, P.; Yu, X.; Conejo-Garcia, J.R.; et al. Exosomes Produced by Mesenchymal Stem Cells Drive Differentiation of Myeloid Cells into Immunosuppressive M2-Polarized Macrophages in Breast Cancer. J. Immunol. 2019, 203, 3447–3460.
  66. Zhang, F.; Lu, Y.; Wang, M.; Zhu, J.; Li, J.; Zhang, P.; Yuan, Y.; Zhu, F. Exosomes derived from human bone marrow mesenchymal stem cells transfer miR-222-3p to suppress acute myeloid leukemia cell proliferation by targeting IRF2/INPP4B. Mol. Cell. Probes 2020, 51, 101513.
  67. Takahara, K.; Ii, M.; Inamoto, T.; Nakagawa, T.; Ibuki, N.; Yoshikawa, Y.; Tsujino, T.; Uchimoto, T.; Saito, K.; Takai, T.; et al. microRNA-145 Mediates the Inhibitory Effect of Adipose Tissue-Derived Stromal Cells on Prostate Cancer. Stem Cells Dev. 2016, 25, 1290–1298.
  68. Xie, C.; Du, L.-Y.; Guo, F.; Li, X.; Cheng, B. Exosomes derived from microRNA-101-3p-overexpressing human bone marrow mesenchymal stem cells suppress oral cancer cell proliferation, invasion, and migration. Mol. Cell. Biochem. 2019, 458, 11–26.
  69. Valastyan, S.; Weinberg, R.A. Tumor Metastasis: Molecular Insights and Evolving Paradigms. Cell 2011, 147, 275–292.
  70. Kahlert, C.; Kalluri, R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J. Mol. Med. 2013, 91, 431–437.
  71. Yang, J.; Antin, P.; Berx, G.; Blanpain, C.; Brabletz, T.; Bronner, M.; Campbell, K.; Cano, A.; Casanova, J.; Christofori, G.; et al. Guidelines and definitions for research on epithelial–mesenchymal transition. Nat. Rev. Mol. Cell Biol. 2020, 21, 341–352.
  72. Steeg, P.S. Targeting metastasis. Nat. Rev. Cancer 2016, 16, 201–218.
  73. Li, S.; Yan, G.; Yue, M.; Wang, L. Extracellular vesicles-derived microRNA-222 promotes immune escape via interacting with ATF3 to regulate AKT1 transcription in colorectal cancer. BMC Cancer 2021, 21, 349.
  74. Wang, Y.; Lin, C. Exosomes miR-22-3p Derived from Mesenchymal Stem Cells Suppress Colorectal Cancer Cell Proliferation and Invasion by Regulating RAP2B and PI3K/AKT Pathway. J. Oncol. 2021, 2021, 3874478.
  75. Li, X.; Liu, L.L.; Yao, J.L.; Wang, K.; Ai, H. Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibit Endometrial Cancer Cell Proliferation and Migration through Delivery of Exogenous miR-302a. Stem Cells Int. 2019, 2019, 8108576.
  76. Yao, X.; Mao, Y.; Wu, D.; Zhu, Y.; Lu, J.; Huang, Y.; Guo, Y.; Wang, Z.; Zhu, S.; Li, X.; et al. Exosomal circ_0030167 derived from BM-MSCs inhibits the invasion, migration, proliferation and stemness of pancreatic cancer cells by sponging miR-338-5p and targeting the Wif1/Wnt8/β-catenin axis. Cancer Lett. 2021, 512, 38–50.
  77. Lugano, R.; Ramachandran, M.; Dimberg, A. Tumor angiogenesis: Causes, consequences, challenges and opportunities. Cell. Mol. Life Sci. 2020, 77, 1745–1770.
  78. Gong, M.; Yu, B.; Wang, J.; Wang, Y.; Liu, M.; Paul, C.; Millard, R.W.; Xiao, D.-S.; Ashraf, M.; Xu, M. Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget 2017, 8, 45200–45212.
  79. Rosenberger, L.; Ezquer, M.; Lillo-Vera, F.; Pedraza, P.L.; Ortúzar, M.I.; González, P.L.; Figueroa-Valdés, A.I.; Cuenca, J.; Ezquer, F.; Khoury, M.; et al. Stem cell exosomes inhibit angiogenesis and tumor growth of oral squamous cell carcinoma. Sci. Rep. 2019, 9, 663.
  80. Alcayaga-Miranda, F.; González, P.L.; Lopez-Verrilli, A.; Varas-Godoy, M.; Aguila-Díaz, C.; Contreras, L.; Khoury, M. Prostate tumor-induced angiogenesis is blocked by exosomes derived from menstrual stem cells through the inhibition of reactive oxygen species. Oncotarget 2016, 7, 44462–44477.
  81. Pakravan, K.; Babashah, S.; Sadeghizadeh, M.; Mowla, S.J.; Mossahebi-Mohammadi, M.; Ataei, F.; Dana, N.; Javan, M. MicroRNA-100 shuttled by mesenchymal stem cell-derived exosomes suppresses in vitro angiogenesis through modulating the mTOR/HIF-1α/VEGF signaling axis in breast cancer cells. Cell. Oncol. 2017, 40, 457–470.
  82. Kalluri, R.; LeBleu, V.S. The biology, function, and biomedical applications of exosomes. Science 2020, 367, eaau6977.
  83. Liu, X.; Wei, Q.; Lu, L.; Cui, S.; Ma, K.; Zhang, W.; Ma, F.; Li, H.; Fu, X.; Zhang, C. Immunomodulatory potential of mesenchymal stem cell-derived extracellular vesicles: Targeting immune cells. Front. Immunol. 2023, 14, 1094685.
  84. Műzes, G.; Sipos, F. Mesenchymal Stem Cell-Derived Secretome: A Potential Therapeutic Option for Autoimmune and Immune-Mediated Inflammatory Diseases. Cells 2022, 11, 2300.
  85. Yang, Y.-P.; Nguyen, P.N.N.; Ma, H.-I.; Ho, W.-J.; Chen, Y.-W.; Chien, Y.; Yarmishyn, A.A.; Huang, P.-I.; Lo, W.-L.; Wang, C.-Y.; et al. Tumor Mesenchymal Stromal Cells Regulate Cell Migration of Atypical Teratoid Rhabdoid Tumor through Exosome-Mediated miR155/SMARCA4 Pathway. Cancers 2019, 11, 720.
  86. Ren, W.; Hou, J.; Yang, C.; Wang, H.; Wu, S.; Wu, Y.; Zhao, X.; Lu, C. Extracellular vesicles secreted by hypoxia pre-challenged mesenchymal stem cells promote non-small cell lung cancer cell growth and mobility as well as macrophage M2 polarization via miR-21-5p delivery. J. Exp. Clin. Cancer Res. 2019, 38, 62.
  87. Zhou, W.; Zhou, Y.; Chen, X.; Ning, T.; Chen, H.; Guo, Q.; Zhang, Y.; Liu, P.; Zhang, Y.; Li, C.; et al. Pancreatic cancer-targeting exosomes for enhancing immunotherapy and reprogramming tumor microenvironment. Biomaterials 2021, 268, 120546.
  88. Christodoulou, I.; Kolisis, F.N.; Papaevangeliou, D.; Zoumpourlis, V. Comparative Evaluation of Human Mesenchymal Stem Cells of Fetal (Wharton’s Jelly) and Adult (Adipose Tissue) Origin during Prolonged In Vitro Expansion: Considerations for Cytotherapy. Stem Cells Int. 2013, 2013, 246134.
  89. Roccaro, A.M.; Sacco, A.; Maiso, P.; Azab, A.K.; Tai, Y.-T.; Reagan, M.; Azab, F.; Flores, L.M.; Campigotto, F.; Weller, E.; et al. BM mesenchymal stromal cell–derived exosomes facilitate multiple myeloma progression. J. Clin. Investig. 2013, 123, 1542–1555.
  90. Kim, J.Y.; Rhim, W.-K.; Yoo, Y.-I.; Kim, D.-S.; Ko, K.-W.; Heo, Y.; Park, C.G.; Han, D.K. Defined MSC exosome with high yield and purity to improve regenerative activity. J. Tissue Eng. 2021, 12, 20417314211008626.
  91. Fitts, C.A.; Ji, N.; Li, Y.; Tan, C. Exploiting Exosomes in Cancer Liquid Biopsies and Drug Delivery. Adv. Healthc. Mater. 2019, 8, 1801268.
  92. Qiu, Y.; Sun, J.; Qiu, J.; Chen, G.; Wang, X.; Mu, Y.; Li, K.; Wang, W. Antitumor Activity of Cabazitaxel and MSC-TRAIL Derived Extracellular Vesicles in Drug-Resistant Oral Squamous Cell Carcinoma. Cancer Manag. Res. 2020, 12, 10809–10820.
  93. Liang, L.; Zhao, L.; Wang, Y.; Wang, Y. Treatment for Hepatocellular Carcinoma Is Enhanced When Norcantharidin Is Encapsulated in Exosomes Derived from Bone Marrow Mesenchymal Stem Cells. Mol. Pharm. 2021, 18, 1003–1013.
  94. Kanchanapally, R.; Khan, M.A.; Deshmukh, S.K.; Srivastava, S.K.; Khushman, M.; Singh, S.; Singh, A.P. Exosomal Formulation Escalates Cellular Uptake of Honokiol Leading to the Enhancement of Its Antitumor Efficacy. ACS Omega 2020, 5, 23299–23307.
  95. Nikfarjam, S.; Rezaie, J.; Zolbanin, N.M.; Jafari, R. Mesenchymal stem cell derived-exosomes: A modern approach in translational medicine. J. Transl. Med. 2020, 18, 449.
  96. Lamparski, H.G.; Metha-Damani, A.; Yao, J.-Y.; Patel, S.; Hsu, D.-H.; Ruegg, C.; Le Pecq, J.-B. Production and characterization of clinical grade exosomes derived from dendritic cells. J. Immunol. Methods 2002, 270, 211–226.
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