The multifaceted role of mesenchymal stem cells in cancer

Seminars in Cancer Biology xxx (xxxx) xxx–xxx

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Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer

Review

The multifaceted role of mesenchymal stem cells in cancer Michael Timanera, Kelvin K Tsaib,c, Yuval Shakeda,

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a

Technion-Integerated Cancer Center, Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel Laboratory of Advanced Molecular Therapeutics, and Division of Gastroenterology, Wan Fang Hospital, and Graduate Institutes of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei Taiwan c National Institute of Cancer Research, National Health Research Institutes, Taiwan b

A R T I C LE I N FO

A B S T R A C T

Keywords: Immunosuppression Angiogenesis Mesenchymal stem cells Resistance Metastasis

Mesenchymal stem cells (MSCs) are multipotent stem cells derived from the mesoderm that give rise to several mesenchymal lineages, including osteoblasts, adipocytes, chondrocytes and myocytes. Their potent ability to home to tumors coupled with their differentiation potential and immunosuppressive function positions MSCs as key regulators of tumor fate. Here we review the existing knowledge on the involvement of MSCs in multiple tumor-promoting processes, including angiogenesis, epithelial-mesenchymal transition, metastasis, immunosuppression and therapy resistance. We also discuss the clinical potential of MSC-based therapy for cancer.

1. Introduction Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, are multipotent stem cells with high differentiation potential and self-renewal abilities [1,2]. MSCs were first isolated from adult bone marrow in the late 1960s and were defined as fibroblast-like cells [3,4]. Only in 1991, Caplan and colleagues termed them MSCs based on their differentiation pattern [5,6]. MSCs give rise to several mesenchymal tissues, as they differentiate into multiple cell types such as osteoblasts, chondroblasts, myocytes and adipocytes [5,7,8]. Furthermore, MSCs are also able to transdifferentiate in vitro into endodermal (epithelial) and ectodermal (neuronal) lineages under certain culture conditions [9–11]. According to most clinical studies, the main source of MSCs is the bone marrow where they exist in low abundance, making up 0.01% to 0.001% of the total nucleated cell population [12,13]. In the bone marrow, MSCs support hematopoietic stem cells and promote hematopoiesis [14]. MSCs can also be isolated from adipose tissue, for example, following routine liposuction procedures. It has been shown that such MSCs give rise to adipose cells and promote an immune-evasive environment [15]. In addition to these two major sources of MSCs, circulating MSCs can be effectively isolated from the peripheral blood [16,17], umbilical cord [16,18,19], placenta [20,21], lungs [22,23], muscle [24,25], and bones [26]. In each of these organs, MSCs play diverse roles, giving rise to several mature mesenchymal cell lineages, controlling inflammation and supporting tissue architecture [27–29]. Besides their normal distribution in specific organs, MSCs are known to accumulate in areas of tissue damage where they play an

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essential role in wound healing and tissue regeneration [29–31]. Overall, MSCs are considered as important regulators of tissue homeostasis and support tissue integrity. Despite decades of intensive investigation, the in vitro characterization of MSCs remains ambiguous. Morphological observation of MSC cultures demonstrates a heterogeneous cell population comprised of several cell subsets shaped as spindle-form fibroblast-like cells, flattened cells, or round cells [32–34]. The functional and differentiation characteristics of each of these cell subsets is not fully known, however, all can give rise to differentiated lineages of MSCs [35]. Correspondingly, immunophenotypic characterization of human MSCs demonstrates that they do not express exclusive cell type-specific markers, but rather a set of variable surface markers which can also characterize other cells. Specifically, they positively express CD105, CD73, CD90, CD44, and CD29, and lack the expression of CD34, CD45, CD11b, CD14, CD19, CD31, and CD133 [36–38]. Others have indicated that MSCs can be sorted using CD271, STRO-1 and CD146 markers [39–41]. In mice, however, MSCs can be defined as being positive for PDGFRα and negative for Sca1, CD45, and TER119 [42,43]. Taken together, these studies highlight the heterogeneity of the MSC population which may explain their ability to differentiate into several distinct cell types [35,44,45]. It should also be noted that most recently, the term MSC was challenged due to the identification of a new type of skeletal stem cell that gives rise to cartilage and bone but not adipose tissue [46]. Nevertheless, most studies define MSCs according to the minimal criteria proposed by the International Society for Cellular Therapy (ISCT). These include: plastic-adherent properties in standard culture

Corresponding author. E-mail address: [email protected] (Y. Shaked).

https://doi.org/10.1016/j.semcancer.2019.06.003 Received 11 May 2019; Received in revised form 3 June 2019; Accepted 4 June 2019 1044-579X/ © 2019 Published by Elsevier Ltd.

Please cite this article as: Michael Timaner, Kelvin K Tsai and Yuval Shaked, Seminars in Cancer Biology, https://doi.org/10.1016/j.semcancer.2019.06.003

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(i.e., hijacking of pre-existing blood vessels from healthy tissue) [94], and de novo blood vessel formation by recruitment of endothelial progenitor cells (CEPs) into tumors [95,96]. The mechanisms of tumor vascularization depend on the tumor type, its stage and aggressiveness. In addition, the composition of cells within the tumor microenvironment such as endothelial cells, macrophages, and pericytes as well as systemic recruitment of bone marrow derived CEPs can also dictate the origin and mechanism of tumor angiogenesis [97]. Numerous studies have demonstrated that MSCs are key players in various mechanisms of tumor vascularization as outlined below. MSCs produce high levels of angiogenesis-stimulating growth factors and cytokines, such as VEGF, βFGF, PDGF, IL-6, IL-8, TGFβ, and angiopoietin, and thus promote tumor angiogenesis [98,99]. Specifically, in pancreatic carcinoma, secretion of high levels of VEGF by tumor-residing MSCs stimulates angiogenesis and increases microvessel density in the tumor [100]. Furthermore, high levels of TGFα enhance MSC-derived VEGF production by inducing MAPK and PI3K pathways, which in turn activate autocrine and paracrine loops and stimulate secretion of pro-angiogenic factors [101,102]. In addition, in colorectal carcinoma, MSCs secrete cytokines such as IL-6 and Angiopoietin-1 (Ang-1), which in turn stimulate cancer cells to secrete endothelin-1 (ET-1), thus activating AKT and ERK pathways in tumor endothelial cells, leading to their mobilization and tumor vessel formation [55,103]. In another study, melanoma cells increase the ability of MSCs to create vascular-like structures in vitro, therefore supporting tumor vasculature by promoting vasculogenic mimicry [104]. Finally, Kalluri and colleagues suggested that MSCs are resting fibroblasts that can be transformed into cancer-associated fibroblasts (CAFs) or cancerassociated MSCs. CAFs strongly promote tumor angiogenesis by secreting immunomodulatory and pro-angiogenic cytokines and chemokines, such as IL-4, IL-6, IL-8, TNF, TGFβ, VEGF and CXCL12 [105]. Thus, MSCs promote tumor vascularization by multiple mechanisms associated with an induction of endothelial cell proliferation and vasculogenic mimicry. In addition to MSC-intrinsic mechanisms, signals from the tumor microenvironment may also dictate the angiogenic potential of MSCs. This occurs especially in aggressive tumors that are severely hypoxic and necrotic. For example, hypoxia leads to overexpression of HIF-1α that in turn downregulates p53 and p21 and upregulates BCL-2 in MSCs, thereby promoting their survival [106]. These surviving MSCs secrete pro-angiogenic factors such as VEGF and PDGF leading to local tumor angiogenesis [107,108]. In addition, secretion of VEGF by MSCs in a hypoxic environment stimulates the recruitment of endothelial cells, supporting both local and systemic tumor angiogenesis [109]. The contribution of MSCs to tumor vasculature is also associated with their ability to stabilize pre-existing blood vessels, similar to the function of pericytes. Specifically, MSC-derived Ang-1 governs maturation and organization of premature tumor microvasculature and increases structural integrity of the existing blood vessels [110,111]. In addition, MSC-derived Ang-1 enhances the expression of cell-to-cell junction proteins such as occludin by endothelial cells, thus reducing blood vessel leakiness [112]. A study reported that MSCs have the ability to differentiate into smooth muscle cells, thus supporting tumor blood vessel maturation [113]. In fact, differentiated pericytes, cells that support blood vessel integrity, are considered to originate from MSCs [114,115]. In particular, MSCs can differentiate into functional NG2, α-SMA, and PDGFR-β expressing pericytes [116], a process dictated by glioma cells [117]. Due to the pro-angiogenic nature of MSCs in growing tumors, studies are currently focused on blocking the angiogenic activities of MSCs in order to improve anti-angiogenic therapy.

conditions; expression of CD105, CD73, and CD90 surface markers; lack of CD45, CD34, CD14 or CD11b, CD19 or CD79α, and HLA-DR markers; and ability to differentiate into osteoblasts, chondroblasts, myoblasts and adipocytes [47]. 2. Pro- and anti-tumorigenic activity of MSCs MSCs exhibit strong tropism to wounds and damaged tissue where they promote regenerative activities [48,49]. Tumors, which can be generally compared to chronic non-healing wounds, also recruit MSCs to support their growth and metastasis [50–52]. Such extensive MSC homing to tumors has been observed in various cancer types including Kaposi’s sarcoma [53], colorectal cancer [54,55], pancreatic cancer [56] glioma [57], breast and melanoma metastases [58,59], gastric [60] skin [61] and ovarian cancers [62]. The exact mechanisms of MSC homing to tumors are still unknown, however it is likely that the same chemokines and receptors that promote trafficking of other accessory cells to tumors (e.g., bone marrow derived immune cells) could be involved in MSC migration. Among these are: growth factors such as SCF, PDGF, EGF, HGF and IGF-1 [63,64]; angiogenic factors such as VEGF, βFGF and HIF1α [65,66]; chemokines such as CCL2, CCL5, CCL22 and CXCL12 [64,67]; inflammatory factors and cytokines such as TNFα, TGFβ, IL-1β, IL-8 and others [68–71]. These data suggest that the recruitment of MSCs to different tumor types may have a crucial contribution to tumor fate. The effect of MSCs on tumor progression depends on the delicate equilibrium between their pro-inflammatory and anti-inflammatory phenotypes [72].Waterman and colleagues suggested that within tumors, MSCs can undergo a functional switch from an anti-tumorigenic MSC-I state into a pro-tumorigenic MSC-II state [73,74]. In their proinflammatory state, MSCs inhibit tumor growth by promoting massive inflammatory cell infiltration into tumors, thereby inducing anti-cancer immunity [75]. In addition, MSCs attenuate cancer cell proliferation by paracrine inhibition of Wnt, AKT and PI3K pathways, essential molecular signaling pathways contributing to tumor cell division and propagation [53,76,77]. Furthermore, pro-inflammatory MSCs induce cancer cell apoptosis and inhibit tumor angiogenesis [78,79]. In contrast, anti-inflammatory MSCs are characterized by their involvement in multiple tumor-supporting activities [80]. For example, MSCs are recruited to spontaneously growing tumors, an effect that is enhanced in response to tumor perturbation [52]. They can suppress the antitumor immune response [81], induce an epithelial-to-mesenchymal transition (EMT) leading to metastasis [82,83], stimulate tumor angiogenesis [84,85], and promote tumor cell resistance to therapy [86]. In addition, MSCs have been shown to support tumor growth by altering its metabolic state. Specifically, MSC-derived prostaglandin E2 protects lymphoblastic leukemic cells from DNA-damage induced apoptosis [87]. Furthermore, in oxidative stress at the tumor microenvironment, MSCs secrete lactate which is uptaken by tumor cells, therefore leading to tumor cell migration via the production of ATP [88]. It should be noted that, while studies have demonstrated both anti- and pro- tumorigenic roles of MSCs, it is widely accepted that, in general, MSCs tend to be more pro-tumorigenic than anti-tumorigenic, where the prominent mechanism is related to their immunosuppressive and regenerative activities [83,89,90]. In the next sections, we discuss the pro-tumorigenic role of MSCs in more detail. 3. MSCs support tumor vasculature and promote angiogenesis Primary tumors and metastatic sites require fast expansion and maturation of the tumor vasculature in order to meet their high demand for oxygen and nutrients [91]. In general, tumor vascularization occurs by several complex mechanisms including: the local angiogenesis sprouting of new blood vessels from pre-existing blood vessels [92], vasculogenic mimicry (i.e., formation of tumor microvascular structures by aggressive, mutated cancer cells) [93], blood vessel co-option

4. MSCs facilitate tumor metastasis Activation of cancer cell invasion and induction of metastasis are major hallmarks of cancer [80]. Numerous studies have demonstrated the involvement of MSCs in tumor cell migration and invasion, EMT, 2

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trafficking of tumor cells expressing its major receptor, CXCR4. [147,148]. Furthermore, MSCs can support bone metastasis by forming metastatic niches at the bone and contributing to tumor cell recruitment to the bone extracellular matrix (ECM) due to their strong adhesive activities mediated by adhesive molecules and integrins [149]. Overall, MSCs are involved in a number of steps in the metastatic process and critically contribute to metastasis, both at the primary tumor and pre-metastatic sites.

and the formation of secondary metastatic lesions [50,82,118,119]. These effects are achieved in part by a vast array of growth factors, cytokines and chemokines secreted by MSCs. Among these factors are C-C and C-X-C types chemokines that promote tumor cell migration to secondary sites [120–123], extracellular matrix modulating factors such as lysyl oxidase (LOX) [118,124], and growth factors such as TGFβ, FGF, HGF and EGF that enhance tumor cell invasiveness and promote EMT [50,125,126]. In addition, MSCs residing in the tumor microenvironment are overstimulated by cancer cells and exhibit enhanced pro-metastatic activities [54,127]. For example, in breast carcinoma, tumor-residing MSCs secrete CCL5 (also known as RANTES) that in turn, stimulates the secretion of matrix metalloproteinase 9 (MMP9) by cancer cells, thus inducing tumor cell invasion and spread [127]. Another study showed that MSCs induce breast cancer cell elongation and directional migration when co-cultured in vitro. These effects are mediated by TGFβ signaling in MSCs, leading to overexpression of rho-associated kinase, focal adhesion kinase and MMPs in breast cancer cells [126]. The effect of MSCs on tumor cell migration is not limited to promoting mesenchymal-like cell morphology; MSCs can also inhibit the epithelial-like tumor cell phenotype. For example, in breast cancer, MSCs downregulate E-cadherin expression in tumor cells by activating ADAM10 [128]. Similar effects were also reported in colon cancer [129]. Thus, MSC activity disrupts cell-cell contact and increases migratory abilities of cancer cells, therefore promoting metastasis [128,130]. MSCs promote EMT by the secretion of growth factors and cytokines including HGF, EGF, PDGF and TGFβ. These factors induce transcriptional regulators, such as Snail, Slug, Twist, Zeb1 and others which are associated with EMT [131,132]. For example, in hepatocellular carcinoma, exposing MSCs to TNFα and IFNγ causes an overexpression of TGFβ which in turn promotes EMT-related functional changes in cancer cells [133]. In another study, TGFβ-stimulated MSCs in pancreatic cancer promote a metastatic phenotype by upregulating Jagged-1 – a major ligand of Notch signaling in cancer cells [134]. In turn, activation of the Notch pathway induces EMT and promotes a cancer stem cell (CSC) phenotype. These findings are supported by other studies that link EMT with CSCs [135]. An alternative mechanism of MSC-induced tumor cell dissemination has been reported in gastric cancer. Specifically, gastric mucosal cells infected with Helicobacter pylori recruit MSCs which then differentiate into gastric cells expressing epithelial markers such as KRT1-19 and TFF2. Such markers along with chronic inflammation promote a CSC phenotype of gastric cancer, thus contributing to EMT and metastatic properties [136]. The effect of MSCs on tumor cell EMT phenotype and dissemination is also achieved indirectly via the differentiation of MSCs into cancerassociated fibroblasts (CAFs), cells with a known role in tumor cell proliferation, invasiveness and EMT [137–139]. In this case, MSCs extensively produce fibroblast-derived factors, such as α-SMA, tenanscinC, fibroblast surface protein (FSP), IL-6, CCL5, CXCL12 among others [140]. Notably, MSC differentiation into CAFs is further augmented by MSC-tumor cell interactions [140–142]. For example, MSCs isolated from metastatic sites in lungs or liver express CAF markers such as αSMA, CXCL12, tenanscin-C, MMP-2 and MMP-9 [143]. Overall, a growing body of literature suggests that fibroblasts and MSCs are similar cell entities in the context of supporting EMT and metastasis [105,144,145]. Lastly, MSCs also contribute to the final step of the metastatic process – establishment of secondary metastatic sites. For instance, MSCs induce migration of tumor cells to metastatic lesions by secreting chemoattractants including CCL5, CXCL1, CXCL5, CXCL7 and CXCL8 [126,127]. Moreover, in response to breast cancer cell-derived osteopontin (OPN) – a multipotent chemoattractant that mobilizes BMDCs to the tumor, facilitates invasion and promotes metastasis - MSCs secrete high levels of CCL5 resulting in increased metastasis in lungs [143,146]. In addition, it has been reported that MSCs secrete high levels of CXCL12 (SDF-1), a chemoattractant that regulates the

5. Immunomodulatory activity of MSCs MSCs are key regulators of innate and adaptive immune responses. They possess strong immunosuppressive properties, supporting the evasion of tumor cells from anti-cancer immunity. Mechanistically, within the immune tumor microenvironment, MSCs induce extensive immunosuppression mainly by the secretion of soluble factors and mediators such as TGFβ, IFNγ, TNFα, prostaglandin E2 (PGE2), HGF, NO, HLA-G, indoleamine 2,3-dioxygenase (IDO), IL-1α, IL-1β, IL-4 and IL-6, as well as by their interactions with various immune cell types, including T cells, B cells, dendritic cells, macrophages and NK cells [150,151]. For example, T cell inhibition by MSCs is partially mediated by PGE2, which in turn induces macrophages to produce the anti-inflammatory factor IL-10, thus inhibiting T cell activation and proliferation [152]. Moreover, MSCs induce the skewing of pro-inflammatory Th1 CD4 cells into an anti-inflammatory Th2 phenotype [153,154]. This reduces IFNγ production by Th1 and enhances IL-4 secretion by Th2, thus minimizing anti-cancer immune cell activation. It was recently reported that in breast cancer, MSCs secrete high levels of immunosuppressive TGFβ, thereby inducing T cell suppression [155,156]. MSC-induced suppression of T cell proliferation and activity is not only limited to the secretion of inhibitory cytokines but also to the production of IDO, which inhibits T cells through tryptophan depletion [157]. Specifically, MSCs promote T cell inhibition by secretion of IDO which in turn induces T helper cell maturation into FOXP3-positive regulatory T cells. These cells inhibit effector T cell responses and thus reduce anti-tumor immunity [158,159]. Finally, MSCs induce the recruitment of inhibitory immune cells referred to as myeloid derived suppressor cells (MDSCs) via CCL2 signaling, thus weakening anticancer T cell activity [160]. Besides the immunosuppressive effects on T cells, MSCs also inhibit other adaptive immune cells. Ucelli et al. reported that MSCs inhibit B cell proliferation by cell cycle arrest [37]. Furthermore, MSCs reduce antibody production by B cells and inhibit their differentiation into plasma cells [161]. It was also reported that IFNγ stimulated-MSCs overexpress galectin-9, which was shown to attenuate B cell proliferation and antibody production [162]. Taken together, MSCs exhibit strong inhibitory behavior against adaptive immune cells, which is well exploited by cancer cells. In addition to the suppression of adaptive immunity mediated by T and B cells, MSCs also suppress innate immune cells, attenuating primary anti-cancer responses. Specifically, MSCs inhibit NK cells mainly by PGE2 and IL-6 secretion. Moreover, MSCs reduce the ability of NK cells to produce IFNγ, thus impairing their anti-cancer activity [163]. In addition, MSCs were shown to attenuate maturation of dendritic and other antigen presenting cells (APCs)_ via PGE2 signaling [164]. It has been demonstrated that MSCs reduce CD80/CD86 expression on APCs thereby downregulating T cell activation [165]. Within the tumor microenvironment, MSCs directly inhibit macrophage activity. Specifically, it was shown that conditioned medium of MSCs decreases the phagocytic abilities of macrophages, thereby promoting a pro-tumorigenic macrophage phenotype [166]. Moreover, MSC-derived IDO and PGE2 induce skewing of macrophages towards the pro-tumorigenic M2 phenotype, resulting in higher levels of immune-inhibitory IL-10 [167]. Similarly, MSCs induce the pro-tumorigenic activity of neutrophils. Coculturing CD11b/Ly6G-positive neutrophils with MSCs results in massive T cell inhibition in vitro, and enhanced breast carcinoma tumor growth in vivo [168]. Others reported that in gastric cancer, MSC3

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inhibition of apoptosis following cytotoxic therapy [184]. IL-6 induced drug resistance was also induced by thymus residing endothelial cells in mice treated with cisplatin therapy, suggesting that IL-6 is a major contributing factor to therapy resistance [185]. Recently, Roodhart et al. demonstrated that MSCs promote systemic drug resistance and tumor re-growth in response to chemotherapy. Specifically, they found that MSCs exposed to cisplatin secrete polyunsaturated fatty acids (12oxo-5,8,10-heptadecatrienoic acid [KHT], and hexadeca-4,7,10,13-tetraenoic acid [16:4(n-3)]) which protect tumor cells from the cytotoxic effects of the drug. While the mechanism by which these fatty acids contribute to drug resistance has not been demonstrated, the authors suggest an indirect effect of fatty acids on tumor cell resistant activities [186]. Their findings suggest that even non tumor-residing MSCs can induce chemoresistance, and that MSCs act as guarding cells of the organism protecting cells from cytotoxic agents. In the previous section we discussed how MSCs contribute to metastasis by facilitating EMT. It is also known that tumor cells that have undergone EMT are considered CSCs or comprise of properties associated with CSCs [135,187]. These CSCs are a unique rare population of cells within tumors that resist many cytotoxic agents in part due to their low proliferative rate, high DNA repair mechanisms and expression of membranal transporters which control cytotoxic drug influx [188,189]. Here we discuss the ability of MSCs to either transform into CSCs or support their niche, thus contributing to drug resistance. Specific methylation of tumor suppressor genes, RasF1A and HIC1, in MSCs represents one mechanism by which MSCs transform into CSCs. When MSCs differentiate into CSCs, they can promote chemoresistance to cisplatin and enables tumor relapse after treatment cessation [190]. In parallel, MSCs support a CSC niche thus contributing to their ability to resist the cytotoxic effects of chemotherapy [191,192]. For example, MSC in breast cancer regulate CSCs through cytokines such as IL-6 and CXCL-7, thereby accelerating tumor growth [193]. In colorectal cancer, MSCs secrete PGE-2 in response to IL-1 released by carcinoma cells, which act in an autocrine fashion to induce the expression of IL-6, IL-8 and CXCL1, which together induce the formation of CSCs [194]. Once differentiated into CAFs, MSCs can maintain CSCs through secreting the Notch ligand Jagged-1 [134]. Furthermore, pre-exposure of MSCs to cisplatin alters phosphorylation of several tyrosine kinases, including WNK-1, c-Jun, STAT3 and p53, promoting MSC survival and production of IL-6 and IL-8 by MSCs. In turn, these effects promote chemoresistance of tumor cells [195]. However, the exact mechanisms by which MSCs contribute to drug resistance and the direct mediators involved have not been elucidated. It has been shown that exposure of MSCs to chemotherapy causes a physiological response within these cells that ultimately supports drug resistance by enriching the CSC population. Specifically, we have previously shown that MSCs are recruited in large numbers to pancreatic adenocarcinoma tumors in response to gemcitabine therapy. At the treated tumor site, they are located near CSCs where they support the CSC niche. Gemcitabine-exposed MSCs significantly increase the production of CXCL10, which in turn promotes CSCs proliferation as they overexpress the CXCL10 receptor, CXCR3. These effects ultimately result in enhanced tumor growth and increased chemoresistance [196].

derived IL-6 promotes neutrophil activation via STAT3-ERK1/2 signaling and induces their polarization towards a tumor-supportive phenotype [169]. Collectively, these data demonstrate the broad immunosuppressive effects of MSCs on effector immune cells, ultimately supporting tumor progression. In the era of immunotherapy, immune checkpoint inhibitors (ICIs) have shown remarkable success for several malignancies including melanoma, lung, bladder, head and neck and colorectal cancers, multiple myeloma, Hodgkin lymphoma and chronic lymphoblastic leukemia (CLL). This treatment approach harnesses the body’s own immune system to destroy cancer cells leading to a dramatic tumor shrinkage and durable response [170–175]. Yet, only a small portion of patients benefit from such treatment modalities, and therefore, efforts are focused on developing strategies to improve the outcome of immunotherapy. The immunosuppressive nature of MSCs suggests that they work against the therapeutic benefits of immunotherapy. Specifically, MSCs support cancer cell evasion of the immune system, thereby promoting tumor aggressiveness. For example, in the pro-inflammatory intra-tumor environment, high levels of IFN-γ cause an increase in PDL1 expression on MSCs, which in turn inhibits T cell activation and attenuates anti-cancer T cell immunity [176]. Moreover, MSCs secrete high levels of soluble PD-1 ligands, which effectively suppress IL-2 T cell activating effects. In parallel, soluble PD-L1 and PD-L2 secreted by MSCs inhibit AKT activation pathway and therefore inhibit T cell proliferation and activation [177]. In addition to PD-1/PD-L1-mediated T cell inhibition, it was recently reported that the immunosuppressive activity of MSCs is partially mediated via CTLA-4, several forms of which are expressed by MSCs. For example, in normoxic conditions, MSCs express membrane-bound dimers of CTLA-4 which bind B7 receptors on APCs, thus preventing CD28-mediated T cell stimulation. However, in hypoxic conditions, MSC inhibitory activity does not require direct cell-cell interactions with APCs, as they produce soluble CTLA-4 monomers. This leads to inefficient T cell activation and therefore a reduced anti-cancer immune response [178]. Taken together, it can be postulated that inhibiting the immunosuppressive function of MSCs can improve immunotherapy outcome. 6. MSCs promote drug resistance Tumor resistance to chemotherapy remains one of the major obstacles of modern clinical oncology. Complex mechanisms underlying chemoresistance involve not only intrinsic resistance mechanisms of cancer cells mediated by aberrant mutations and multi-drug resistance proteins, but also various factors within the tumor microenvironment [179]. The latter effects are also associated with MSC function within tumors which could explain therapy resistance. Multiple studies have demonstrated that pro-tumorigenic activities of MSCs are enhanced in response to tumor perturbation, therefore explaining tumor regrowth and resistance to therapy [52]. For example, in hematological malignancies such as chronic myeloid leukemia (CML), MSCs secrete CXCL12 which attenuates caspase 3 activity in a CXCR4 dependent manner and reduces imatinib-induced cell death [180]. Other protective activities were demonstrated in chronic lymphoid leukemia (CLL), in which MSCs protect CLL cells from the cytotoxic effects of Forodesine by increasing RNA and protein synthesis in cancer cells [181]. In addition to hematological malignancies, MSCs were also shown to promote resistance to therapy in solid tumors. For instance, in head and neck carcinoma, it was shown that bone marrow derived MSCs induce chemoresistance to paclitaxel by paracrine secretion of IL-6, IL-7, IL-8, EGF, and IGF [182]. In ovarian cancer, it was reported that tumor-residing MSCs protect cancer cells from hyperthermia-induced cell death promoted by intraperitoneal chemotherapy via the activation of CXCL12-CXCR4 axis. The authors demonstrated that by blocking the CXCR4 axis, they restored the thermo-sensitivity of ovarian cancer cells [183]. Another mechanism of resistance involves the expression of IL-6 by MSCs. IL-6 induces the expression of Bcl-2 and Bcl-XL in tumor cells leading to

7. Therapeutic potential of MSCs in cancer The ability of MSCs to induce an immunosuppressive environment along with their regenerative potential mark them as a promising therapeutic tool for various clinical indications. In recent years MSCs were approved for the treatment of degenerative arthritis and graft versus host disease (GvHD) [197]. In cancer, MSC-based cell therapies are currently being assessed in numerous clinical studies, as presented in Table 1. In addition, owing to their strong tropism and recruitment to tumors, MSCs are being developed as selective vehicles for drug delivery especially in aggressive tumors. For example, MSCs were used to deliver oncolytic viral loads into tumors, therefore selectively inducing 4

Mesenchymal Stem Cells In Cisplatin-Induced Acute Renal Failure In Patients With Solid Organ Cancers MV-NIS Infected Mesenchymal Stem Cells in Treating Patients With Recurrent Ovarian Cancer

Genetically Modified Mesenchymal Stem Cell Therapeutic Against Head and Neck Cancer Using Mesenchymal Stem Cells to Fill Bone Void Defects in Patients With Benign Bone Lesions Donor Mesenchymal Stem Cell Infusion in Treating Patients With Acute or Chronic Graft-Versus-Host Disease After Undergoing a Donor Stem Cell Transplant

5

7

5

23

22

21

20

18 19

17

Unrelated Umbilical Cord Blood Transplantation With Coinfusion of Mesenchymal Stem Cells Intracavernous Bone Marrow Stem-cell Injection for Post Prostatectomy Erectile Dysfunction Treatment Of Bone Cyst With Bone Marrow Mesenchymal Cell Transplantation The Role of RING Ubiquitin Ligases in Biologic and Oncologic Processes in Tissues of Mesenchymal Origin

Mobilization of Mesenchymal Stem Cells During Liver Transplantation Mesenchymal Stem Cell Infusion as Prevention for Graft Rejection and Graft-versus-host Disease Laparoscopic Endoscopic Cooperative Surgery in the Treatment of Gastric Stromal Tumors Mesenchymal Stem cells for Radiation Induced Xerostomia Phase I Platinum Based Chemothera-py Plus Indomethacin

15 16

14

13

12

Stem Cell Injection in Cancer Survivors Safety and Efficacy of Repeated Infusion of CELYVIR in Children and Adults With Metastatic and Refractory Tumors. Mesenchymal Stem Cell Infusion in Haploidentical Hematopoietic Stem Cell Transplantation in Patients with Hematological Malignancies Mesenchymal Stem Cells (MSCs) for Treatment of Acute Respiratory Distress Syndrome (ARD) in Patients With Malignancies Cord Blood (CB) Ex-vivo Mesenchymal Stem Cell (MSC) Expansion + Fucosylation

10 11

9

8

6

4

3

Mesenchymal Stem Cells (MSC) for Ovarian Cancer Allogeneic Human Bone Marrow Derived Mesenchymal Stem Cells in Localized Prostate Cancer Tissue and Hematopoietic/Mesen-chymal Stem Cell for Humanized Xenograft Studies in Melanoma and Squamous Head and Neck Cancer Stem Cell Therapy Combined With NeuroRegen Scaffold™ in Patients With Erectile Dysfunction After Rectal Cancer Surgery

1 2

Trial’s title

Phase 1

• Other: Laboratory Biomarker Analysis • Procedure: Mesenchymal Stem Cell Transplantation • Biological: Oncolytic Measles Virus Encoding Thyroidal Sodium Iodide Symporter

• Biological: GX-051

• Malignant Ovarian Brenner Tumor • Ovarian Clear Cell Adenocarcinoma • Ovarian Endometrioid Adenocarcinoma • Ovarian Mucinous Adenocarcinoma • Ovarian Seromucinous Carcinoma • Ovarian Serous Adenocarcinoma • Ovarian Transitional Cell Carcinoma • Recurrent Ovarian Carcinoma • Recurrent Primary Peritoneal Carcinoma • Undifferentiated Ovarian Carcinoma • Head and Neck Cancer

• Biological: injection of bone marrow mononucleated cells • Biological: cell injection

• Prostate Cancer • Erectile Dysfunction • Bone Cyst • Group 1: Trauma Operation for Otherwise Healthy Patients • Group 2: Primary Tumors of Mesenchymal Origin

• Other: cord blood transplantation

• Xerostomia • Colorectal Neoplasms • Esophageal Neoplasms • Ovarian Neoplasms • Allogeneic Stem Cell Transplantation

• Gastrointestinal Stromal Tumors

• Phase 1 • Phase 2 • Phase 1 • Phase 2 Phase 1

Phase 2 Phase 1

n/a

(continued on next page)

• Procedure: laparoscopic and endoscopic cooperative surgery • Procedure: laparoscopic surgery • Drug: Mesenchymal stem cell • Drug: Isotonic NaCl • Drug: Indomethacin

• Drug: Busulfan • Drug: Rituximab • Drug: ATG • Drug: Fludarabine • Drug: Clofarabine • Radiation: Total Body Irradiation • Procedure: Cord Blood Transplant • Drug: Mycofenolate mofetil • Drug: Tacrolimus • Drug: Filgrastim-sndz • and 3 more • Procedure: blood samples • Procedure: Mesenchymal stem cell infusion

n/a Phase 2

Phase 2

• Biological: Mesenchymal Stem Cells (MSCs)

• Blood And Marrow Transplantation • Adult Respiratory Distress Syndrome • Hematopoietic/Lymphoid Cancer

• Liver Failure • Liver Neoplasm • Hematological Malignancies

Phase 2

• Biological: mesenchymal stem cells • Drug: cyclophosphamide administration

Phase 1 • Phase 1 • Phase 2 Phase 3

• Phase 2 • Phase 3 Phase 1

Phase 1

• Phase 1 • Phase 2

n/a

• Hematopoietic Stem Cell Transplantation

• Cardiomyopathy Due to Anthracyclines • Children • Solid Tumors • Metastases

• Cancer

• Bone Neoplasms

• Biological: Trinity multipotent stem cells • Biological: Demineralized bone matrix(DBM) • Biological: graft versus host disease prophylaxis/therapy • Genetic: fluorescence in situ hybridization • Other: immunoenzyme technique • Other: immunohistochemistry staining method • Other: laboratory biomarker analysis • Procedure: in vitro-treated bone marrow transplantation • Procedure: management of therapy complications • Biological: Allo-MSCs • Biological: Placebo • Biological: CELYVIR

• Phase 1 • Phase 2

• Procedure: Laparoscopic surgery • Device: NeuroRegen scaffold transplantation • Biological: NeuroRegen scaffold/BMMCs transplantation • Biological: NeuroRegen scaffold/HUC- MSCs transplantation • Biological: Mesenchymal stromal cell infusion

• Rectal Cancer • Erectile Dysfunction

• Solid Tumors • Acute Kidney Injury

• Drug: Filgrastim

• Malignant Melanoma • Head and Neck Cancer

Phase 1 Phase 1

• Genetic: MSC-INF# • Behavioral: Questionnaires • Biological: Allogeneic Human Mesenchymal Stem Cells

• Ovarian Cancer • Prostate Cancer

Trial’s phase

Intervention

Cancer type

Table 1 Clinical studies exploring the contribution of MSCs to the therapy of several malignancies.

M. Timaner, et al.

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OTI-010 for Graft-Versus-Host Disease Prophylaxis in Treating Patients Who Are Undergoing Donor Peripheral Stem Cell Transplantation for Hematologic Malignancies

CTC, Free DNA, Stem Cells and EMT-related Antigens as Biomarkers of Activity of Cabazitaxel in CRPC. Mesenchymal Stem Cells After Renal or Liver Transplantation

MSC and HSC Coinfusion in Mismatched Minitransplants

Research for Human Umbilical Cord Mesenchymal Stem Cells in the Treatment of Myelodysplastic Syndrome (MDS) Targeted Stem Cells Expressing TRAIL as a Therapy for Lung Cancer

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29

30

Clinical Ex Vivo Expansion of Human Umbilical Cord Blood Stem and Progenitor Cells Constitution of a Biological Cohort Following Bone Marrow Sampling From MDS or AML Patients and Age-matched Healthy Donors Healing of the Esophageal Mucosa After RFA of Barrett's Esophagus

• Biological: SCM-010 • Drug: Reparixin • Drug: AB-16B5 • Biological: Tri-virus specific cytotoxic t-cells • Drug: iodine I 131 metaiodobenzylguanidine • Drug: Fludarabine • Drug: Thiotepa • Procedure: T-cell depletion • Procedure: Haploidentical stem cell transplantation • Procedure: Donor Lymphocyte Infusion • Drug: Rituximab • Procedure: Co-transplantation of mesenchymal stem cells • Other: Ex vivo expanded cord blood cells

• Secondary Progressive Multiple Sclerosis (SPMS) • Breast Cancer • Solid Tumor • Metastatic Cancer • Neuroblastoma • Neuroblastoma

• Procedure: Baseline surveillance endoscopy • Procedure: Radiofrequency ablation • Procedure: Follow up endoscopy 1 • Procedure: Follow up endoscopy 2 • Procedure: Follow up endoscopy 3

• Other: Bone marrow analyses

• Biological: MSC-PLGA

• Aneurysmal Bone Cyst

• Acute Leukemia • Chronic Leukemia • Myelodysplastic Syndrome • Lymphoma • Myeloma • Myelodysplastic Syndromes • Acute Myeloid Leukemia • Cardiovascular Surgery • Barrett Esophagus

• Other: Human umbilical cord-derived MSCs • Other: cyclosporine A (CsA)

• Biological: Allogeneic umbilical cord mesenchymal stem cells • Drug: Decitabine • Genetic: MSCTRAIL • Drug: Placebo

• Biological: Mesenchymal stem cells • Other: Isotonic solution

• Myelodysplastic Syndromes

• Adenocarcinoma of Lung

• Leukemia, Myeloid, Acute • Leukemia, Lymphoblastic, Acute • Leukemia, Myelocytic, Chronic • Myeloproliferative Disorders • Myelodysplastic Syndromes • Multiple Myeloma • Leukemia, Lymphocytic, Chronic • Hodgkin's Disease • Lymphoma, NonHodgkin • Myelodysplastic Syndromes

• Prostate Cancer • Metastatic Cancer • Castration-resistant Prostate Cancer • Circulating Tumor Cells • Liver Failure • Kidney Failure • Biological: Mesenchymal Stem Cells

Phase 1

• Procedure: Cord Blood Infusion • Drug: Busulfan • Drug: Fludarabine • Drug: Rituximab • Other: ATG • Drug: Cyclophosphamide • Drug: Clofarabine • Radiation: Total Body Irradiation (TBI) • Drug: Melphalan • Drug: Tacrolimus • Drug: Mycophenolate Mofetil • Drug: G-CSF • Biological: autologous expanded mesenchymal stem cells OTI-010 • Drug: busulfan • Drug: cyclophosphamide • Drug: cyclosporine • Drug: methotrexate • Procedure: peripheral blood stem cell transplantation • Radiation: radiation therapy • Procedure: blood and FFPE sample collection

n/a

• Phase 1 • Phase 2 n/a

Early Phase 1

Phase 1

Phase 1

• Phase 1 • Phase 2 • Phase 1 • Phase 2 Phase 2

• Phase 1 • Phase 2 • Phase 1 • Phase 2 Phase 2

• Phase 1 • Phase 2 Phase 2

n/a

Phase 2

Early Phase 1

• Drug: cyclophosphamide • Drug: fludarabine phosphate • Radiation: totalbody irradiation • Drug: cyclosporine • Drug: mycophenolate mofetil • Procedure: umbilical cord blood transplantation • Procedure: mesenchymal stem cell transplantation

• Acute Lymphoblastic Leukemia • Acute Myelogenous Leukemia • Myelodysplastic Syndromes • Myelofibrosis • Relapsed Non-Hodgkin Lymphoma • Refractory Non-Hodgkin Lymphoma • Hodgkin Lymphoma • Refractory Hodgkin Lymphoma • Relapsed Chronic Lymphocytic Leukemia • Refractory Chronic Lymphocytic Leukemia • Lymphoid Malignancies • Chronic Myelogenous Leukemia • Myelodysplastic Syndrome • Leukemia

• Graft Versus Host Disease • Leukemia • Myelodysplastic Syndromes

Trial’s phase

Intervention

Cancer type

The data in this table was collected from clinical studies registered at www.clinicaltrials.gov by May 2019. n/a for not available.

41

40

39

38

37

36

35

34

33

32

31

Safety and Efficacy Study of Umbilical Cord/Placenta-Derived Mesenchymal Stem Cells to Treat Myelodysplastic Syndromes Use of Stem Cells Cultured on a Scaffold for the Treatment of Aneurysmal Bone Cysts (ABC) Study to Assess the Safety and Efficacy of an IT Administration of SCM010 in SPMS Pilot Study to Evaluate the Safety and Biological Effects of Orally Administered Reparixin in Early Breast Cancer Patients Phase I Dose Escalation Study of AB-16B5 in Subjects With an Advanced Solid Malignancy Study of Donor Derived, Multi-virus-specific, Cytotoxic TLymphocytes for Relapsed/Refractory Neuroblastoma Haploidentical Stem Cell Transplantation in Neuroblastoma

Cord Blood Expansion on Mesenchymal Stem Cells

25

28

Intra-Osseous Co-Transplant of UCB and hMSC

24

Trial’s title

Table 1 (continued)

M. Timaner, et al.

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Fig. 1. Mesenchymal stem cells induce multiple tumor-supportive processes. Angiogenesis – Mesenchymal stem cells (MSCs) secrete pro-angiogenic factors, induce the recruitment of circulating endothelial progenitor cells (CEPs), and differentiate into pericytes and smooth muscle cells, thereby promoting angiogenesis, vasculogenesis and the stabilization of blood vessels, respectively. Metastasis – MSCs secrete factors that induce epithelial-to-mesenchymal transition (EMT) of tumor cells. MSCs also have the ability to differentiate into cancer stems cells (CSCs) or cancer-associated fibroblasts (CAFs) which, in turn, promote the invasive and metastatic properties of tumor cells. Immunosuppression – MSCs dampen anti-tumor immunity by inhibiting Th1 cells, B cells, and NK cells, activating T regulatory cells (Treg) and Th2 cells, and skewing macrophages towards the M2 phenotype. Drug resistance – MSCs protect cancer cells from the cytotoxic effects of anti-cancer drugs. MSCs also enrich and protect the resistant CSC population following therapy or directly transdifferentiate into CSCs. Table 2 The effect of MSC-derived soluble factors on tumor progression. Pro-tumorigenic activity

Factors secreted by MSCs

Induction of tumor angiogenesis

VEGFA, VEGFC, βFGF, PDGF, Angiopoietin I, PDGF, IL-6, IL-8, CXCL12

Stimulation of metastasis and EMT

CCL5, CCL9, IL-6, EGF, HGF, FGF-10, MMPs, LOX, CXCL1, CXCL2, CXCL5, CXCL12, TGFβ

Immunosuppression

CCL2, IDO, PGE2, TGFβ, INFγ, HLA-G, TNFα, IL4, IL-6, galectin-9, soluble PD-L1 and PD-L2, soluble CTLA-4

Interactions with other cells of CEPs; • Recruitment into smooth muscle cells • Transformation and pericytes; to CAFs; • Differentiation to CAFs; • Differentiation to CSCs; • Transformation of tumor cells to • Chemoattraction metastatic lesions B, and NK cell inhibition; • T,Recruitment MDSCs • Skewing of Tofcells, and • neutrophils into themacrophages tumor-supportive

References [227], [101], [103], [108], [109], [112], [113] [115],

[118], [121], [122], [123], [124], [125], [126], [228], [127], [133], [136], [140], [141], [143] [148], [37], [152], [153], [156], [157], [158], [159], [160], [161], [162], [163], [164], [166], [169], [177] [178],

state;

Promotion of drug resistance

CXCL7, CXLC10, CXCL12, polyunsaturated fatty acids, IL-6, IL-7, IL-8, EGF, IGF

of dendritic cells and APCs; • Suppression of CSC niche; • Enrichment • Transformation to CSCs;

[196], [180], [182], [183], [184], [185], [186], [190], [191] [193],

MSCs contribute to pro-tumorigenic activities and support several hallmarks of cancer. The factors secreted by MSCs for these activities are mentioned and the type of cells MSCs interact with in order to promote tumor growth and metastasis.

cancer delivery agents, characterized by improved tumor-specificity and reduced systemic toxicity. An additional therapeutic strategy involves genetic modification of MSCs such that they overexpress selected immunomodulatory cytokines that promote cancer cell killing effects. For instance, IL-12-expressing MSCs enhance anti-tumor T cell responses and decrease tumor growth when compared to treatment with IL-12-expressing adenovirus [204]. Other studies have reported that MSCs genetically modified to produce IFNβ induce significant anti-proliferative effects in melanoma cells [205]. A similar anti-tumor activity of IFNβ-expressing MSCs was also reported in a metastatic prostate cancer preclinical model [206]. In the same line, IL-2-expressing MSCs were shown to extensively delay tumor

cancer cell killing preclinically and most recently also clinically [198,199]. Alternatively, MSCs have been genetically manipulated to express specific enzymes, such as cytosine deaminase or herpes simplex virus-thymidine kinase (HSV-TK). These enzymes convert inactive systemically administrated prodrugs like fluorouracil (5-FU) and ganciclovir into active cytotoxic agents, thereby facilitating tumor-localized chemotherapy activity hence reducing potential toxicity [200,201]. In prostate cancer, MSCs have been used to increase drug specificity by delivering inactive prodrugs that are activated in the tumor by tumor-specific proteases such as prostate-specific antigen (PSA) or prostate-specific membrane antigen (PSMA) [202,203]. Together, these treatment approaches position MSCs as effective anti7

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characterization of MSCs and redefine their subtypes. Second, MSC harvesting methods should be better standardized in order to reach reproducibility for regulatory purposes. This will allow physicians and research groups to focus on a selected pure population of MSCs with a specifically desired cellular activity. In summary, MSCs possess a wide range of tumor supporting activities as illustrated in Fig. 1. This includes a pro-angiogenic function, an ability to promote metastasis by inducing EMT of cancer cells, promotion of drug resistance, enrichment of CSC niches, and profound immunoinhibitory effects. Such activities are manifested by factors secreted by MSCs that support several hallmarks of cancer as shown in Table 2. A better understanding of the specific molecular mechanisms underlying these pro-tumorigenic activities is crucial to improve existing anti-cancer treatments. By attenuating MSC recruitment into tumors and inhibiting their tumor-supportive activities, one can improve the therapeutic outcome of cancer patients by combining other anticancer drugs such as immunotherapy. Moreover, the potent ability of MSCs to home to tumors positions them as excellent candidates to be used as drug delivery vehicles of therapeutic agents into tumors. In parallel, genetically modified MSCs have great potential for the specific targeting of cancer cells with minimal systemic toxicity and adverse effects.

growth, in part by enhancing CD8 cytotoxic T cell anti-cancer immunity [207]. Genetic modification of MSCs can also be used to induce direct targeting of cancer cells. For example, MSCs overexpressing TNF-related apoptosis-inducing ligand (TRAIL) can effectively eliminate cancer cells in several cancer models including glioma, pancreatic, lung, and colorectal cancers [208–212]. Moreover, it has been demonstrated that TRAIL-expressing MSCs specifically target CSCs in lung carcinoma, thus decreasing tumor aggressiveness and reducing chemoresistance and relapse [213]. Another therapeutic application of MSCs is in the adjuvant settings for treatment of residual disease following extensive chemotherapy or radiotherapy together with surgery. Specifically, TRAIL-expressing MSCs and/or oncolytic viruses were effective in residual tumor cell killing of glioblastoma tumor models in mice [214,215]. Overall, genetically-modified MSCs represent a promising therapeutic platform. MSC-based cell therapy has several potential drawbacks that may restrict the expected clinical benefit. These include non-specific dissemination throughout the organism and non-effective local concentration of therapeutic agents within tumors [216]. Moreover, their physiological differentiation into mesenchymal lineages may decrease therapeutic potential, increase immunogenicity and even facilitate tumorigenesis [217]. To overcome these challenges, MSC-derived extracellular vesicles (EV) have been generated as a drug delivery platform for the direct targeting of tumor cells. These MSC-derived EVs maintain tumor homing ability [218] and possess immune-suppressive characteristics similar to the original (parental) MSCs [219]. In this regard, it was reported that exosomes from BM-derived MSCs can transfer miRNA, proteins, cytokines, and adhesion molecules, thereby affecting tumor progression. For example, injecting exosomes derived from miR146b expressing MSCs reduced glioma tumor growth [220]. Furthermore, MSC-derived exosomes expressing miR-124a decreased survival of glioma stem cells and, when loaded with miR-143, reduced migratory properties of osteosarcoma cells [221, 222]. Other studies reported that MSC-derived EVs loaded with siRNA can silence genes driving tumorigenesis. For example, MSC-derived exosomes loaded with siRNA for polo—like kinase I decreased bladder cancer cell proliferation [223]. By the same token, MSC-derived EVs can be loaded with cytotoxic chemotherapy agents and thus target cancer cells. Specifically, MSC-derived EVs loaded with paclitaxel, doxorubicin or gemcitabine reduce cell viability and inhibit oral squamous cancer cell growth [224]. MSC-derived Nanoghosts (NGs) – nanovesicles produced from the outer membrane of MSCs – represent another type of MSCderived EVs that exploit the unique properties of MSCs [225]. NGs preserve the majority of MSC adhesion molecules and receptors, and therefore, their ability to home to tumors is maintained [196, 226]. It has been shown that NGs loaded with RNA inhibit lung and prostate tumor growth [226]. In addition, MSC-derived NGs loaded with a small molecule antagonist of CXCR3 sensitize CSCs of pancreatic tumors to therapy, thereby improving chemotherapy efficacy and delaying tumor re-growth [196]. Overall, the inherent immunosuppressive and regenerative properties of MSCs highlight their potential as therapeutic agents for various cancer types. The combination of MSC therapy with existing treatment modalities is likely to improve clinical outcome.

Declaration of Competing Interest Michael Timaner and Yuval Shaked declare that they hold a patent on the use of mesenchymal stem cells for therapeutic purposes. Acknowledgments This review is supported by a grant from the European Research Council (no. 711222) given to YS. This work was supported in part by Ministry of Science and Technology, Taiwan (MOST 105-2314-B-400018 to K.K.T.), Taipei Medical University (DP2-107-21121-C-04 to K.K.T.), Wanfang Hospital, Chi-Mei Medical Center, and Hualien TzuChi Hospital Joint Cancer Center Grant, Ministry of Health and Welfare, Taiwan (MOHW108-TDU-B-212-124020 to K.K.T.) References [1] H.K. Salem, C. Thiemermann, Mesenchymal stromal cells: current understanding and clinical status, Stem Cells 28 (3) (2010) 585–596. [2] X. Wei, X. Yang, Z.P. Han, F.F. Qu, L. Shao, Y.F. Shi, Mesenchymal stem cells: a new trend for cell therapy, Acta Pharmacol. Sin. 34 (6) (2013) 747–754. [3] A.J. Friedenstein, S. Piatetzky II, K.V. Petrakova, Osteogenesis in transplants of bone marrow cells, J. Embryol. Exp. Morphol. 16 (3) (1966) 381–390. [4] A.J. Friedenstein, R.K. Chailakhjan, K.S. Lalykina, The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells, Cell Tissue Kinet. 3 (4) (1970) 393–403. [5] A.I. Caplan, Mesenchymal stem cells, J. Orthop. Res. 9 (5) (1991) 641–650. [6] J. Goshima, V.M. Goldberg, A.I. Caplan, The osteogenic potential of culture-expanded rat marrow mesenchymal cells assayed in vivo in calcium phosphate ceramic blocks, Clin. Orthop. Relat. Res. (262) (1991) 298–311. [7] D.J. Prockop, Marrow stromal cells as stem cells for nonhematopoietic tissues, Science 276 (5309) (1997) 71–74. [8] M.F. Pittenger, A.M. Mackay, S.C. Beck, R.K. Jaiswal, R. Douglas, J.D. Mosca, M.A. Moorman, D.W. Simonetti, S. Craig, D.R. Marshak, Multilineage potential of adult human mesenchymal stem cells, Science 284 (5411) (1999) 143–147. [9] J.L. Spees, S.D. Olson, J. Ylostalo, P.J. Lynch, J. Smith, A. Perry, A. Peister, M.Y. Wang, D.J. Prockop, Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma, Proc Natl Acad Sci U S A 100 (5) (2003) 2397–2402. [10] D.G. Phinney, I. Isakova, Plasticity and therapeutic potential of mesenchymal stem cells in the nervous system, Curr. Pharm. Des. 11 (10) (2005) 1255–1265. [11] P. Tropel, N. Platet, J.C. Platel, D. Noel, M. Albrieux, A.L. Benabid, F. Berger, Functional neuronal differentiation of bone marrow-derived mesenchymal stem cells, Stem Cells 24 (12) (2006) 2868–2876. [12] I. Kan, E. Melamed, D. Offen, Integral therapeutic potential of bone marrow mesenchymal stem cells, Curr. Drug Targets 6 (1) (2005) 31–41. [13] S.A. Wexler, C. Donaldson, P. Denning-Kendall, C. Rice, B. Bradley, J.M. Hows, Adult bone marrow is a rich source of human mesenchymal’ stem’ cells but umbilical cord and mobilized adult blood are not, Br. J. Haematol. 121 (2) (2003) 368–374.

8. Conclusions and perspective MSCs remain one of the most promising therapeutic agents in tissue regeneration, wound healing and cancer. However, after decades of research, limitations still exist. First, MSCs are not a pure cell population, but rather a heterogeneous mix of stromal cells that are probably composed of several cell subtypes with different morphological and functional activities. These cells may possess opposing immunomodulatory properties and variable proliferation and differentiation potentials. These crucial heterogeneity within the MSC population may certainly affect therapeutic activity and thus negate the overall positive outcome. Therefore, it is important to revisit the 8

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