The Role of Mesenchymal Stem Cells and Exosomes in Tumor Development and Targeted Antitumor Therapies

Yang, Enguang; Jing, Suoshi; Wang, Yuhan; Wang, Hanzhang; Rodriguez, Ronald; Wang, Zhiping

doi:https://doi.org/10.1155/2023/7059289

Stem Cells International

On this page

Abstract Introduction Conclusion Abbreviations Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Review Article | Open Access

Volume 2023 | Article ID 7059289 | https://doi.org/10.1155/2023/7059289

The Role of Mesenchymal Stem Cells and Exosomes in Tumor Development and Targeted Antitumor Therapies

Enguang Yang,¹Suoshi Jing,¹Yuhan Wang,¹Hanzhang Wang,²Ronald Rodriguez,³and Zhiping Wang¹

Academic Editor: Sumanta Chatterjee

Received30 Apr 2022

Revised17 Jan 2023

Accepted03 Feb 2023

Published14 Feb 2023

Abstract

Mesenchymal stem cells (MSCs) can be isolated from various tissues in adults and differentiated into cells of the osteoblasts, adipocytes, chondrocytes, and myocytes. Recruitments of MSCs towards tumors have a crucial contribution to tumor development. However, the role of MSCs in the tumor microenvironment is uncertain. In addition, due to its tropism to the tumor and low immunogenic properties, more and more pieces of evidence indicate that MSCs may be an ideal carrier for antitumor biologics such as cytokines, chemotherapeutic agents, and oncolytic viruses. Here, we review the existing knowledge on the anti- and protumorigenic effect of MSCs and their extracellular vesicles and exosomes, the role of MSCs, and their extracellular vesicles and exosomes as antitumor vectors.

1. Introduction

In addition to a large number of immune cells, various other types of stromal cells, including mesenchymal stem cells (MSCs), fibroblasts, endothelial cells, and pericytes, are present in the tumor microenvironment [1]. MSCs could be recruited towards tumors, which have been confirmed in many kinds of tumors [2–10]. Chemokines produced by tumor cells, immune cells, and tumor stromal cells, including CCchemokine ligand 2 (CCL2), CCL5, CXCchemokine ligand 12 (CXCL12, also known as SDF1) and CXCL1, are involved in this process [11–14]. Additionally, growth factors such as insulin-like growth factor 1 (IGF1), basic fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), plateletderived growth factor (PDGF), and transforming growth factorβ (TGFβ) are found to have a role in the recruitment of MSCs [15–18]. Recruitments of MSCs to tumors have a crucial contribution to tumor fate. The review systematically summarizes the role of mesenchymal stem cells and exosomes in tumor development and targeted antitumor therapies.

2. The Antitumorigenic Activity of MSCs

MSCs are considered to be antitumor factors in hematological tumor cell lines, including Jurkat leukemia [19], human erythroid leukemia [20], Burkitt’s lymphoma [21], non-Hodgkin’s lymphoma [22], and T-cell lymphoma [23], and solid tumor cell lines such as breast cancer [24, 25], hepatocellular carcinoma (HCC) [26, 27], prostate cancer [25, 28], melanoma [29], neck squamous cell carcinoma [30], Kaposi’s sarcoma [31], pancreatic tumors [31], and multiple myeloma [32] (showed in Table 1). The mechanism of the antitumor effect of MSCs is multifaceted. Lin et al. showed that the growth of lymphoma cells was inhibited by the molecules secreted by umbilical cord MSCs (UC-MSCs) via the oxidative stress pathway by alteration of antioxidant enzymes [21]. In non-Hodgkin’s lymphoma, MSCs induce endothelial cell migration in the Transwell test but promotes endothelial cell apoptosis in direct MSC/endothelial cell cocultures. The cytotoxic activity of MSC requires MSC/endothelial cell contact [22]. The MSCs suppress tumor growth in vivo by inhibiting Akt activity in Kaposi’s sarcoma [2]. Type I interferon is expressed in high-density cultured adipose tissue MSCs (AT-MSCs). AT-MSCs and their conditioned medium inhibit the growth of breast cancer MCF-7 cells in vitro [25]. Paracrine factors of human fetal MSCs inhibit liver cancer growth by reducing the activation of IGF-1R/PI3K/Akt signaling [26]. AT-MSCs can effectively inhibit the proliferation and division of HCC cells and induce HCC cell death by downregulating the Akt signaling pathway [27].UC-MSCs inhibit the proliferation of prostate cancer PC-3 cells by activating JNK and downregulating PI3K/AKT signals under coculture conditions [28]. Interactions of bone marrow MSCs (BM-MSCs) with head and neck squamous cell carcinoma cell line PCI-13 decrease the expression of epithelia-mesenchymal transition (EMT) markers via reducing expression of Wnt3, MMP14, and beta-catenin [30]. AT-MSCs induce androgen-responsive and androgen-nonresponsive prostate cancer cell apoptosis via the TGF-β signaling pathway [33].

3. The Protumorigenic Activity of MSCs

However, studies are arguing for the protumorigenic role of MSCs on tumors, including tumor growth, angiogenesis, metastasis, and resistance to drugs [14]. The mechanism of supporting tumor vasculature of MSCs remains controversial. The biologically active factors secreted by MSCs contribute to the angiogenesis of tumors. Tumor-residing MSCs secreted high levels of VEGF in pancreatic carcinoma, which stimulates angiogenesis and increases microvessel density in the tumor [34]. The secretion of interleukin-6 (IL-6) from MSCs increases the secretion of endothelin-1 (ET-1) in colorectal cancer cells, which activates Akt and ERK in endothelial cells, thus enhancing their capacities for vessel formation [35]. Even more, the differentiation of MSCs into endothelial cells is a direct contribution to blood vessel formation. To examine the differentiation of MSCs into endothelial cells, the MSCs were cultured for several weeks in an endothelial cell culture medium containing VEGF. And the results showed that the expression of typical endothelial cell markers could be detected only in very few MSCs [34]. However, another study showed that melanoma cells educated MSCs to create vascular-like structures in vitro, thereby supporting tumor vasculature [36].

MSCs can facilitate tumor cell migration and invasion, EMT, and the formation of secondary metastatic lesions by a vast array of growth factors, cytokines, and chemokines derived from MSCs. MSC-derived C-C and CXC type chemokines, extracellular matrix modulating factors such as lysyl oxidase, and growth factors such as TGFβ, FGF, HGF, and EGF critically contribute to metastasis [37].

MSCs can promote tumor resistance to chemotherapy. IL-6, IL-7, IL-8, EGF, and IGF secreted from BM-MSCs induce chemoresistance to paclitaxel in head and neck carcinoma [38]. MSCs activated by platinum-based chemotherapy release two unique fatty acids inducing resistance to multiple types of chemotherapy [39]. Moreover, the clinical benefit of chemotherapy can be enhanced by blocking the release of these fatty acids from MSCs. Timaner et al. thought that MSCs could transform into cancer stem cells (CSCs) to support drug resistance [37].

As described above, some reports claim that MSCs can promote tumor progression, while others report that MSCs have antitumor effects. The observed differences may be due to the inherent biological differences in the source of MSCs, the heterogeneity of MSCs, the interaction of MSCs and their secreted factors with the surrounding microenvironment, and other parameters, such as the dose and time of MSCs administration/analysis, as well as the optimal culture condition [22, 40]. The same amount of human amniotic membrane protein extract has different degrees of antipromoting or mitogenic effects on different tumor cells, indicating that the effect of MSCs may depend on the type of main receptors expressed on specific tumor cells [41]. This is why MSCs derived from different sources and acting in different tumor environments have tumor-promoting or antitumor behaviors.

4. MSCs as Antitumor Vectors

More and more evidence indicates that MSCs may be an ideal carrier for antitumor biologics such as cytokines (shown in Table 2), chemotherapeutic agents (shown in Table 3), and oncolytic viruses (shown in Table 4). The main reasons of which are listed as follows: (1) MSCs expressing transgenes maintain long-term expression in the body, because of their low immunogenic properties and the production of immunosuppressive molecules [86]. (2) MSCs show a strong tropism to tumors [2–10]. (3) MSCs have the advantages of less ethical controversy, easy access, and rapid proliferation.

4.1. MSCs as Antitumor Vectors of Cytokines

4.1.1. Interleukin (IL)

IL-12 is a heterodimeric proinflammatory cytokine, secreted primarily from antigen-presenting cells. This cytokine has very strong antitumor and antiangiogenic properties [87]. Gene modification of MSCs by infection with an adenoviral or retroviral vector encoding human IL-12 augments the antitumor effect in melanoma, renal cell carcinoma, breast tumor, hepatoma, and glioma [51–57]. The antitumor effects of MSC-IL-12 depend on the stronger tumor-specific T-cell responses [51, 57]. Moreover, the antitumor activity of the MSCs-IL-12 is related to the presence of natural killer (NK) cells and interferon-γ (IFN-γ) [52]. However, MSCs-IL-12 embedded in Matrigel exhibits significant antitumor effects even in immunodeficient mice lacking T, B, and NK cells, but not in IFN-γ knockout mice [51]. Fortunately, the intratumoral expression levels of IL-12 are enhanced by MSCs-IL-12 to be tenfold greater than that of free IL-12 groups in the ultimate stage [55]. A 20-day course of intravenous injection of MSC-IL-12 is without systemic toxic effects [55]. Similarly, the tumor growth is inhibited, and survival is prolonged in ovarian-cancer-bearing mice treated with MSCs-IL-21. The number of IFN-γ-secreting splenocytes and NK cytotoxicity significantly increase after MSCs-IL-21 administration [59].

4.1.2. Interferon (IFN)

Type I interferons (IFN-α and -β) show a variety of antitumor effects, including inhibiting cell proliferation, limiting tumor angiogenesis, inducing cell apoptosis, and activating the host’s defense against tumors [88]. Systemic administration of MSCs-IFN-α significantly inhibits the growth of B16F10 melanoma cells and prolongs the survival. The result of immunohistochemical analysis reveals the promoted apoptosis and the decreased proliferation and vascular system [42]. IFN-β produced by MSCs inhibits the growth of malignant cells such as breast cancer, prostate cancer, bronchioloalveolar carcinoma, lung cancer, tongue squamous cell carcinoma, melanoma, lung metastatic melanoma, and pancreatic tumors metastases to the lung [31, 43–48]. Antitumor effect of IFN-β may be related to the increase of apoptosis [45] and NK cell activity [44] and inhibition of Stat3 signaling [43]. However, the combination of MSCs-IFNβ and anti-inflammatory drugs in the treatment of pancreatic tumors may lose these beneficial effects [31]. INF-β-MSCs specifically target tumor cells and do not cause damage to internal organs due to the use of INF-β alone [46]. The combination of canine MSCs-IFN-β and low-dose cisplatin improves the therapeutic effect of canine melanoma [48]. As a type II interferon, IFN-γ is mainly produced by lymphocytes and NK cells and plays an important role in the adaptive cellular immune response against tumors [88]. IFN-γ is considered to be a promising antitumor drug; however, the clinical application of the protein form of IFN-γ is hindered by serious side effects [89]. IFN-γ-modified MSCs selectively induce lung tumor cell apoptosis through the activation of caspase-3 in vitro and inhibit the growth and progression of lung cancer in vivo [50].

4.2. Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)

TRAIL is a member of the tumor necrosis factor (TNF) cytokine superfamily with attractive potent antitumor function owing to its unique competence to target cancerous cells without any harm to adjacent normal cells. This is because the expression of TRAIL-specific receptors, termed death receptors, is significantly higher in cancer cells compared with normal cells [90]. MSCs transduced with a lentiviral vector encoding TRAIL are shown to kill multiple tumor cell lines, including lung cancer, malignant mesothelioma, colon cancer, renal cancer lines, human oral squamous cell carcinoma, and breast cancer [60–62]. MSC full-length TRAIL can induce more powerful cytotoxicity against cancer cells than MSCs soluble form TRAIL and also can defeat cancer cell resistance to recombinant TRAIL [62].

4.3. MSCs as Delivery of the Chemotherapeutic Agent

Toxicity and acquired resistance to chemotherapeutic drugs still represent the major obstacles to improving the prognosis of patients with cancer. Improving the targeting delivery of cancer therapies to tumor sites is a key point to decreasing their negative side effects. MSCs have been proposed as cellular vehicles for targeted cancer therapies, thanks to their tumor-homing properties. Taking up and releasing chemotherapeutic drugs is the key to MSC-based therapy. MSCs from different sources, including adipose tissues, bone marrow, dental pulp, interdental papilla, and gingiva, acquire strong antitumor activity after priming with chemotherapeutic drugs such as paclitaxel (PTX), doxorubicin (DOX), gemcitabine (GCB), and pemetrexed (PMX) [63–70]. Salehi et al. [63] monitored the path of PTX transported by dental pulp MSCs and absorbed by breast cancer MCF-7 cells through confocal Raman microscopy. The results showed that PTX could be loaded in the dental pulp MSCs of 100%, while almost 86% of the MCF-7 cells uptake it from the conditioned medium [63]. Brini et al. believed that MSCs from interdental papilla were able to take up and release a sufficient amount of PTX against pancreatic carcinoma in vitro [65]. However, BM-MSCs did not take up and release PMX in effective amounts on mesothelioma, although PTX-loaded BM-MSCs dramatically inhibited mesothelioma proliferation [68]. Therefore, we speculate that MSCs have a certain specificity for the absorption and release of drugs, which may be closely associated with the structure of the drug, the surface protein of the MSCs, and the tolerance of the MSCs to the drug. Considering current research primarily in vitro, whether the MSCs loaded with chemotherapeutic drugs are protected by the immune system in systematic administration remains to be explored.

MSCs or engineered MSCs carried chemotherapeutic drugs may be a promising method for the treatment of drug-resistant tumors. The coculture of ovarian cancer cells with PTX-AT-MSCs inhibited cell viability in 2D and 3D models and counteracted PTX-resistance cells [64]. Coccè et al. demonstrated that AT-MSCs engineered with TRAIL were resistant to PTX and able to incorporate and then release the drug. The PTX delivery together with TRAIL secretion resulted in increased antitumor efficacy in human pancreatic carcinoma and glioblastoma in vitro [66].

The efficiency of drug-loaded nanoparticles is determined by the enhanced permeation and retention effect. As a result, the underperfused or hypoxic location within tumors rarely benefits from nanomedicine [71]. MSCs are recognized as ideal carriers of nanomedicine for tumor-targeting therapy because of their tumor-homing potential in response to proinflammatory cytokines in the tumor microenvironment. MSCs are engineered with drug-loaded nanoparticles and result in an antitumor effect [71–73]. MSCs loaded with nano-PTX result in significant inhibition of tumor growth and superior survival. Furthermore, at doses that result in equivalent therapeutic efficacy, nanoengineered MSCs do not affect white blood cell count, whereas PTX solution and PTX nanoparticle treatments cause leukopenia [72]. A silica nanorattle-DOX drug delivery system is efficiently anchored to MSCs by specific antibody-antigen recognitions at the cytomembrane interface. MSCs-nano-DOX can track down the U251 glioma tumor cells and deliver DOX with wide distribution and long retention lifetime in tumor tissues with low systematic toxicity in vivo [73]. Zhao et al. [71] prepared DOX-loaded poly (d, l-lactic-co-glycolic acid) (PLGA) nanoparticles and loaded them in MSCs. The average DOX content was measured at pg/cell in PLGA-DOX-loaded MSCs, which resulted in improved drug concentration in the lungs and sites of the metastasis and enhanced antitumor efficacy [71].

4.4. MSCs as Delivery of Oncolytic Virus

The oncolytic virus (OV) has shown promising results in various clinical trials for the treatment of various cancers. However, systemic administration of OV is severely restricted by their immunogenic nature and poor tumor-homing ability; thus, oncolytic adenovirus (OADV) cannot be utilized to treat disseminated metastases [74]. The MSC-based delivery system which could circumvent humoral immunity is an ideal solution. The success of this strategy depends on efficient ex vivo cellular loading with the virus, intracellular virus amplification, effective cellular targeting of tumor sites following systemic administration, and successful virus hand-off at the tumor site. MSCs acquire strong antitumor activity after transducing with the OVs such as OADV, oncolytic herpes simplex virus (OHSV), and oncolytic measles virus (OMV) (shown in Table 4) [74–85, 91].

It is critical to load viruses into MSCs efficiently ex vivo. Conventional OADV cannot be efficiently loaded into human MSCs due to the low surface expression of coxsackie and adenovirus receptors in MSCs. Na et al. showed that the loading efficiency of OADV into MSCs could be greatly enhanced by complexing the OADV with cationic polymer PCDP, a poly(ethylenimine)- (PEI-) conjugated poly(cystaminebis(acrylamide)-diaminohexane). Furthermore, systemic administration of OADV-PCDP-MSCs elicited a more potent antitumor effect compared to naked OADV alone in the pancreatic tumor model [74].

OVs engineered with molecular methods and then loaded into MSCs can improve virus titers and the effective cellular targeting of tumor sites following systemic administration. Yoon et al. inserted a sequence encoding a Wnt-inhibiting decoy receptor (WNTi) into the OADV that targets alpha-fetoprotein- (AFP-) positive HCCs and then loaded it into MSCs. Both OADV and OADV-MSC elicited minimal killing effects in the normal BJ cell line, showing that the oncolytic effects occur with high specificity toward cancer cells. In the orthotopic HCC tumor model, the systemic administration of OADV-MSC resulted in a markedly 8.1-fold antitumor activity than OADV alone at 35 days postimplantation [75]. OADV deleted the antiapoptotic viral gene E1B19K or downregulated expression of the death ligand TRAIL increased virus titers released from MSCs, which resulted in improved killing of the pancreatic cancer cells [78]. Menstrual blood MSCs (MB-MSCs) combined with ICOVIR15-cBiTE, an OADV expressing an epidermal growth factor receptor- (EGFR-) targeting bispecific T-cell engager (cBiTE), enhanced the antitumor efficacy compared to MB-MSCs loaded with the unarmed virus ICOVIR15 [80]. Guo et al. demonstrated that MB-MSCs specifically targeted tumor cells and served as an OADV delivery platform. MB-MSCs loaded with OADV (CRAd5/F11) inhibited tumor growth in vivo and in vitro [76]. The growth of ovarian cancer lung metastases and breast cancer brain metastases were strongly inhibited after a single injection of MSCs loading OHSV retargeted to HER2 [83]. MSCs-OHSV resulted in significantly increased antiglioblastoma efficacy compared with direct injection of purified OHSV in a preclinical model of glioblastoma resection, ensuing in extended median survival in mice. And MSCs loaded with OHSV-TRAIL successfully induced apoptosis-mediated killing and extended median survival in mice bearing OHSV- and TRAIL-resistant glioblastoma in vitro [81].

Enhancement of antitumor efficacy of MSCs-OV not only benefits from its ability to circumvent humoral immunity to homing but also infiltration of immune cells and differentiation ability of MSCs. MSCs-OMV was protected from antiviral antibodies, which was why therapy with MSCs-OMV resulted in significant inhibition of tumor growth in both measles antibody-naïve and passively immunized SCID mice. By contrast, when OMV was delivered systemically alone, antitumor activity was evident only in measles antibody-naïve SCID mice [84]. Similarly, BM-MSCs enhanced the therapeutic efficacy of systemically delivered OMV in the presence of preexisting high titer anti-MV antibodies in the SCID murine model of acute lymphoblastic leukemia [85]. Rincón et al. suggested that the use of MSCs as carriers of OADV could improve the clinical efficacy of anticancer virotherapy, not only by driving the adenovirus to tumors but also through their potential to recruit T cells, including CD8+ and CD4+ T cells [77]. Intracarotid-delivered MSCs-OHSV, but not purified OHSV, efficiently tracked metastatic tumor deposits in the brain, suppressed brain tumor growth, and prolonged survival in mouse models of melanoma brain metastasis. Furthermore, an increased CD8 + IFNγ+ tumor-infiltrating T lymphocytes population was observed after injecting MSC-OHSV intracarotid [82]. Combination therapy of MSCs-OHSV and anti-PD-L1 improved therapeutic efficacy in a syngeneic mouse model of melanoma brain metastasis [82]. The UC-MSC-loaded OADV could be home to the tumor sites and differentiate into hepatocyte-like cells within the tumor microenvironment first. Subsequently, the OADV lysed tumor cells selectively to exhibit tumor inhibition on both orthotopic and subcutaneous hepatic xenograft tumor model mice with less toxicity on normal organs [79].

5. Effect of MSC Extracellular Vesicles (EVs)/Exosomes on Tumors

Exosomes derived from MSCs serve as paracrine mediators to inhibit or promote tumor progression by transferring signaling molecules (shown in Table 5). Human UC-MSC-EVs exert potently antiproliferative and proapoptotic results on bladder tumor T24 cells both in vitro and in vivo through restraining phosphorylation of Akt and upregulating p-p53/p21 and cleaved Caspase 3 [92]. EVs derived from human BM-MSCs induce apoptosis to inhibit cell cycle progression and the growth of HepG2 hepatoma, Kaposi’s sarcoma, and Skov-3 ovarian tumor cell lines in vitro and in vivo [93]. miR-16 shuttled by MSC-derived exosomes can downregulate the expression of VEGF in tumor cells to suppress angiogenesis and tumor progression in vitro and in vivo [95]. Normal BM-MSC exosomes miR-15a inhibit the growth of multiple myeloma cells, although multiple myeloma BM-MSC-derived exosomes promoted multiple myeloma tumor growth [94]. TRIM14 can promote the proliferation of AML cells via activating PI3K/AKT pathway, which is reversed by BM-MSC exosomes through delivering miR-23b-5p [100].

Nevertheless, it has also been reported that MSC-derived exosomes or EVs are involved in modulating tumor growth and advancing tumor progression. BM-MSC-derived EVs support the tumor growth and angiogenesis of breast cancer in vivo and in vitro [96]. BM-MSC-derived exosomes promote human osteosarcoma and gastric cancer cell proliferation through the activation of the hedgehog signaling pathway [97]. In addition, BM-MSC-derived exosomes enhance VEGF expression in tumor cells by activating the extracellular signal-regulated kinase1/2 (ERK1/2) pathway [98]. AT-MSC-derived exosomes promote migration of the breast cancer cell line MCF7 via activation of the Wnt signaling pathway [99].

It is worth noting that the effects of MSC exosomes or EVs from different sources on the same tumor cell line may be inconsistent. MSC exosomes derived from the same tissue may have different effects on different cell lines. For example, BM-MSC-derived exosomes inhibited the angiogenesis of the murine breast cancer cell line 4T1 [95], while AT-MSC-derived exosomes promote the migration of the human cell line MCF-7 [99]. In addition, BM-MSC-derived EVs promote the proliferation and metastasis of human breast cancer cell line MCF-7 [96]. The effect of protumor or antitumor of MSC exosomes may be related to the source of MSCs, the protocol of MSC culture and exosome extraction, the heterogeneity of cancer cells, and the surrounding microenvironment. Given this, if natural MSC exosomes are used alone to treat tumors, the protocol of MSC culture and exosome extraction must be standardized, and the effects and mechanisms of MSC exosomes for specific tumors must be clarified. In addition, local treatment by intratumoral injection may be safer than systemic administration.

6. Extracellular Vesicles and Exosomes Derived from MSCs as Antitumor Vectors

The exosomes are smaller, less complex, and less immunogenic than their parent cells since they have a lower content of membrane-bound proteins [113]. In addition, exosomes contain transmembrane and membrane-anchored proteins that likely enhance endocytosis, thus promoting the delivery of their internal content [114]. As demonstrated by Smyth et al. [115], the internalization of exosomes within tumor cells is ten times greater than liposomes of comparable size, representing a superior specificity of exosomes for cancer targeting. EVs and exosomes derived from MSCs may be ideal antitumor vectors (shown in Table 6).

6.1. miRNA

miR-122-transfected AT-MSCs can efficaciously package miR-122 into secreted exosomes, which can mediate the miR-122 conversation between AT-MSCs and HCC cells, thereby rendering cancer cells sensitive to chemotherapeutic agents through alteration of miR-122-target gene expression in HCC cells [106]. Systemic administration of miR-379-enriched EVs causes a significant reduction in tumor activity over the 6 weeks of monitoring [107]. Exosomal miR-9-3p secreted from BM-MSCs inhibits viability, migration, and invasion while promoting apoptosis in bladder cancer via the downregulation of ESM1 [112]. The delivery of miR-139-5p from UC-MSC-derived exosomes results in the repression of proliferation, invasion, and migration of T24 cells together with the inhibition of bladder tumorigenesis in nude mice [101]. BM-MSC-derived exosomes expressing miR-146b inhibit glioma growth via decreasing expression of EGFR and NF-κB protein [104]. BM-MSC-derived exosomes containing miR-143 are easily transferred into recipient cells and suppressed the migration of osteosarcoma cell lines [105]. MSC exosomes are effectively used as a delivery vector to transport PLK-1 siRNA to bladder cancer cells in vitro, resulting in selective gene silencing of PLK-1 [108]. The delivery of anti-miR-9 to the resistant glioblastoma cells reverses the expression of the multidrug transporter and reverses the chemoresistance of glioblastoma cells [103].

6.2. Drugs

PTX-loaded MSC-derived EVs are loaded with PTX and possess strong antiproliferative activity on the pancreatic adenocarcinoma cell line CFPAC-1 [102]. PTX-loaded MSC exosomes are successfully isolated using a miniextruder. They significantly decrease the viability of MDA-MB-231 cells of breast cancer in vitro and inhibit tumor growth in vivo [110]. The MSC exosomes loaded with DOX are prepared by mixing exosome with DOX, desalinizing with triethylamine, and then dialyzing against PBS overnight. Compared with the free DOX, the prepared exosome-DOX shows enhanced cellular uptake efficiency and antitumor effect in the osteosarcoma MG63 cell line [111].

7. Conclusion and Prospect

Recently, it has been increasingly verified that MSCs play a prominent role in tumor growth, progression, and treatment response. However, the role of MSCs and EVs in tumor progression is controversial, with apparently contradictory results having been published. Such contradicting observations may be related to the heterogeneity of MSCs and experimental condition, such as the dose and time of MSC or EV administration and the optimal culture condition. Generation methods and culture systems of MSCs should be better standardized to make results more reproducible in future research. Furthermore, although MSCs are clinically used as therapeutic agents in inflammatory disease and regenerative medicine, the potential functional role of multipotential differentiation of MSCs during cancer development in vivo is so far uncertain. Large and stringently designed studies are required to answer whether MSCs contribute to carcinogenesis for people without tumors following systemic administration.

Also, because of their tropism to the tumor and low immunogenic properties, MSCs have been recently developed as carriers for against cancer biologics like cytokines, chemotherapeutic agents, and OVs. Few studies focus on the biosafety of engineered MSCs, despite the fact that a small number of MSCs may be present in other regions of the body and may affect healthy tissues after delivery of modified MSCs. As a result, a comprehensive evaluation of the optimal dose, therapeutic routine, drug distribution, and biological safety of engineered MSCs in cancer treatment is required. Furthermore, most of the research examining the efficacy of engineered MSCs on tumors is mainly performed in cancer cells and/or animal models. It would be meaningful to launch clinical studies to demonstrate the safety and efficacy of engineered MSCs in tumors.

Herein, we present several promising research directions for the future. First, MSCs as vehicles of chemotherapeutic drugs augment the targeting delivery of antitumor efficacy to tumor sites and avoid toxicity and acquired resistance to chemotherapy. Next, whether MSC-loaded nanoparticles have an advantage over nanoparticles remains to be seen, such as reduction of nanotoxicity and circumventing immune rejection.

Abbreviations

MSCs:	Mesenchymal stem cells
IGF1:	Insulin-like growth factor 1
VEGF:	Vascular endothelial growth factor
PDGF:	Plateletderived growth factor
TGFβ:	Transforming growth factorβ
UC-MSC:	Umbilical cord MSC
AT-MSC:	Adipose tissue MSC
HCC:	Hepatocellular carcinoma cells
BM-MSC:	Bone marrow MSC
EMT:	Epithelia-mesenchymal transition
IL:	Interleukin
NK:	Natural killer cells
TRAIL:	Tumour necrosis factor-related apoptosis-inducing ligand
TNF:	Tumor necrosis factor
PTX:	Paclitaxel
DOX:	Doxorubicin
GCB:	Gemcitabine
PMX:	Pemetrexed
OV:	Oncolytic virus
OADV:	Oncolytic adenovirus
OHSV:	Oncolytic herpes simplex virus
OMV:	Oncolytic measles virus
AFP:	Alpha-fetoprotein
EGFR:	Epidermal growth factor receptor
EVs:	Extracellular vesicles
AF-MSCs:	Human amniotic fluid mesenchymal stem cells
UCB-MSCs:	Human umbilical cord blood-derived mesenchymal stem cells
G-MSC:	Gingiva-derived mesenchymal stromal cells
IFN:	Interferon
MB-MSCs:	Menstrual blood-derived mesenchymal stem cells
CSCs:	Cancer stem cells
MVs:	Microvesicles.

Conflicts of Interest

The authors declare that they have no competing interests.

Authors’ Contributions

Enguang Yang and Suoshi Jing contributed equally to this work. Enguang Yang and Suoshi Jing drafted the manuscript. Yuhan Wang and Hanzhang Wang revised the manuscript. Zhiping Wang and Ronald Rodriguez conceived the hypothesis and contributed to the preparation of the final version of the manuscript. All authors reviewed the manuscript and approved the final manuscript.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (grant no. 81874088).

References

S. J. Turley, V. Cremasco, and J. L. Astarita, “Immunological hallmarks of stromal cells in the tumour microenvironment,” Nature Reviews Immunology, vol. 15, no. 11, pp. 669–682, 2015.
View at: Publisher Site | Google Scholar
A. Y. Khakoo, S. Pati, S. A. Anderson et al., “Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi’s sarcoma,” The Journal of Experimental Medicine, vol. 203, no. 5, pp. 1235–1247, 2006.
View at: Publisher Site | Google Scholar
L. G. Menon, S. Picinich, R. Koneru et al., “Differential gene expression associated with migration of mesenchymal stem cells to conditioned medium from tumor cells or bone marrow cells,” Stem Cells, vol. 25, no. 2, pp. 520–528, 2007.
View at: Publisher Site | Google Scholar
C. Zischek, H. Niess, I. Ischenko et al., “Targeting tumor stroma using engineered mesenchymal stem cells reduces the growth of pancreatic carcinoma,” Annals of Surgery, vol. 250, no. 5, pp. 747–753, 2009.
View at: Publisher Site | Google Scholar
A. Nakamizo, F. Marini, T. Amano et al., “Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas,” Cancer Research, vol. 65, no. 8, pp. 3307–3318, 2005.
View at: Publisher Site | Google Scholar
M. Quante, S. P. Tu, H. Tomita et al., “Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth,” Cancer Cell, vol. 19, no. 2, pp. 257–272, 2011.
View at: Publisher Site | Google Scholar
H. Mirzaei, A. Sahebkar, A. Avan et al., “Application of mesenchymal stem cells in melanoma: a potential therapeutic strategy for delivery of targeted agents,” Current Medicinal Chemistry, vol. 23, no. 5, pp. 455–463, 2016.
View at: Publisher Site | Google Scholar
M. Studeny, F. C. Marini, J. L. Dembinski et al., “Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents,” Journal of the National Cancer Institute, vol. 96, no. 21, pp. 1593–1603, 2004.
View at: Publisher Site | Google Scholar
H. Xin, M. Kanehira, H. Mizuguchi et al., “Targeted delivery of CX3CL1 to multiple lung tumors by mesenchymal stem cells,” Stem Cells, vol. 25, no. 7, pp. 1618–1626, 2007.
View at: Publisher Site | Google Scholar
S. Komarova, Y. Kawakami, M. A. Stoff-Khalili, D. T. Curiel, and L. Pereboeva, “Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses,” Molecular Cancer Therapeutics, vol. 5, no. 3, pp. 755–766, 2006.
View at: Publisher Site | Google Scholar
J. Stagg, “Mesenchymal stem cells in cancer,” Stem Cell Reviews, vol. 4, no. 2, pp. 119–124, 2008.
View at: Publisher Site | Google Scholar
Y. Jung, J. K. Kim, Y. Shiozawa et al., “Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis,” Nature Communications, vol. 4, no. 1, p. 1795, 2013.
View at: Publisher Site | Google Scholar
R. M. Dwyer, S. M. Potter-Beirne, K. A. Harrington et al., “Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells,” Clinical Cancer Research, vol. 13, no. 17, pp. 5020–5027, 2007.
View at: Publisher Site | Google Scholar
Y. Shi, L. Du, L. Lin, and Y. Wang, “Tumour-associated mesenchymal stem/stromal cells: emerging therapeutic targets,” Nature Reviews Drug Discovery, vol. 16, no. 1, pp. 35–52, 2017.
View at: Publisher Site | Google Scholar
A. M. Abarbanell, A. C. Coffey, J. W. Fehrenbacher et al., “Proinflammatory cytokine effects on mesenchymal stem cell therapy for the ischemic heart,” The Annals of Thoracic Surgery, vol. 88, no. 3, pp. 1036–1043, 2009.
View at: Publisher Site | Google Scholar
M. S. Chen, C. Y. Lin, Y. H. Chiu, C. P. Chen, P. J. Tsai, and H. S. Wang, “IL-1 β-Induced Matrix Metalloprotease-1 Promotes Mesenchymal Stem Cell Migration via PAR1 and G-Protein-Coupled Signaling Pathway,” Stem Cells International, vol. 2018, Article ID 3524759, 11 pages, 2018.
View at: Publisher Site | Google Scholar
M. J. Dubon, J. Yu, S. Choi, and K. S. Park, “Transforming growth factor β induces bone marrow mesenchymal stem cell migration via noncanonical signals and N-cadherin,” Journal of Cellular Physiology, vol. 233, no. 1, pp. 201–213, 2018.
View at: Publisher Site | Google Scholar
S. Lourenco, V. H. Teixeira, T. Kalber, R. J. Jose, R. A. Floto, and S. M. Janes, “Macrophage migration inhibitory factor-CXCR4 is the dominant chemotactic axis in human mesenchymal stem cell recruitment to tumors,” Journal of Immunology, vol. 194, no. 7, pp. 3463–3474, 2015.
View at: Publisher Site | Google Scholar
X. Liang, L. Hao, X. Chen et al., “Effects of bone marrow stromal cells and umbilical cord blood-derived stromal cells on daunorubicin-resistant residual Jurkat cells,” Transplantation Proceedings, vol. 42, no. 9, pp. 3767–3772, 2010.
View at: Publisher Site | Google Scholar
M. Fonseka, R. Ramasamy, B. C. Tan, and H. F. Seow, “Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) inhibit the proliferation of K562 (human erythromyeloblastoid leukaemic cell line),” Cell Biology International, vol. 36, no. 9, pp. 793–801, 2012.
View at: Publisher Site | Google Scholar
H. D. Lin, C. Y. Fong, A. Biswas, M. Choolani, and A. Bongso, “Human Wharton’s jelly stem cells, its conditioned medium and cell-free lysate inhibit the growth of human lymphoma cells,” Stem Cell Reviews and Reports, vol. 10, no. 4, pp. 573–586, 2014.
View at: Publisher Site | Google Scholar
P. Secchiero, S. Zorzet, C. Tripodo et al., “Human bone marrow mesenchymal stem cells display anti-cancer activity in SCID mice bearing disseminated non-Hodgkin’s lymphoma xenografts,” PLoS One, vol. 5, no. 6, article e11140, 2010.
View at: Publisher Site | Google Scholar
J. O. Ahn, J. S. Chae, Y. R. Coh et al., “Human adipose tissue-derived mesenchymal stem cells inhibit T-cell lymphoma growth in vitro and in vivo,” Anticancer Research, vol. 34, no. 9, pp. 4839–4847, 2014.
View at: Google Scholar
L. Leng, Y. Wang, N. He et al., “Molecular imaging for assessment of mesenchymal stem cells mediated breast cancer therapy,” Biomaterials, vol. 35, no. 19, pp. 5162–5170, 2014.
View at: Publisher Site | Google Scholar
H. Ryu, J. E. Oh, K. J. Rhee et al., “Adipose tissue-derived mesenchymal stem cells cultured at high density express IFN-β and suppress the growth of MCF-7 human breast cancer cells,” Cancer Letters, vol. 352, no. 2, pp. 220–227, 2014.
View at: Publisher Site | Google Scholar
Y. Yulyana, I. A. Ho, K. C. Sia et al., “Paracrine factors of human fetal MSCs inhibit liver cancer growth through reduced activation of IGF-1R/PI3K/Akt signaling,” Molecular Therapy, vol. 23, no. 4, pp. 746–756, 2015.
View at: Publisher Site | Google Scholar
W. Zhao, G. Ren, L. Zhang et al., “Efficacy of mesenchymal stem cells derived from human adipose tissue in inhibition of hepatocellular carcinoma cells in vitro,” Cancer Biotherapy & Radiopharmaceuticals, vol. 27, no. 9, pp. 606–613, 2012.
View at: Publisher Site | Google Scholar
I. Han, M. Yun, E. O. Kim, B. Kim, M. H. Jung, and S. H. Kim, “Umbilical cord tissue-derived mesenchymal stem cells induce apoptosis in PC-3 prostate cancer cells through activation of JNK and downregulation of PI3K/AKT signaling,” Stem Cell Research & Therapy, vol. 5, no. 2, p. 54, 2014.
View at: Publisher Site | Google Scholar
J. O. Ahn, Y. R. Coh, H. W. Lee, I. S. Shin, S. K. Kang, and H. Y. Youn, “Human adipose tissue-derived mesenchymal stem cells inhibit melanoma growth in vitro and in vivo,” Anticancer Research, vol. 35, no. 1, pp. 159–168, 2015.
View at: Google Scholar
F. Böhrnsen, M. Fricke, C. Sander, A. Leha, H. Schliephake, and F. J. Kramer, “Interactions of human MSC with head and neck squamous cell carcinoma cell line PCI-13 reduce markers of epithelia-mesenchymal transition,” Clinical Oral Investigations, vol. 19, no. 5, pp. 1121–1128, 2015.
View at: Publisher Site | Google Scholar
S. Kidd, L. Caldwell, M. Dietrich et al., “Mesenchymal stromal cells alone or expressing interferon-β suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment,” Cytotherapy, vol. 12, no. 5, pp. 615–625, 2010.
View at: Publisher Site | Google Scholar
S. Ciavarella, A. Caselli, A. V. Tamma et al., “A peculiar molecular profile of umbilical cord-mesenchymal stromal cells drives their inhibitory effects on multiple myeloma cell growth and tumor progression,” Stem Cells and Development, vol. 24, no. 12, pp. 1457–1470, 2015.
View at: Publisher Site | Google Scholar
K. Takahara, M. Ii, T. Inamoto et al., “Adipose-derived stromal cells inhibit prostate cancer cell proliferation inducing apoptosis,” Biochemical and Biophysical Research Communications, vol. 446, no. 4, pp. 1102–1107, 2014.
View at: Publisher Site | Google Scholar
B. M. Beckermann, G. Kallifatidis, A. Groth et al., “VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma,” British Journal of Cancer, vol. 99, no. 4, pp. 622–631, 2008.
View at: Publisher Site | Google Scholar
W. H. Huang, M. C. Chang, K. S. Tsai, M. C. Hung, H. L. Chen, and S. C. Hung, “Mesenchymal stem cells promote growth and angiogenesis of tumors in mice,” Oncogene, vol. 32, no. 37, pp. 4343–4354, 2013.
View at: Publisher Site | Google Scholar
A. Vartanian, S. Karshieva, V. Dombrovsky, and A. Belyavsky, “Melanoma educates mesenchymal stromal cells towards vasculogenic mimicry,” Oncology Letters, vol. 11, no. 6, pp. 4264–4268, 2016.
View at: Publisher Site | Google Scholar
M. Timaner, K. K. Tsai, and Y. Shaked, “The multifaceted role of mesenchymal stem cells in cancer,” Seminars in Cancer Biology, vol. 60, pp. 225–237, 2020.
View at: Publisher Site | Google Scholar
A. Scherzed, S. Hackenberg, K. Froelich et al., “BMSC enhance the survival of paclitaxel treated squamous cell carcinoma cells in vitro,” Cancer Biology & Therapy, vol. 11, no. 3, pp. 349–357, 2011.
View at: Publisher Site | Google Scholar
J. M. L. Roodhart, L. G. M. Daenen, E. C. A. Stigter et al., “Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids,” Cancer Cell, vol. 20, no. 3, pp. 370–383, 2011.
View at: Publisher Site | Google Scholar
H. Shen, “Stricter standards sought to curb stem-cell confusion,” Nature, vol. 499, no. 7459, p. 389, 2013.
View at: Publisher Site | Google Scholar
A. C. Mamede, M. Laranjo, M. J. Carvalho et al., “Effect of amniotic membrane proteins in human cancer cell lines: an exploratory study,” The Journal of Membrane Biology, vol. 247, no. 4, pp. 357–360, 2014.
View at: Publisher Site | Google Scholar
C. Ren, S. Kumar, D. Chanda, J. Chen, J. D. Mountz, and S. Ponnazhagan, “Therapeutic potential of mesenchymal stem cells producing interferon-alpha in a mouse melanoma lung metastasis model,” Stem Cells, vol. 26, no. 9, pp. 2332–2338, 2008.
View at: Publisher Site | Google Scholar
X. Ling, F. Marini, M. Konopleva et al., “Mesenchymal stem cells overexpressing IFN-β inhibit breast cancer growth and metastases through stat 3 signaling in a syngeneic tumor model,” Cancer Microenvironment, vol. 3, no. 1, pp. 83–95, 2010.
View at: Publisher Site | Google Scholar
C. Ren, S. Kumar, D. Chanda et al., “Cancer gene therapy using mesenchymal stem cells expressing interferon-β in a mouse prostate cancer lung metastasis model,” Gene Therapy, vol. 15, no. 21, pp. 1446–1453, 2008.
View at: Publisher Site | Google Scholar
T. Matsuzuka, R. S. Rachakatla, C. Doi et al., “Human umbilical cord matrix-derived stem cells expressing interferon-β gene significantly attenuate bronchioloalveolar carcinoma xenografts in SCID mice,” Lung Cancer, vol. 70, no. 1, p. 28-36, 2010.
View at: Publisher Site | Google Scholar
X. Chen, K. Wang, S. Chen, and Y. Chen, “Effects of mesenchymal stem cells harboring the Interferon- β gene on A549 lung cancer in nude mice,” Pathology, Research and Practice, vol. 215, no. 3, pp. 586–593, 2019.
View at: Publisher Site | Google Scholar
L. Du, Q. Liang, S. Ge, C. Yang, and P. Yang, “The growth inhibitory effect of human gingiva-derived mesenchymal stromal cells expressing interferon-β on tongue squamous cell carcinoma cells and xenograft model,” Stem Cell Research & Therapy, vol. 10, no. 1, p. 224, 2019.
View at: Publisher Site | Google Scholar
J. Ahn, H. Lee, K. Seo, S. . Kang, J. . Ra, and H. Youn, “Anti-tumor effect of adipose tissue derived-mesenchymal stem cells expressing interferon-β and treatment with cisplatin in a xenograft mouse model for canine melanoma,” PLoS One, vol. 8, no. 9, article e74897, 2013.
View at: Publisher Site | Google Scholar
M. Studeny, F. C. Marini, R. E. Champlin, C. Zompetta, I. J. Fidler, and M. Andreeff, “Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors,” Cancer Research, vol. 62, no. 13, pp. 3603–3608, 2002.
View at: Google Scholar
X. Yang, J. Du, X. Xu, C. Xu, and W. Song, “IFN-γ-Secreting-Mesenchymal Stem Cells Exert an Antitumor Effect In Vivo via the TRAIL Pathway,” Journal of Immunology Research, vol. 2014, Article ID 318098, 9 pages, 2014.
View at: Publisher Site | Google Scholar
S. H. Seo, K. S. Kim, S. H. Park et al., “The effects of mesenchymal stem cells injected via different routes on modified IL-12-mediated antitumor activity,” Gene Therapy, vol. 18, no. 5, pp. 488–495, 2011.
View at: Publisher Site | Google Scholar
P. Gao, Q. Ding, Z. Wu, H. Jiang, and Z. Fang, “Therapeutic potential of human mesenchymal stem cells producing IL-12 in a mouse xenograft model of renal cell carcinoma,” Cancer Letters, vol. 290, no. 2, pp. 157–166, 2010.
View at: Publisher Site | Google Scholar
N. Eliopoulos, M. Francois, M.-N. Boivin, D. Martineau, and J. Galipeau, “Neo-organoid of marrow mesenchymal stromal cells secreting interleukin-12 for breast cancer therapy,” Cancer Research, vol. 68, no. 12, pp. 4810–4818, 2008.
View at: Publisher Site | Google Scholar
C. H. Ryu, S. H. Park, S. A. Park et al., “Gene therapy of intracranial glioma using interleukin 12-secreting human umbilical cord blood-derived mesenchymal stem cells,” Human Gene Therapy, vol. 22, no. 6, pp. 733–743, 2011.
View at: Publisher Site | Google Scholar
X. Chen, X. Lin, J. Zhao et al., “A tumor-selective biotherapy with prolonged impact on established metastases based on cytokine gene-engineered MSCs,” Molecular Therapy, vol. 16, no. 4, pp. 749–756, 2008.
View at: Publisher Site | Google Scholar
K. Nakamura, Y. Ito, Y. Kawano et al., “Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model,” Gene Therapy, vol. 11, no. 14, pp. 1155–1164, 2004.
View at: Publisher Site | Google Scholar
J. Stagg, L. Lejeune, A. Paquin, and J. Galipeau, “Marrow stromal cells for interleukin-2 delivery in cancer immunotherapy,” Human Gene Therapy, vol. 15, no. 6, pp. 597–608, 2004.
View at: Publisher Site | Google Scholar
Q. You, Y. Yao, Y. Zhang, S. Fu, M. Du, and G. Zhang, “Effect of targeted ovarian cancer therapy using amniotic fluid mesenchymal stem cells transfected with enhanced green fluorescent protein-human interleukin-2 in vivo,” Molecular Medicine Reports, vol. 12, no. 4, pp. 4859–4866, 2015.
View at: Publisher Site | Google Scholar
W. Hu, J. Wang, X. He et al., “Human umbilical blood mononuclear cell–derived mesenchymal stem cells serve as interleukin-21 gene delivery vehicles for epithelial ovarian cancer therapy in nude mice,” Biotechnology and Applied Biochemistry, vol. 58, no. 6, pp. 397–404, 2011.
View at: Publisher Site | Google Scholar
E. K. Sage, K. K. Kolluri, K. McNulty et al., “Systemic but not topical TRAIL-expressing mesenchymal stem cells reduce tumour growth in malignant mesothelioma,” Thorax, vol. 69, no. 7, pp. 638–647, 2014.
View at: Publisher Site | Google Scholar
M. R. Loebinger, E. K. Sage, D. Davies, and S. M. Janes, “TRAIL-expressing mesenchymal stem cells kill the putative cancer stem cell population,” British Journal of Cancer, vol. 103, no. 11, pp. 1692–1697, 2010.
View at: Publisher Site | Google Scholar
Z. Yuan, K. K. Kolluri, E. K. Sage, K. H. C. Gowers, and S. M. Janes, “Mesenchymal stromal cell delivery of full-length tumor necrosis factor-related apoptosis-inducing ligand is superior to soluble type for cancer therapy,” Cytotherapy, vol. 17, no. 7, pp. 885–896, 2015.
View at: Publisher Site | Google Scholar
H. Salehi, S. Al-Arag, E. Middendorp, C. Gergely, F. Cuisinier, and V. Orti, “Dental pulp stem cells used to deliver the anticancer drug paclitaxel,” Stem Cell Research & Therapy, vol. 9, no. 1, p. 103, 2018.
View at: Publisher Site | Google Scholar
C. Borghese, N. Casagrande, G. Corona, and D. Aldinucci, “Adipose-derived stem cells primed with paclitaxel inhibit ovarian cancer spheroid growth and overcome paclitaxel resistance,” Pharmaceutics, vol. 12, no. 5, p. 401, 2020.
View at: Publisher Site | Google Scholar
A. T. Brini, V. Coccè, L. M. Ferreira et al., “Cell-mediated drug delivery by gingival interdental papilla mesenchymal stromal cells (GinPa-MSCs) loaded with paclitaxel,” Expert Opinion on Drug Delivery, vol. 13, no. 6, pp. 789–798, 2016.
View at: Publisher Site | Google Scholar
V. Coccè, A. Bonomi, L. Cavicchini et al., “Paclitaxel priming of TRAIL expressing mesenchymal stromal cells (MSCs-TRAIL) increases antitumor efficacy of their secretome,” Current Cancer Drug Targets, vol. 21, no. 3, pp. 213–222, 2021.
View at: Publisher Site | Google Scholar
V. Coccè, D. Farronato, A. T. Brini et al., “Drug Loaded Gingival Mesenchymal Stromal Cells (GinPa-MSCs) Inhibit In Vitro Proliferation of Oral Squamous Cell Carcinoma,” Scientific Reports, vol. 7, no. 1, p. 9376, 2017.
View at: Publisher Site | Google Scholar
F. Petrella, V. Coccè, C. Masia et al., “Paclitaxel-releasing mesenchymal stromal cells inhibit in vitro proliferation of human mesothelioma cells,” Biomedicine & Pharmacotherapy, vol. 87, pp. 755–758, 2017.
View at: Publisher Site | Google Scholar
S. Kalimuthu, L. Zhu, J. M. Oh et al., “Migration of mesenchymal stem cells to tumor xenograft models and in vitro drug delivery by doxorubicin,” International Journal of Medical Sciences, vol. 15, no. 10, pp. 1051–1061, 2018.
View at: Publisher Site | Google Scholar
A. Bonomi, V. Sordi, E. Dugnani et al., “Gemcitabine-releasing mesenchymal stromal cells inhibit in vitro proliferation of human pancreatic carcinoma cells,” Cytotherapy, vol. 17, no. 12, pp. 1687–1695, 2015.
View at: Publisher Site | Google Scholar
Y. Zhao, S. Tang, J. Guo et al., “Targeted delivery of doxorubicin by nano-loaded mesenchymal stem cells for lung melanoma metastases therapy,” Scientific Reports, vol. 7, no. 1, p. 44758, 2017.
View at: Publisher Site | Google Scholar
B. Layek, T. Sadhukha, J. Panyam, and S. Prabha, “Nano-engineered mesenchymal stem cells increase therapeutic efficacy of anticancer drug through true active tumor targeting,” Molecular Cancer Therapeutics, vol. 17, no. 6, pp. 1196–1206, 2018.
View at: Publisher Site | Google Scholar
L. Li, Y. Guan, H. Liu et al., “Silica nanorattle-doxorubicin-anchored mesenchymal stem cells for tumor-tropic therapy,” ACS Nano, vol. 5, no. 9, pp. 7462–7470, 2011.
View at: Publisher Site | Google Scholar
Y. Na, J. P. Nam, J. Hong et al., “Systemic administration of human mesenchymal stromal cells infected with polymer-coated oncolytic adenovirus induces efficient pancreatic tumor homing and infiltration,” Journal of Controlled Release, vol. 305, pp. 75–88, 2019.
View at: Publisher Site | Google Scholar
A. R. Yoon, J. Hong, Y. Li et al., “Mesenchymal stem cell-mediated delivery of an oncolytic adenovirus enhances antitumor efficacy in hepatocellular carcinoma,” Cancer Research, vol. 79, no. 17, pp. 4503–4514, 2019.
View at: Publisher Site | Google Scholar
Y. Guo, Z. Zhang, X. Xu et al., “Menstrual blood-derived stem cells as delivery vehicles for oncolytic adenovirus virotherapy for colorectal cancer,” Stem Cells and Development, vol. 28, no. 13, pp. 882–896, 2019.
View at: Publisher Site | Google Scholar
E. Rincón, T. Cejalvo, D. Kanojia et al., “Mesenchymal stem cell carriers enhance antitumor efficacy of oncolytic adenoviruses in an immunocompetent mouse model,” Oncotarget, vol. 8, no. 28, pp. 45415–45431, 2017.
View at: Publisher Site | Google Scholar
K. Hammer, A. Kazcorowski, L. Liu et al., “Engineered adenoviruses combine enhanced oncolysis with improved virus production by mesenchymal stromal carrier cells,” International Journal of Cancer, vol. 137, no. 4, pp. 978–990, 2015.
View at: Publisher Site | Google Scholar
X. Yuan, Q. Zhang, Z. Li et al., “Mesenchymal stem cells deliver and release conditionally replicative adenovirus depending on hepatic differentiation to eliminate hepatocellular carcinoma cells specifically,” Cancer Letters, vol. 381, no. 1, pp. 85–95, 2016.
View at: Publisher Site | Google Scholar
P. Barlabé, J. Sostoa, C. A. Fajardo, R. Alemany, and R. Moreno, “Enhanced antitumor efficacy of an oncolytic adenovirus armed with an EGFR- targeted BiTE using menstrual blood-derived mesenchymal stem cells as carriers,” Cancer Gene Therapy, vol. 27, no. 5, pp. 383–388, 2020.
View at: Publisher Site | Google Scholar
M. Duebgen, J. Martinez-Quintanilla, K. Tamura et al., “Stem cells loaded with multimechanistic oncolytic herpes simplex virus variants for brain tumor therapy,” Journal of the National Cancer Institute, vol. 106, no. 6, article dju090, 2014.
View at: Publisher Site | Google Scholar
W. Du, I. Seah, O. Bougazzoul et al., “Stem cell-released oncolytic herpes simplex virus has therapeutic efficacy in brain metastatic melanomas,” Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 30, pp. E6157–E6165, 2017.
View at: Publisher Site | Google Scholar
V. Leoni, V. Gatta, A. Palladini et al., “Systemic delivery of HER2-retargeted oncolytic-HSV by mesenchymal stromal cells protects from lung and brain metastases,” Oncotarget, vol. 6, no. 33, pp. 34774–34787, 2015.
View at: Publisher Site | Google Scholar
H. T. Ong, M. J. Federspiel, C. M. Guo et al., “Systemically delivered measles virus-infected mesenchymal stem cells can evade host immunity to inhibit liver cancer growth,” Journal of Hepatology, vol. 59, no. 5, pp. 999–1006, 2013.
View at: Publisher Site | Google Scholar
A. Castleton, A. Dey, B. Beaton et al., “Human mesenchymal stromal cells deliver systemic oncolytic measles virus to treat acute lymphoblastic leukemia in the presence of humoral immunity,” Blood, vol. 123, no. 9, pp. 1327–1335, 2014.
View at: Publisher Site | Google Scholar
N. Eliopoulos, A. Al-Khaldi, M. Crosato, K. A. Lachapelle, and J. Galipeau, “A neovascularized organoid derived from retrovirally engineered bone marrow stroma leads to prolonged in vivo systemic delivery of erythropoietin in nonmyeloablated, immunocompetent mice,” Gene Therapy, vol. 10, no. 6, pp. 478–489, 2003.
View at: Publisher Site | Google Scholar
G. Trinchieri, “Interleukin-12 and the regulation of innate resistance and adaptive immunity,” Nature Reviews Immunology, vol. 3, no. 2, pp. 133–146, 2003.
View at: Publisher Site | Google Scholar
E. C. Borden, “Interferons: pleiotropic cellular modulators,” Clinical Immunology and Immunopathology, vol. 62, no. 1, pp. S18–S24, 1992.
View at: Publisher Site | Google Scholar
J. R. Jett, A. W. Maksymiuk, J. Q. Su et al., “Phase III trial of recombinant interferon gamma in complete responders with small-cell lung cancer,” Journal of Clinical Oncology, vol. 12, no. 11, pp. 2321–2326, 1994.
View at: Publisher Site | Google Scholar
M. Nagane, H. J. Huang, and W. K. Cavenee, “The potential of TRAIL for cancer chemotherapy,” Apoptosis, vol. 6, no. 3, pp. 191–197, 2001.
View at: Publisher Site | Google Scholar
M. A. Stoff-Khalili, A. A. Rivera, J. M. Mathis et al., “Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma,” Breast Cancer Research and Treatment, vol. 105, no. 2, pp. 157–167, 2007.
View at: Publisher Site | Google Scholar
S. Wu, G. Q. Ju, T. Du, Y. J. Zhu, and G. H. Liu, “Microvesicles derived from human umbilical cord Wharton’s jelly mesenchymal stem cells attenuate bladder tumor cell growth in vitro and in vivo,” PLoS One, vol. 8, no. 4, article e61366, 2013.
View at: Publisher Site | Google Scholar
S. Bruno, F. Collino, M. C. Deregibus, C. Grange, C. Tetta, and G. Camussi, “Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth,” Stem Cells and Development, vol. 22, no. 5, pp. 758–771, 2013.
View at: Publisher Site | Google Scholar
A. M. Roccaro, A. Sacco, P. Maiso et al., “BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression,” The Journal of Clinical Investigation, vol. 123, no. 4, pp. 1542–1555, 2013.
View at: Publisher Site | Google Scholar
J. K. Lee, S. R. Park, B. K. Jung et al., “Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells,” PLoS One, vol. 8, no. 12, article e84256, 2013.
View at: Publisher Site | Google Scholar
K. C. Vallabhaneni, P. Penfornis, S. Dhule et al., “Extracellular vesicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA, proteins, and metabolites,” Oncotarget, vol. 6, no. 7, pp. 4953–4967, 2015.
View at: Publisher Site | Google Scholar
J. Qi, Y. Zhou, Z. Jiao et al., “Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth through hedgehog signaling pathway,” Cellular Physiology and Biochemistry, vol. 42, no. 6, pp. 2242–2254, 2017.
View at: Publisher Site | Google Scholar
W. Zhu, L. Huang, Y. Li et al., “Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo,” Cancer Letters, vol. 315, no. 1, pp. 28–37, 2012.
View at: Publisher Site | Google Scholar
R. Lin, S. Wang, and R. C. Zhao, “Exosomes from human adipose-derived mesenchymal stem cells promote migration through Wnt signaling pathway in a breast cancer cell model,” Molecular and Cellular Biochemistry, vol. 383, no. 1-2, pp. 13–20, 2013.
View at: Publisher Site | Google Scholar
H. Cheng, J. Ding, G. Tang et al., “Human mesenchymal stem cells derived exosomes inhibit the growth of acute myeloid leukemia cells via regulating miR-23b-5p/TRIM14 pathway,” Molecular Medicine, vol. 27, no. 1, p. 128, 2021.
View at: Publisher Site | Google Scholar
Y. Jia, X. Ding, L. Zhou, L. Zhang, and X. Yang, “Mesenchymal stem cells-derived exosomal microRNA-139-5p restrains tumorigenesis in bladder cancer by targeting PRC1,” Oncogene, vol. 40, no. 2, pp. 246–261, 2021.
View at: Publisher Site | Google Scholar
L. Pascucci, V. Coccè, A. Bonomi 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,” Journal of Controlled Release, vol. 192, pp. 262–270, 2014.
View at: Publisher Site | Google Scholar
J. L. Munoz, S. A. Bliss, S. J. Greco, S. H. Ramkissoon, K. L. Ligon, and P. Rameshwar, “Delivery of functional anti-miR-9 by mesenchymal stem cell-derived exosomes to glioblastoma multiforme cells conferred chemosensitivity,” Molecular Therapy--Nucleic Acids, vol. 2, no. 10, article e126, 2013.
View at: Publisher Site | Google Scholar
M. Katakowski, B. Buller, X. Zheng et al., “Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth,” Cancer Letters, vol. 335, no. 1, pp. 201–204, 2013.
View at: Publisher Site | Google Scholar
K. Shimbo, S. Miyaki, H. Ishitobi et al., “Exosome-formed synthetic microRNA-143 is transferred to osteosarcoma cells and inhibits their migration,” Biochemical and Biophysical Research Communications, vol. 445, no. 2, pp. 381–387, 2014.
View at: Publisher Site | Google Scholar
G. Lou, X. Song, F. Yang et al., “Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma,” Journal of Hematology & Oncology, vol. 8, no. 1, p. 122, 2015.
View at: Publisher Site | Google Scholar
K. P. O’brien, S. Khan, K. E. Gilligan et al., “Employing mesenchymal stem cells to support tumor-targeted delivery of extracellular vesicle (EV)-encapsulated microRNA-379,” Oncogene, vol. 37, no. 16, pp. 2137–2149, 2018.
View at: Publisher Site | Google Scholar
K. A. Greco, C. A. Franzen, K. E. Foreman, R. C. Flanigan, P. C. Kuo, and G. N. Gupta, “PLK-1 silencing in bladder cancer by siRNA delivered with exosomes,” Urology, vol. 91, no. 241, pp. 241.e1–241.e7, 2016.
View at: Publisher Site | Google Scholar
H. K. Lee, S. Finniss, S. Cazacu et al., “Mesenchymal stem cells deliver synthetic microRNA mimics to glioma cells and glioma stem cells and inhibit their cell migration and self-renewal,” Oncotarget, vol. 4, no. 2, pp. 346–361, 2013.
View at: Publisher Site | Google Scholar
S. Kalimuthu, P. Gangadaran, R. L. Rajendran et al., “A new approach for loading anticancer drugs into mesenchymal stem cell-derived exosome mimetics for cancer therapy,” Frontiers in Pharmacology, vol. 9, p. 1116, 2018.
View at: Publisher Site | Google Scholar
H. Wei, J. Chen, S. Wang et al., “A nanodrug consisting of doxorubicin and exosome derived from mesenchymal stem cells for osteosarcoma treatment in vitro,” International Journal of Nanomedicine, vol. Volume 14, pp. 8603–8610, 2019.
View at: Publisher Site | Google Scholar
H. Cai, X. Yang, Y. Gao et al., “Exosomal microRNA-9-3p secreted from BMSCs downregulates ESM1 to suppress the development of bladder cancer,” Molecular Therapy--Nucleic Acids, vol. 18, pp. 787–800, 2019.
View at: Publisher Site | Google Scholar
G. Lou, Z. Chen, M. Zheng, and Y. Liu, “Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases,” Experimental & Molecular Medicine, vol. 49, no. 6, article e346, 2017.
View at: Publisher Site | Google Scholar
P. Vader, E. A. Mol, G. Pasterkamp, and R. M. Schiffelers, “Extracellular vesicles for drug delivery,” Advanced Drug Delivery Reviews, vol. 106, no. Part A, pp. 148–156, 2016.
View at: Publisher Site | Google Scholar
T. J. Smyth, J. S. Redzic, M. W. Graner, and T. J. Anchordoquy, “Examination of the specificity of tumor cell derived exosomes with tumor cells in vitro,” Biochimica et Biophysica Acta, vol. 1838, no. 11, pp. 2954–2965, 2014.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2023 Enguang Yang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

627

Downloads

476

Citations