Mesenchymal stem cells in progression and treatment of cancers

Abstract

Mesenchymal stem or stromal cells (MSCs) from bone marrow or local tissues are recruited to stroma of almost all types of cancers during initiation and/or progression of cancer. The recruited MSCs and their derivative cancer-associated fibroblasts interact with cancer cells to promote stemness, invasion and metastasis of cancer cells. Targeting these cancer-recruited MSCs and/or the interaction between MSCs and cancer cells are promising strategies to improve cancer therapy. On the other hand, the unique tumor-homing capacity of MSCs makes them a promising vehicle to deliver various anti-cancer agents. This review summarized the recent advancement of our understanding on the interaction between MSCs and cancer cells, as well as the potential of MSCs for cancer therapy.

Keywords

mesenchymal stem or stromal cells / cancer / cancer-associated fibroblasts / gene therapy / cell therapy

Introduction

The progression of tumors toward a malignant phenotype does not depend exclusively on the cell-autonomous properties of cancer cells themselves but is also deeply influenced by tumor microenvironmental elements including hypoxia, extracellular matrix (ECM) and various stromal cells (Marx, 2008). Among these stromal cells, Mesenchymal stem or stromal cells (MSCs) and the derivative Cancer-associated fibroblasts (CAFs) are rate-limiting determinants for growth and metastasis of cancers (Shimoda et al., 2010). Their roles in cancer progression include ECM remodeling, secretion of pro-tumor factors, inhibition of anti-tumor immune response, hormone production, tumor metabolism remodeling, regulation of motility and stemness, and preparation of metastatic niche (Marx, 2008).

MSCs are originally isolated from bone marrow, and later from adipose tissues and many other organs. These cells are capable of self-renewing and differentiating to bone, fat, or cartilage cells under appropriate conditions (García-Castro et al., 2010). Bone marrow MSCs serve as an essential component of niche for hematopoietic stem cell through secretion of growth factors and cytokines with trophic, immunomodulatory, anti-inflammatory, anti-apoptotic, and pro-angiogenic properties (Wu and Zhou, 2010). MSCs from bone marrow, fat and local tissues are capable of homing to stroma of various primary and metastatic cancers (Loebinger and Janes, 2010; Quante et al., 2011; Song and Li, 2011; Chaturvedi et al., 2013; Jung et al., 2013). The tumor-tropic capacity, the immuno-privileged status and the ease of harvest, culture, and transduction of MSCs made them promising vehicles for gene therapy of various invasive cancers including lung, breast, squamous-cell, colon, pancreas and cervical cancers (Loebinger et al., 2009; Grisendi et al., 2010). In addition, the combination of osteogenic potential and capability to deliver anti-cancer agents made MSCs a promising option to treat tumor-induced osteolysis (Komlev et al., 2009). However, exogenous MSCs have also shown the tendency to promote rather than inhibit cancers in many circumstances (Liu et al., 2011a; Li et al., 2012) similar to the roles of endogenous MSCs.

Homing of MSCs to tumor

MSCs are often involved in tissue remodeling after injury or chronic inflammation. Tumors resemble chronic wounds or “wounds that never heal” to form the tumor stroma (Dvorak, 1986). Inflammatory cytokines such as IL-1β (Carrero et al., 2012) or substance P (Hong et al., 2009) have been suggested to mediate the mobilization of MSCs after injury. For trafficking and engraftment of MSCs to the infarcted myocardium, integrins such as ITGA6 and ITGB1 and podocalyxin-like protein (PODXL) are essential (Ip et al., 2007; Lee et al., 2009b).

The dominant factors to recruit MSCs may be different for particular types of cancers. In inflammation-dependent models of gastric cancer, bone marrow MSCs are recruited to the tumor in a TGFβ- and SDF1a-dependent manner (Houghton et al., 2004; Quante et al., 2011). In primary and metastatic prostate cancer, CXCL16 is highly expressed compared with normal prostate epithelial cells, and the interaction of CXCL16 and its specific receptor CXCR6 in MSCs plays a key role in recruiting MSCs into tumors and supporting tumor growth (Jung et al., 2013). In mouse breast and ovarian cancer models, the expression of CD44 in MSCs is critical for their migration to tumors, suggesting the eseential roles of CD44 ligands such as hyaluronan (HA) and osteopontin produced by cancer cells that have been implicated as prognostic markers of cancer progression and metastases in breast, prostrate, lung, and ovarian cancers (Spaeth et al., 2013). In human breast cancer xenograft models, human breast cancer cells and MSCs expressed placental growth factor (PGF) and its cognate receptor VEGFR1, respectively, in a Hypoxia-inducible factor-dependent manner, and PGF facilitated homing of MSCs to tumors (Chaturvedi et al., 2013). In both murine and human multiple myeloma models, myeloma-produced chemokine CCL25 attracted BM-MSCs (Xu et al., 2012).

When are MSCs recruited to cancer may dependent on the inflammation and tissue damages caused by carcinogens or cancer cells. In mouse gastric cancer models caused by chronic infection with Helicobacter or IL-1β overexpression, bone marrow MSCs were attracted to the dysplasia lesions and contribute to the carcinogenesis (Houghton et al., 2004; Quante et al., 2011). In mouse models, established tumors release factors such as exosomes (Peinado et al., 2012) and Lysyl oxidase (Erler et al., 2009) that can act on cells in distant organs to recruit bone-marrow-derived cells (BMDCs) including MSCs, and these recruited BMDCs create an pre-metastatic niche to promote the survival and proliferation of newly arrived metastatic cells. The recuritment of MSCs into primary or metastatic cancer is illustrated in Fig. 1.

The pro-tumor properties of MSCs

MSCs recruited to tumor stromal may promote tumor progression through multiple mechanisms. The first one is producing pro-tumor factors directly stimulating cancer cells. In 2007, Karnoub et al. demonstrated that mixing bone marrow MSCs with weakly metastatic variant of human MDA-MB-231 breast cancer cells at subcutaneous sites in a xenograft model dramatically enhanced the frequency of lung metastases, and this pro-tumor effect was attributed to the de novo secretion of the chemokine CCL5/RANTES from cancer-stimulated MSCs (Karnoub et al., 2007). Later, more MSC-derived pro-tumor cytokines were identified. For instances, CXCL7, CXCL10 or IL6 produced by MSCs promote metastasis and/or stemness of breast cancer (Liu et al., 2011a; Shangguan et al., 2012; Chaturvedi et al., 2013); neuregulin 1 (NRG1) secreted by BM-MSCs activates the HER2/HER3-dependent PI3K/AKT signaling cascade in colorectal cancer cells to promote their invasion and survival (De Boeck et al., 2013). A common mechanism of the direct pro-tumor effect of MSCs is promoting epithelial-mesenchymal transition (EMT) of cancer cells, which in turn promotes stemness, invasion and metastasis of cancer cells. The EMT can be induced through activation of Wnt/β-catenin signaling with MSC-derived Prostaglandin E2 (PGE2) (Li et al., 2012) or activation of CD44/Lysyl Oxidase (LOX)/TWIST signaling pathway with MSC-derived Hyaluronan acid (HA) (El-Haibi et al., 2012). Tumor necrosis factor α-induced protein 6 (TSG6), a secreted protein highly expressed by BM-MSCs (Lee et al., 2009a), enhances or induces the binding of HA to cell surface CD44 (Lesley et al., 2004), hence might also contributes to the pro-EMT effect of MSCs.

Secondly, MSCs promote angiogenesis in various organs through paracrine effects (Kinnaird et al., 2004) or endothelial differentiation (Chen et al., 2009). In a colon cancer model, MSCs stimulated by inflammatory cytokines such as IFN-γ and TNF-α in the tumor microenvironment express higher levels of vascular endothelial growth factor (VEGF) via the HIF-1α signaling pathway to enhance tumor angiogenesis, finally leading to colon cancer growth in mice (Liu et al., 2011b). In a mouse Lewis lung carcinoma, co-injected MSCs directly supported the tumor vasculature by localizing close to vascular walls and by expressing an endothelial marker. Furthermore, coculture of MSCs with cancer cells increased secretion of multiple pro-angiogenesis factors such as leukemia inhibitory factor, macrophage colony-stimulating factor, macrophage inflammatory protein-2 and VEGF (Suzuki et al., 2011).

Thirdly, MSCs have immune inhibitory effects under various circumstances (Nasef et al., 2007). In vitro, MSCs protect breast cancer cells through expansion of regulatory T cells (Tregs), which is probably mediated by MSC-derived TGF-β (Patel et al., 2010). In a Helicobacter pylori model of gastric cancer, BM-MSCs favor the immunosuppressive T cells skewing, i.e., an increase in IL-10-secreting T cells and Tregs (Lin et al., 2013). In human pediatric malignancies, MSC-like cells isolated from tumor stroma impair NK cell cytotoxicity related with reduced expression of the activating NK cell receptors NKp44 and NKp46, and displayed a strong antiproliferative effect on peripheral blood mononuclear cells (Johann et al., 2010).

Lastly, the fusion of MSCs with cancer cells may also promote cancer progression through EMT and generation of cancer stem cells. Cocultured MSCs and breast or non-small cell lung cancer cells fused spontaneously at low frequency (1.2% –3.2%) (Rappa et al., 2012; Xu et al., 2014). The breast cancer hybrid cells acquired mesenchymal characteristics, are tumorigenic and some hybrids had an increased metastatic capacity and expression of stem cell markers. The lung cancer hybrid cells underwent EMT and acquired stem cell-like properties such as increased tumor initiating capacity. However, the evidences for the fusion of MSCs with cancer cells in vivo are not strong. Such fusion was obvious and frequent between human cancer cells and stromal cells of mouse or hamster (>30%) (Jacobsen et al., 2006; Goldenberg et al., 2013), but the in vivo fusion of human cancer cells and human MSCs or stromal cells is very rare and not well characterized. The proof of fusion between cancer cells and BDMCs in human patients can only be found in cancer patients received allogeneic bone marrow transplantation. The first and only evidence was found in such a patient with metastatic melanoma, and the initiator of the metastasis was a hybrid cell acting as a stem cell or tumor-initiating cell (Lazova et al., 2013). However, whether the fusion was with MSCs or other lineage of BDMSs such as macrophages remains to be explored.

Cancer cells activate the pro-tumor effects of MSCs via multiple mechanisms. The expression of CCL5 by MSCs is probably induced by Osteopontin produced by cancer cells (Mi et al., 2011). For cancer cells expressing high level of Interleukin-1 (IL1) such as many colorectal or breast cancer cells, the pro-tumor effect of MSCs is mainly mediated by IL1 receptor (IL1R)/PGE2 pathway (Li et al., 2012). TGFβ signaling is also essential for the pro-tumor effects of BM-MSCs by induction of multiple pro-tumor factors such as SDF1 and IL6 (Quante et al., 2011; Shangguan et al., 2012).

Differentiation of MSCs to cancer associated fibroblasts

CAFs are phenotypically similar to myofibroblasts (MFs) and promote growth and metastasis of cancer cells by multiple mechanisms such as secreting pro-tumor factors (Stroncek et al., 2010) and inhibiting anti-tumor immunity (Kraman et al., 2010). CAFs are heterogeneous populations and originated from resting resident fibroblasts, epithelial and endothelial cells within the tumor, pericytes or bone marrow MSCs (Stroncek et al., 2010). A study in mouse models of pancreatic cancer and inflammation-induced gastric cancer suggested that at least 20% CAFs are originated from bone marrow MSCs (Tokar et al., 2010).

Differentiation to CAFs of human bone marrow MSCs (hBM-MSCs) can be induced by tumor-conditioned medium (TCM) (Mishra et al., 2008), indicating the essential roles of secreted factors in tumor microenvironments in CAF differentiation. Transforming growth factor β (TGF-β) is highly expressed by various carcinoma (Peter, 2009) and is required to induce CAF differentiation of mouse BM-MSCs in vivo (Tokar et al., 2010), and can induce expression of some CAF markers in hBM-MSCs in vitro (Varnat et al., 2009). Consistently, in CAFs derived from hBM-MSCs, genes in TGF-β signaling pathway are highly enriched (Mishra et al., 2008), further suggesting that TGF-β signaling might be essential for CAF differentiation of human BM-MSCs. Recently, we found that inhibiting TGF-β/Smad signaling in human BM-MSCs blocked their differentiation to CAFs in tumor microenvironments and abolished their pro-tumor effects, but did not alter their stem cell properties and tumor tropism (Shangguan et al., 2012). Particularly, the remarkable upregulation of two pro-tumor factors, CCL5 and SDF-1, from MSCs exposed to tumor microenvironments was significantly blocked by inhibiting TGF-β/Smad signaling. In mouse orthotopic breast or ovarian tumor models and a human xenograft model using SKOV-3 cells with high expression of HA synthetase 2 (HAS2), the expression of CD44 in MSCs is also critical for their differentiation to CAFs, suggesting the essential roles of CD44 ligands such as HA or osteopontin produced by cancer cells (Spaeth et al., 2013). CD44 activation by TCM stimulates Twist expression in MSCs by increased association of CD44 at the Twist1 promoter, whereas exogenously expressed Twist1 in CD44 knockdown MSCs partially restored the proangiogenic function of the MSCs, suggesting that Twist1 is essential for CD44-mediated CAF differentiation of MSCs. The interactions between cancer cells, MSCs and CAFs are illustrated in Fig. 2.

Targeting the interaction between cancer cells and MSCs for cancer treatment

Considered the essential roles of MSCs in cancer progression, targeting the factors essential for the interaction between MSCs and cancer cells is a promising strategy to improve cancer treatment and also contributes to the efficacy of many anti-cancer agents tested before. All the factors involved in homing, CAF differentiation and pro-tumor effects mentioned in Section 2 to 4 could be targeted for such purpose. For instance, Osteopontin is highly expressed by malignant cells and associated with metastasis, partially by stimulating MSCs to produce pro-metastatic cytokine CCL5. RNA aptamer blockade of osteopontin inhibits growth and metastasis of MDA-MB231 breast cancer cells (Mi et al., 2009). In surgical specimens of human colon cancer the expression of platelet-derived growth factor receptor (PDGFR) in tumor stroma is associated with vascularity and tumor stage (Kitadai et al., 2006), whereas PDGF signaling pathways are known to be crucial to migration and survival of MSCs to infarcted myocardium (Krausgrill et al., 2009). Blockade of PDGFR signaling with imatinib impairs the tumor-promoting effect of BM-MSCs in an orthotopic transplantation model of colon cancer by inhibiting the tumor homing and survival of intravenously infused MSCs (Shinagawa et al., 2013).

The intrinsic anti-tumor properties of exogenous MSCs

Human MSCs also have intrinsic anti-tumor properties under certain circumstances via various mechanisms. MSCs pre-treated with TNFα inhibited the progression of lung tumors formed from MDA-MB-231 breast cancer cells and induced their apoptosis via the induction of expression of TNF-related apoptosis-inducing ligand (TRAIL) in MSCs; moreover, the TRAIL expression in MSCs was further induced by direct contact with breast cancer cells in a TLR3-dependent manner (Lee et al., 2012). The downregulation of the Wnt signaling pathway in breast cancer cells by Dickkopf proteins (DKK1/3) derived from MSCs also contribute to the anti-tumor effort via the reduction of cancer cell proliferation (Qiao et al., 2008; Lee et al., 2012). For several lung adenocarcinoma cell lines MSCs effectively inhibited their migration, invasion, and cell-cycle progression through Oncostatin M mediated mesenchymal-epithelial transition (MET) of these cancer cells (Wang et al., 2012). For Kaposi’s sarcoma, intravenously delivered MSCs were able to inhibit their growth in a mouse model via cell-cell contact-induced inhibition of Akt activity within sarcoma cells in an E-cadherin-dependent manner (Khakoo et al., 2006). In a human pancreatic carcinoma orthotopical xenograft model using PANC-1 cells, intraperitoneally injected MSCs inhibited tumor growth (Kidd et al., 2010). For mouse hepatoma, lymphoma and insulinoma, mouse BM-MSCs arrest these malignant cells at G₀/G₁ and increase their apoptosis in vitro, and reduced malignant ascites when hepatoma cells were co-injected intraperitoneally (Lu et al., 2008). For human glioma, human BM-MSCs suppress tumor growth through inhibition of angiogenesis likely via downregulation of PDGF/PDGFR axis (Ho et al., 2013). In addition, microvesicles derived from human BM-MSCs inhibit in vitro and in vivo growth of HepG2 hepatoma, Kaposi's sarcoma, and Skov-3 ovarian tumor cell lines (Bruno et al., 2013), whereas those from human umbilical cord Wharton’s jelly MSCs attenuate bladder tumor cell growth in vitro and in vivo (Wu et al., 2013).

Cancer therapy with engineered MSCs

The unique tumor-homing capacity and the immuno-privileged status of MSCs enable them as promising vehicles for delivering anti-cancer agents. The anti-cancer agents successfully delivered by MSCs include pro-drug enzymes, immune-stimulating cytokines, cell death inducers, oncolytic viruses, and nanoparticles. Most of these agents are introduced into MSCs by genetic engineering, whereas incorporation of drug-laden nano/microparticles on the cell surface or intracellularly has been tested recently. The approaches tested and corresponding references are summarized in Table 1. In addition to the tumor targeting, MSC-mediated delivery of many anti-cancer agents significantly improved the efficacy of these agents by protecting them from immune reaction or degradation or expressing them in the cell membrane. For instance, the effectiveness of the TRAIL recombinant protein has been limited by the short half-life of the protein and the fact that it is less potent than membrane-tethered forms of the protein, whereas MSCs expressing TRAIL effectively induce apoptosis of cancer cells in culture and in mouse models (Kolluri et al., 2013).

Generally, combination of MSC-mediated gene therapy with conventional chemo/radio-therapy such as Doxrubincine achieved better efficacy of controlling tumor (Lee et al., 2012). To eliminate the potential pro-tumor risk and other safety issues of MSC therapy, suicide genes such HSV-TK (herpes simplex thymidine kinase) or inducible caspase 9 (Di Stasi et al., 2011) should better be introduced into MSCs. Moreover, recent reports from two laboratories indicated that bone marrow MSCs expressing TRAIL together with HSV-TK killed cancer cells much more efficiently in vitro and in vivo than MSCs expressing either transgenes alone, and even achieved complete regression of metastatic cancer in lung when infused repeatedly (Kim et al., 2013; Martinez-Quintanilla et al., 2013). These data indicate that the by-stander effect of HSV-TK, i.e., generating phosphorylated metabolites of pro-drug ganciclovir that kill cells expressing the enzyme as well as adjacent cells, is ideal for improving both safety and efficacy of MSC-mediated cancer treatment.

One major issue of MSC-mediated cancer therapy is the trapping of MSCs in lung after intravenous injection (Lee et al., 2009a). Recently, a new approach circumvented this issue by reconstructing nanoghosts from MSCs. Briefly, intact MSC cell membranes are isolated (ghost cells) and homogenized into nanosized vesicles (nanoghosts). The MSC-derived nanoghosts preserve the tumor tropism of MSCs in a subcutaneous prostate cancer model, lack immunogenicity, and are cleared from blood-filtering organs due to much smaller size around 180nm (Toledano Furman et al., 2013). One dose intraperitoneal injection of TRAIL-encapsulating nanoghosts made from MSCs significantly inhibited the growth of prostate cancer for more than 70%, indicating the high efficiency of this delivery system. However, there are several limitations of this system such as the relative low encapsulation efficiency of TRAIL (30%) and huge amount of MSCs needed for cancer treatment (5×10⁷ MSCs per mouse), which might be overcome by expressing membrane-bound TRAIL in MSCs and using pluripotent stem cells derived MSCs as mentioned below.

Prospects

One major issue in the field of MSC research is that MSCs are being prepared with a variety of protocols in different laboratories. As a result, standardization of the cells has been extremely difficult and the data presented in different publications are difficult to compare. Hence large banks of reference cells are needed to advance the MSC research (Viswanathan et al., 2014). Moreover, MSCs from various adult tissues have a limited proliferation potential and lose some of their important biological functions as they are expanded (Larson et al., 2010). Therefore, it is difficult to prepare large banks of the cells with uniform biological activities and/or transgene expression required for experiments in large animals and for future clinical therapies. Large amounts of MSC-like cells with uniform biology properties have been derived from embryonic stem cells or iPS cells in many laboratories including mine. These pluripotent stem cells (PSC) derived MSCs express typical MSC surface markers, are capable of differentiation to osteocytes, adipocytes and chondrocytes, and have similar immunosuppressive and anti-inflammatory properties as BM-MSCs (Sánchez et al., 201; de Peppo et al., 2013). Meanwhile, these PSC-MSCs have much better expandability in vitro and regeneration capacity in vivo. My laboratory is testing the potential of these PSC-MSCs in cancer treatment in collaboration with Dr. Darwin Prockop’s team at TAMHSC.

A particular concern of MSC-mediated cancer therapy is the pro-tumor risk of MSCs. Transducing MSCs with inducible suicide genes and inducing their suicide shortly after their homing to cancer may decrease this risk. However, MSCs significantly induced the expression of pro-EMT genes in cocultured cancer cells within 12 h (Li et al., 2012), suggesting that even the short-term effect of infused MSCs may promote metastasis and expansion of cancer stem cells. Hence, the pro-tumor potentials of MSCs should be considered cautiously for cancer therapy and approaches to reduce such risk should be explored.

Compliance with ethics guidelines

Qingguo Zhao and Fei Liu declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

References

[1] BolontradeM F, SgangaL, PiaggioE, VialeD L, SorrentinoM A, RobinsonA, SevleverG, GarcíaM G, MazzoliniG, PodhajcerO L (2012). A specific subpopulation of mesenchymal stromal cell carriers overrides melanoma resistance to an oncolytic adenovirus. Stem Cells Dev, 21(14): 2689–2702

[2] BrunoS, CollinoF, DeregibusM C, GrangeC, TettaC, CamussiG (2013). Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth. Stem Cells Dev, 22(5): 758–771

[3] CarreroR, CerradaI, LledóE, DopazoJ, García-GarcíaF, RubioM P, TriguerosC, DorronsoroA, Ruiz-SauriA, MonteroJ A, SepúlvedaP (2012). IL1β induces mesenchymal stem cells migration and leucocyte chemotaxis through NF-κB. Stem Cell Rev, 8(3): 905–916

[4] CastletonA, DeyA, BeatonB, PatelB, AucherA, DavisD M, FieldingA K (2014). Human mesenchymal stromal cells deliver systemic oncolytic measles virus to treat acute lymphoblastic leukemia in the presence of humoral immunity. Blood, 123(9): 1327–1335

[5] CavarrettaI T, AltanerovaV, MatuskovaM, KucerovaL, CuligZ, AltanerC (2010). Adipose tissue-derived mesenchymal stem cells expressing prodrug-converting enzyme inhibit human prostate tumor growth. Mol Ther, 18(1): 223–231

[6] ChaturvediP, GilkesD M, WongC C, LuoW, ZhangH, WeiH, TakanoN, SchitoL, LevchenkoA, SemenzaG L, and the Kshitiz (2013). Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis. J Clin Invest, 123(1): 189–205

[7] ChenM Y, LieP C, LiZ L, WeiX (2009). Endothelial differentiation of Wharton’s jelly-derived mesenchymal stem cells in comparison with bone marrow-derived mesenchymal stem cells. Exp Hematol, 37(5): 629–640

[8] De BoeckA, PauwelsP, HensenK, RummensJ L, WestbroekW, HendrixA, MaynardD, DenysH, LambeinK, BraemsG, GespachC, BrackeM, De WeverO (2013). Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling. Gut, 62(4): 550–560

[9] de PeppoG M, Marcos-CamposI, KahlerD J, AlsalmanD, ShangL, Vunjak-NovakovicG, MaroltD (2013). Engineering bone tissue substitutes from human induced pluripotent stem cells. Proc Natl Acad Sci USA, 110(21): 8680–8685

[10] Di StasiA, TeyS K, DottiG, FujitaY, Kennedy-NasserA, MartinezC, StraathofK, LiuE, DurettA G, GrilleyB, LiuH, CruzC R, SavoldoB, GeeA P, SchindlerJ, KranceR A, HeslopH E, SpencerD M, RooneyC M, BrennerM K (2011). Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med, 365(18): 1673–1683

[11] DuchiS, SotgiuG, LucarelliE, BallestriM, DozzaB, SantiS, GuerriniA, DambruosoP, GianniniS, DonatiD, FerroniC, VarchiG (2013). Mesenchymal stem cells as delivery vehicle of porphyrin loaded nanoparticles: effective photoinduced in vitro killing of osteosarcoma. J Control Release, 168(2): 225–237

[12] DvorakH F (1986). Tumors: wounds that do not heal.Similarities between tumor stroma generation and wound healing. N Engl J Med, 315(26): 1650–1659

[13] El-HaibiC P, BellG W, ZhangJ, CollmannA Y, WoodD, ScherberC M, CsizmadiaE, MarianiO, ZhuC, CampagneA, TonerM, BhatiaS N, IrimiaD, Vincent-SalomonA, KarnoubA E (2012). Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy. Proc Natl Acad Sci USA, 109(43): 17460–17465

[14] ErlerJ T, BennewithK L, CoxT R, LangG, BirdD, KoongA, LeQ T, GiacciaA J (2009). Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell, 15(1): 35–44

[15] García-CastroJ, AlemanyR, CascallóM, Martínez-QuintanillaJ, ArrieroM M, LassalettaA, MaderoL, RamírezM (2010). Treatment of metastatic neuroblastoma with systemic oncolytic virotherapy delivered by autologous mesenchymal stem cells: an exploratory study. Cancer Gene Ther, 17(7): 476–483

[16] GoldenbergD M, GoldD V, LooM, LiuD, ChangC H, JaffeE S (2013). Horizontal transmission of malignancy: in-vivo fusion of human lymphomas with hamster stroma produces tumors retaining human genes and lymphoid pathology. PLoS ONE, 8(2): e55324

[17] GrisendiG, BussolariR, CafarelliL, PetakI, RasiniV, VeronesiE, De SantisG, SpanoC, TagliazzucchiM, Barti-JuhaszH, ScarabelliL, BambiF, FrassoldatiA, RossiG, CasaliC, MorandiU, HorwitzE M, PaolucciP, ConteP, DominiciM (2010). Adipose-derived mesenchymal stem cells as stable source of tumor necrosis factor-related apoptosis-inducing ligand delivery for cancer therapy. Cancer Res, 70(9): 3718–3729

[18] HoI A, TohH C, NgW H, TeoY L, GuoC M, HuiK M, LamP Y (2013). Human bone marrow-derived mesenchymal stem cells suppress human glioma growth through inhibition of angiogenesis. Stem Cells, 31(1): 146–155

[19] HongH S, LeeJ, LeeE, KwonY S, LeeE, AhnW, JiangM H, KimJ C, SonY (2009). A new role of substance P as an injury-inducible messenger for mobilization of CD29(+) stromal-like cells. Nat Med, 15(4): 425–435

[20] HoughtonJ, StoicovC, NomuraS, RogersA B, CarlsonJ, LiH, CaiX, FoxJ G, GoldenringJ R, WangT C (2004). Gastric cancer originating from bone marrow-derived cells. Science, 306(5701): 1568–1571

[21] IpJ E, WuY, HuangJ, ZhangL, PrattR E, DzauV J (2007). Mesenchymal stem cells use integrin beta1 not CXC chemokine receptor 4 for myocardial migration and engraftment. Mol Biol Cell, 18(8): 2873–2882

[22] JacobsenB M, HarrellJ C, JedlickaP, BorgesV F, Varella-GarciaM, HorwitzK B (2006). Spontaneous fusion with, and transformation of mouse stroma by, malignant human breast cancer epithelium. Cancer Res, 66(16): 8274–8279

[23] JohannP D, VaeglerM, GiesekeF, MangP, Armeanu-EbingerS, KlubaT, HandgretingerR, MüllerI (2010). Tumour stromal cells derived from paediatric malignancies display MSC-like properties and impair NK cell cytotoxicity. BMC Cancer, 10(1): 501

[24] JungY, KimJ K, ShiozawaY, WangJ, MishraA, JosephJ, BerryJ E, McGeeS, LeeE, SunH, WangJ, JinT, ZhangH, DaiJ, KrebsbachP H, KellerE T, PientaK J, TaichmanR S (2013). Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. Nat Commun, 4: 1795

[25] KarnoubA E, DashA B, VoA P, SullivanA, BrooksM W, BellG W, RichardsonA L, PolyakK, TuboR, WeinbergR A (2007). Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature, 449(7162): 557–563

[26] KhakooA Y, PatiS, AndersonS A, ReidW, ElshalM F, RoviraI I, NguyenA T, MalideD, CombsC A, HallG, ZhangJ, RaffeldM, RogersT B, Stetler-StevensonW, FrankJ A, ReitzM, FinkelT (2006). Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi’s sarcoma. J Exp Med, 203(5): 1235–1247

[27] KiddS, CaldwellL, DietrichM, SamudioI, SpaethE L, WatsonK, ShiY, AbbruzzeseJ, KonoplevaM, AndreeffM, MariniF C (2010). Mesenchymal stromal cells alone or expressing interferon-beta suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment. Cytotherapy, 12(5): 615–625

[28] KimS W, KimS J, ParkS H, YangH G, KangM C, ChoiY W, KimS M, JeunS S, SungY C (2013). Complete regression of metastatic renal cell carcinoma by multiple injections of engineered mesenchymal stem cells expressing dodecameric TRAIL and HSV-TK. Clin Cancer Res, 19(2): 415–427

[29] KinnairdT, StabileE, BurnettM S, LeeC W, BarrS, FuchsS, EpsteinS E (2004). Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res, 94(5): 678–685

[30] KitadaiY, SasakiT, KuwaiT, NakamuraT, BucanaC D, HamiltonS R, FidlerI J (2006). Expression of activated platelet-derived growth factor receptor in stromal cells of human colon carcinomas is associated with metastatic potential. Int J Cancer, 119(11): 2567–2574

[31] Kolluri,K.K., Laurent,G.J., and Janes,S.M. (2013). Mesenchymal stem cells as vectors for lung cancer therapy. Respiration; international review of thoracic diseases85, 443–451.

[32] KomlevV S, MastrogiacomoM, PeyrinF, CanceddaR, RustichelliF (2009). X-ray synchrotron radiation pseudo-holotomography as a new imaging technique to investigate angio- and microvasculogenesis with no usage of contrast agents. Tissue Eng Part C Methods, 15(3): 425–430

[33] KramanM, BambroughP J, ArnoldJ N, RobertsE W, MagieraL, JonesJ O, GopinathanA, TuvesonD A, FearonD T (2010). Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science, 330(6005): 827–830

[34] KrausgrillB, VantlerM, BurstV, RathsM, HalbachM, FrankK, SchynkowskiS, SchenkK, HeschelerJ, RosenkranzS, Müller-EhmsenJ (2009). Influence of cell treatment with PDGF-BB and reperfusion on cardiac persistence of mononuclear and mesenchymal bone marrow cells after transplantation into acute myocardial infarction in rats. Cell Transplant, 18(8): 847–853

[35] KucerovaL, AltanerovaV, MatuskovaM, TyciakovaS, AltanerC (2007). Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. Cancer Res, 67(13): 6304–6313

[36] KucerovaL, MatuskovaM, PastorakovaA, TyciakovaS, JakubikovaJ, BohovicR, AltanerovaV, AltanerC (2008). Cytosine deaminase expressing human mesenchymal stem cells mediated tumour regression in melanoma bearing mice. J Gene Med, 10(10): 1071–1082

[37] LarsonB L, YlostaloJ, LeeR H, GregoryC, ProckopD J (2010). Sox11 is expressed in early progenitor human multipotent stromal cells and decreases with extensive expansion of the cells. Tissue Eng Part A, 16(11): 3385–3394

[38] LazovaR, LabergeG S, DuvallE, SpoelstraN, KlumpV, SznolM, CooperD, SpritzR A, ChangJ T, PawelekJ M (2013). A melanoma brain metastasis with a donor-patient hybrid genome following bone marrow transplantation: first evidence for fusion in human cancer. PLoS ONE, 8(6): e66731

[39] LeeR H, PulinA A, SeoM J, KotaD J, YlostaloJ, LarsonB L, Semprun-PrietoL, DelafontaineP, ProckopD J (2009a). Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell, 5(1): 54–63

[40] LeeR H, SeoM J, PulinA A, GregoryC A, YlostaloJ, ProckopD J (2009b). The CD34-like protein PODXL and alpha6-integrin (CD49f) identify early progenitor MSCs with increased clonogenicity and migration to infarcted heart in mice. Blood, 113(4): 816–826

[41] LeeR H, YoonN, ReneauJ C, ProckopD J (2012). Preactivation of human MSCs with TNF-α enhances tumor-suppressive activity. Cell Stem Cell, 11(6): 825–835

[42] LesleyJ, GálI, MahoneyD J, CordellM R, RuggM S, HymanR, DayA J, MikeczK (2004). TSG-6 modulates the interaction between hyaluronan and cell surface CD44. J Biol Chem, 279(24): 25745–25754

[43] LiH J, ReinhardtF, HerschmanH R, WeinbergR A (2012). Cancer-stimulated mesenchymal stem cells create a carcinoma stem cell niche via prostaglandin E2 signaling. Cancer Discov, 2(9): 840–855

[44] LinR, MaH, DingZ, ShiW, QianW, SongJ, HouX (2013). Bone marrow-derived mesenchymal stem cells favor the immunosuppressive T cells skewing in a Helicobacter pylori model of gastric cancer. Stem Cells Dev, 22(21): 2836–2848

[45] LiuS, GinestierC, OuS J, ClouthierS G, PatelS H, MonvilleF, KorkayaH, HeathA, DutcherJ, KleerC G, JungY, DontuG, TaichmanR, WichaM S (2011a). Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res, 71(2): 614–624

[46] LiuY, HanZ P, ZhangS S, JingY Y, BuX X, WangC Y, SunK, JiangG C, ZhaoX, LiR, GaoL, ZhaoQ D, WuM C, WeiL X (2011b). Effects of inflammatory factors on mesenchymal stem cells and their role in the promotion of tumor angiogenesis in colon cancer. J Biol Chem, 286(28): 25007–25015

[47] LoebingerM R, EddaoudiA, DaviesD, JanesS M (2009). Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res, 69(10): 4134–4142

[48] LoebingerM R, JanesS M (2010). Stem cells as vectors for antitumour therapy. Thorax, 65(4): 362–369

[49] LuY R, YuanY, WangX J, WeiL L, ChenY N, CongC, LiS F, LongD, TanW D, MaoY Q, ZhangJ, LiY P, ChengJ Q (2008). The growth inhibitory effect of mesenchymal stem cells on tumor cells in vitro and in vivo. Cancer Biol Ther, 7(2): 245–251

[50] MaderE K, MaeyamaY, LinY, ButlerG W, RussellH M, GalanisE, RussellS J, DietzA B, PengK W (2009). Mesenchymal stem cell carriers protect oncolytic measles viruses from antibody neutralization in an orthotopic ovarian cancer therapy model. Clin Cancer Res, 15(23): 7246–7255

[51] Martinez-QuintanillaJ, BhereD, HeidariP, HeD, MahmoodU, ShahK (2013). Therapeutic efficacy and fate of bimodal engineered stem cells in malignant brain tumors. Stem Cells, 31(8): 1706–1714

[52] MarxJ (2008). Cancer biology.All in the stroma: cancer’s Cosa Nostra. Science, 320(5872): 38–41

[53] MatuskovaM, HlubinovaK, PastorakovaA, HunakovaL, AltanerovaV, AltanerC, KucerovaL (2010). HSV-tk expressing mesenchymal stem cells exert bystander effect on human glioblastoma cells. Cancer Lett, 290(1): 58–67

[54] MiZ, BhattacharyaS D, KimV M, GuoH, TalbotL J, KuoP C (2011). Osteopontin promotes CCL5-mesenchymal stromal cell-mediated breast cancer metastasis. Carcinogenesis, 32(4): 477–487

[55] MiZ, GuoH, RussellM B, LiuY, SullengerB A, KuoP C (2009). RNA aptamer blockade of osteopontin inhibits growth and metastasis of MDA-MB231 breast cancer cells. Mol Ther, 17(1): 153–161

[56] MishraP J, MishraP J, HumeniukR, MedinaD J, AlexeG, MesirovJ P, GanesanS, GlodJ W, BanerjeeD (2008). Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res, 68(11): 4331–4339

[57] NasefA, MathieuN, ChapelA, FrickJ, FrançoisS, MazurierC, BoutarfaA, BouchetS, GorinN C, ThierryD, FouillardL (2007). Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation, 84(2): 231–237

[58] PatelS A, MeyerJ R, GrecoS J, CorcoranK E, BryanM, RameshwarP (2010). Mesenchymal stem cells protect breast cancer cells through regulatory T cells: role of mesenchymal stem cell-derived TGF-beta. J Immunol, 184(10): 5885–5894

[59] PeinadoH, AlečkovićM, LavotshkinS, MateiI, Costa-SilvaB, Moreno-BuenoG, Hergueta-RedondoM, WilliamsC, García-SantosG, GhajarC, Nitadori-HoshinoA, HoffmanC, BadalK, GarciaB A, CallahanM K, YuanJ, MartinsV R, SkogJ, KaplanR N, BradyM S, WolchokJ D, ChapmanP B, KangY, BrombergJ, LydenD (2012). Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med, 18(6): 883–891

[60] PeterM E (2009). Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression. Cell Cycle, 8(6): 843–852

[61] QiaoL, XuZ L, ZhaoT J, YeL H, ZhangX D (2008). Dkk-1 secreted by mesenchymal stem cells inhibits growth of breast cancer cells via depression of Wnt signalling. Cancer Lett, 269(1): 67–77

[62] QuanteM, TuS P, TomitaH, GondaT, WangS S, TakashiS, BaikG H, ShibataW, DipreteB, BetzK S, FriedmanR, VarroA, TyckoB, WangT C (2011). Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell, 19(2): 257–272

[63] RappaG, MercapideJ, LoricoA (2012). Spontaneous formation of tumorigenic hybrids between breast cancer and multipotent stromal cells is a source of tumor heterogeneity. Am J Pathol, 180(6): 2504–2515

[64] RenC, KumarS, ChandaD, ChenJ, MountzJ D, PonnazhaganS (2008a). Therapeutic potential of mesenchymal stem cells producing interferon-alpha in a mouse melanoma lung metastasis model. Stem Cells, 26(9): 2332–2338

[65] RenC, KumarS, ChandaD, KallmanL, ChenJ, MountzJ D, PonnazhaganS (2008b). Cancer gene therapy using mesenchymal stem cells expressing interferon-beta in a mouse prostate cancer lung metastasis model. Gene Ther, 15(21): 1446–1453

[66] SageE K, KolluriK K, McNultyK, LourencoS D, KalberT L, OrdidgeK L, DaviesD, Gary LeeY C, GiangrecoA, JanesS M (2014). Systemic but not topical TRAIL-expressing mesenchymal stem cells reduce tumour growth in malignant mesothelioma. Thorax,

[67] SánchezL, Gutierrez-ArandaI, LigeroG, RubioR, Muñoz-LópezM, García-PérezJ L, RamosV, RealP J, BuenoC, RodríguezR, DelgadoM, MenendezP (2011). Enrichment of human ESC-derived multipotent mesenchymal stem cells with immunosuppressive and anti-inflammatory properties capable to protect against experimental inflammatory bowel disease. Stem Cells, 29(2): 251–262

[68] SasportasL S, KasmiehR, WakimotoH, HingtgenS, van de WaterJ A, MohapatraG, FigueiredoJ L, MartuzaR L, WeisslederR, ShahK (2009). Assessment of therapeutic efficacy and fate of engineered human mesenchymal stem cells for cancer therapy. Proc Natl Acad Sci USA, 106(12): 4822–4827

[69] SeoK W, LeeH W, OhY I, AhnJ O, KohY R, OhS H, KangS K, YounH Y (2011a). Anti-tumor effects of canine adipose tissue-derived mesenchymal stromal cell-based interferon-β gene therapy and cisplatin in a mouse melanoma model. Cytotherapy, 13(8): 944–955

[70] SeoS H, KimK S, ParkS H, SuhY S, KimS J, JeunS S, SungY C (2011b). The effects of mesenchymal stem cells injected via different routes on modified IL-12-mediated antitumor activity. Gene Ther, 18(5): 488–495

[71] ShangguanL, TiX, KrauseU, HaiB, ZhaoY, YangZ, LiuF (2012). Inhibition of TGF-β/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects. Stem Cells, 30(12): 2810–2819

[72] ShimodaM, MellodyK T, OrimoA (2010). Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression. Semin Cell Dev Biol, 21(1): 19–25

[73] ShinagawaK, KitadaiY, TanakaM, SumidaT, OnoyamaM, OhnishiM, OharaE, HigashiY, TanakaS, YasuiW, ChayamaK (2013). Stroma-directed imatinib therapy impairs the tumor-promoting effect of bone marrow-derived mesenchymal stem cells in an orthotopic transplantation model of colon cancer. Int J Cancer, 132(4): 813–823

[74] SongC, LiG (2011). CXCR4 and matrix metalloproteinase-2 are involved in mesenchymal stromal cell homing and engraftment to tumors. Cytotherapy, 13(5): 549–561

[75] SpaethE L, LabaffA M, TooleB P, KloppA, AndreeffM, MariniF C (2013). Mesenchymal CD44 expression contributes to the acquisition of an activated fibroblast phenotype via TWIST activation in the tumor microenvironment. Cancer Res, 73(17): 5347–5359

[76] StroncekD, BerlyneD, FoxB, GeeA, HeimfeldS, LindbladR, LoperK, McKennaD Jr, RooneyC, SabatinoM, WagnerE, WhitesideT, WoodD, Heath-MondoroT (2010). Developments in clinical cell therapy. Cytotherapy, 12(3): 425–428

[77] SuzukiK, SunR, OriguchiM, KanehiraM, TakahataT, ItohJ, UmezawaA, KijimaH, FukudaS, SaijoY (2011). Mesenchymal stromal cells promote tumor growth through the enhancement of neovascularization. Mol Med, 17(7-8): 579–587

[78] TokarE J, DiwanB A, WaalkesM P (2010). Arsenic exposure transforms human epithelial stem/progenitor cells into a cancer stem-like phenotype. Environ Health Perspect, 118(1): 108–115

[79] Toledano FurmanN E, Lupu-HaberY, BronshteinT, KanetiL, LetkoN, WeinsteinE, BaruchL, MachlufM (2013). Reconstructed stem cell nanoghosts: a natural tumor targeting platform. Nano Lett, 13(7): 3248–3255

[80] UchiboriR, OkadaT, ItoT, UrabeM, MizukamiH, KumeA, OzawaK (2009). Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy. J Gene Med, 11(5): 373–381

[81] VarnatF, DuquetA, MalerbaM, ZbindenM, MasC, GervazP, Ruiz i AltabaA (2009). Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol Med, 1(6-7): 338–351

[82] ViswanathanS, KeatingA, DeansR, HemattiP, ProckopD, StroncekD F, StaceyG, WeissD J, MasonC, RaoM S (2014). Soliciting Strategies for Developing Cell-Based Reference Materials to Advance MSC Research and Clinical Translation. Stem Cells Dev: 140310064908006

[83] WangM L, PanC M, ChiouS H, ChenW H, ChangH Y, LeeO K, HsuH S, WuC W (2012). Oncostatin m modulates the mesenchymal-epithelial transition of lung adenocarcinoma cells by a mesenchymal stem cell-mediated paracrine effect. Cancer Res, 72(22): 6051–6064

[84] WuS, JuG Q, DuT, ZhuY J, LiuG H (2013). Microvesicles derived from human umbilical cord Wharton’s jelly mesenchymal stem cells attenuate bladder tumor cell growth in vitro and in vivo. PLoS ONE, 8(4): e61366

[85] WuY, ZhouB P (2010). Snail: More than EMT. Cell Adhes Migr, 4(2): 199–203

[86] XinH, KanehiraM, MizuguchiH, HayakawaT, KikuchiT, NukiwaT, SaijoY (2007). Targeted delivery of CX3CL1 to multiple lung tumors by mesenchymal stem cells. Stem Cells, 25(7): 1618–1626

[87] XuM H, GaoX, LuoD, ZhouX D, XiongW, LiuG X (2014). EMT and acquisition of stem cell-like properties are involved in spontaneous formation of tumorigenic hybrids between lung cancer and bone marrow-derived mesenchymal stem cells. PLoS ONE, 9(2): e87893

[88] XuS, MenuE, De BeckerA, Van CampB, VanderkerkenK, Van RietI (2012). Bone marrow-derived mesenchymal stromal cells are attracted by multiple myeloma cell-produced chemokine CCL25 and favor myeloma cell growth in vitro and in vivo. Stem Cells, 30(2): 266–279

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg