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OPEN ACCESS ARTICLE
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TRANSLATIONAL AND CLINICAL RESEARCH |
aInstitut National de la Santé et de la Recherche Médicale, Montpellier, France;
bUniversity of Montpellier I, Montpellier, France
Key Words. Multipotent stromal cells • Mesenchymal stem cells • Cellular therapy • Cancer • Cellular proliferation • Angiogenesis • Chemokines
Correspondence: Gwendal Lazennec, Ph.D., INSERM, U844, Site Saint Eloi, Bâtiment INM, 80 rue Augustin Fliche, BP 74103, 34091 Montpellier cedex 5, France; University of Montpellier I, Montpellier, France. Telephone: 33-4-99-63-60-27; Fax: 33-4-99-63-60-20; e-mail: Gwendal.Lazennec{at}inserm.fr
Received November 29, 2007;
accepted for publication March 22, 2008.
First published online in STEM CELLS EXPRESS April 3, 2008.
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ABSTRACT |
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 TopFootnotes Abstract General Properties of...Roles of Multipotent Stromal...ConclusionDisclosure of Potential...AcknowledgmentsReferences |
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Disclosure of potential conflicts of interest is found at the end of this article.
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GENERAL PROPERTIES OF MULTIPOTENT STROMAL CELLS |
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TopFootnotesAbstractGeneral Properties of...Roles of Multipotent Stromal...ConclusionDisclosure of Potential...AcknowledgmentsReferences |
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–, CD34–, CD45–, HLA-DR–, CD73+, CD90+, CD105+; and (c) its capacity to be differentiated into three lineages, chondrocyte, osteoblast, and adipocyte. Although the MSCs are defined by their capacity to be differentiated toward these three cell lineages, they display a broader differentiation potential. Thus, the MSCs are also described according to their potential to differentiate into myocytes, tendinocytes, ligamentocytes [2], cardiomyocytes [3], neuronal cells [4, 5], and other cell types [6].
MSCs derive from mesodermal progenitors, as well as from mesoepithelial cells expressing sox1 in the embryo [7]. MSCs have been isolated from bone marrow (BM), adipose tissue, peripheral blood, fetal liver, lung, amniotic fluid, chorionic villi of the placenta, and umbilical cord blood [8–15]. Concerning the particular case of MSCs isolated from adipose tissue (AT-MSCs), like BM-MSCs, they express CD13, CD29, CD44, CD90, CD105, SH-3, and STRO-1 markers but lack CD106 [9, 10]. On the other hand, AT-MSCs express markers such as CD49d (4-integrin), CD34, and CD54, which are not present on BM MSCs [9]. Thus, in conclusion, although AT-MSCs have the capacity to differentiate along the adipogenic, osteogenic, chondrogenic, and myogenic lineages, they should be considered MSC-like cells.
MSCs possess numerous properties, including immune effects, proliferative and invasive effects, and osteogenic potential, making them an attractive choice as a cell-mediated gene therapy for several diseases, including bone diseases, and in the treatment of human malignancies. Recent studies suggest that MSCs could home to sites of active tumorigenesis, paving the way toward the potential use of MSCs as cellular vehicles for the delivery of anticancer agents within the tumor.
MSCs and Hematopoiesis
MSCs play a role of hematopoiesis support through their adhesion/interaction with hematopoietic stem cells (HSC) and the secretion of cytokines and growth factors that are necessary to the HSC differentiation [16]. Indeed, MSCs secrete a number of growth factors, such as stem cell factor (SCF), interleukin (IL)-6, lymphocyte inhibitory factor, granulocyte macrophage-colony stimulating factor (GM-CSF), granulocyte colony-stimulating factor, and macrophage colony-stimulating factor (M-CSF), suggesting a possible growth effect on hematopoiesis [17]. They also produce negative regulators of hematopoiesis, such as IL-8/CXCL8, macrophage inflammatory protein-1 (MIP-1/chemokine C-C motif ligand [CCL3]), transforming growth factor (TGF-β), and cytokines that induce the synthesis of other cytokines by the macrophages (in particular, the proinflammatory cytokines, IL-1, and tumor necrosis factor [TNF-]) [18]. These cytokines can act at various levels of hematopoiesis, being at the same time negative regulators and growth factors (TGF-β, MIP-1) according to the targeted cells and acting not only on the hematopoietic cells but also on the stromal cells to control their proliferation (M-CSF, IL-6, TGF-β, IL-1, TNF-) [17].
MSCs express adhesion molecules, which are mediators involved in the migration and homing of the cells to the bone marrow. They include the integrin family (1β1, 5β1), the immunoglobulin superfamily (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, human carcinoma antigen), CD44, the ligand of hyaluronic acid, and other molecules of the extracellular matrix (ECM) [19, 20]. In addition, the stromal cells synthesize and assemble many molecules of the ECM: fibronectins, laminins, collagens, tenascins, syndecans, and other glycosaminoglycans. Thus, molecules of the ECM are part of the architecture of the adherent layer allowing the anchoring of HSC and the site of accumulation of a great number of cytokines (SCF, IL-3, GM-CSF, M-CSF, TGF-β, basic fibroblast growth factor, MIP-1) secreted by stromal cells [17].
Immunosuppressive Properties of MSCs
At least some of the effects of MSCs on tumor growth could arise from their immunosuppressive properties. MSCs have been shown to suppress the lymphocyte proliferative response to allogenic or xenogenic antigens [21–23]. MSCs modulate the function of the major immune cell populations when stimulated by a mitogenic signal [24]. The inhibitory effect of MSCs on B lymphocytes was recently shown to occur through an arrest in the G0/G1 phase of the cell cycle and not through the induction of apoptosis [25]. MSCs are not sensitive to CD8+ cytotoxic T lymphocyte (CTL)-mediated lysis and are able to inhibit CTL cytotoxicity in a dose-dependent manner when present at CTL priming [26, 27]. Although MSCs were reported to be unable to activate natural killer (NK) cells [27], they inhibit interferon-
(IFN-) production by IL-2-stimulated NK cells [28] and are lysed by IL-2-activated NK cells [29, 30].
This suppressive effect of MSCs is dose-dependent, decreasing with lower amounts of MSCs in the mixed lymphocyte reaction, but a weak concentration of MSCs has been shown to have a stimulating effect on T-cell proliferation [31, 32]. The suppression of the immune response is mediated by soluble factors after MSC activation by culture in the presence of immune cells, but the identity of these soluble factors is still the subject of controversy.
MSCs Are a Source of Soluble Factors Involved in Angiogenesis
Multipotent stromal cells express several proangiogenic factors, including angiopoietin-1 (Ang1), vascular endothelial growth factor (VEGF), and growth factors such as platelet-derived growth factor, fibroblast growth factor 2 (FGF-2), and FGF-7, but also cytokines (IL-6, TNF-), as well as plasminogen activator [33, 34]. All these molecules act synergistically on endothelial cells to promote vasculogenesis and angiogenesis. Moreover, MSCs express chemokines such as IL-8, which is involved in the recruitment of endothelial progenitors [33]. Multipotent stromal cells have been shown to activate endothelial cells through soluble factors, as well as cell contacts between the two types of cells. Indeed, MSCs induce vascular endothelial growth factor receptor 2 (Flk-1) and Tie2 expression on the target cells, and cell coculture resulted in a high expression of VEGF and Ang1, the corresponding ligand [35]. Besides the promotion of angiogenesis, MSCs induce the expression of junction proteins, such as occludin, and an increase in microvascular integrity [35].
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ROLES OF MULTIPOTENT STROMAL CELLS IN CARCINOGENESIS |
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TopFootnotesAbstractGeneral Properties of...Roles of Multipotent Stromal...ConclusionDisclosure of Potential...AcknowledgmentsReferences |
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The homing of MSCs in whole animals was first investigated in the nontumoral context. It was shown that allogeneic and autologous MSCs distributed to a wide range of tissues in baboons, including the lung, thymus, bone, skin, cerebellum, and gastrointestinal tract [36]. In rats, injection of MSCs led to an engraftment in the lung and thereafter in the liver [37]. In mouse, MSCs home to many organs, including the lung, marrow, bone, skin, brain, and spleen [38]. In breast cancer patients, after i.v. infusion, human MSCs were detected in the circulation of some patients only within the first hour of injection [39]. Patients with severe osteogenesis imperfecta, injected with MSCs, displayed MSC engraftment in the marrow, the bone, and the skin [40], whereas MSC DNA was detected in the colon and lymph node of a patient treated with MSCs for steroid-resistant graft-versus-host-disease [41]. In summary, on the basis of these different studies, MSCs have the ability to home to a wide range of organs, without specificity. In the case of local inflammation, as in experimental autoimmune encephalomyelitis, Zappia et al. showed that MSCs injected i.p. migrated to the subarachnoïdal space in close contact with the immune cells [42]. This suggests that chronic inflammation might alter the homing of MSCs. In the context of cancer, Houghton et al. were the first to report, in a model of gastric cancer induced by helicobacter, that the transplantation of MSCs led to their engraftment into gastric glands [43].
A number of groups have been interested in the homing of MSCs toward glioblastoma. Using BM-MSCs, it was shown that injection of MSCs in the contralateral hemisphere into the carotid vein or the tail vein led to the homing of MSCs to the hemisphere bearing the tumor, suggesting that MSCs could cross the blood-brain barrier [44, 45].
MSCs are also able to target tumors that have been implanted subcutaneously (s.c.). Indeed, in a model of Kaposi's sarcoma (KS), human BM-MSCs injected intravenously (i.v.) home to sites of tumorigenesis [46]. When administered i.v., human AT-MSCs and colon cancer cells implanted s.c., and AT-MSCs are also able to home early after injection, primarily to tumor sites, the lungs, and the liver [47]. Other routes of administration of MSCs have been used, in particular intraperitoneal injections. Komarova et al. showed that BM-MSCs homed primarily to tumor sites, in a model of ovarian cancer in which intraperitoneally established xenografts were subsequently injected with MSCs [48].
A recurrent question was the ability of MSCs to migrate to the metastatic sites and, in particular, to the lung. BM-MSCs injected into the tail vein of nude mice migrate to the lung metastasis sites of mice bearing melanoma metastases [49, 50]. However, one might argue that in this type of setting, the ability of MSCs to migrate to metastatic sites is questionable, as many types of cells home to the lung when injected iv.
Collectively, these studies suggest that MSCs can migrate toward the primary tumor and metastatic sites, although the homing is not completely specific to tumor cell locations. Indeed, in most cases, MSCs were also able to colonize organs that did not bear tumor cells, such as lung, kidney, liver, or spleen. Therefore, one might question the fact that MSC tropism is clearly dictated by the presence of tumor cells. The efficiency of MSCs homing to tumors is also questionable, as there is no quantification of the percentage of MSCs, which really migrate to the carcinoma. One important point will also be to assess possible side effects of MSCs on other organs, as the homing of MSCs does not appear completely selective. Indeed, the engraftment sites of MSCs do not seem very different in the absence and the presence of carcinoma. Furthermore, it is also important to mention that the issue of the homing of MSCs has been raised by using MSCs that were injected in the animals. So far, there has been no demonstration that in the pathologic situation, MSCs detected in the primary tumor site originate from the local mesenchyme or from bone marrow. This will be a key issue for future developments of anticancer therapies based on MSCs.
Potential Effects of MSCs on Tumor Growth and Development
In addition to the homing ability of MSCs, the main controversial issue remains their ability to modulate tumor growth. The results arise both from in vitro studies and in vivo studies, either by coinjection in the same sites of tumor cells with MSCs or by the injection of MSCs at distance from the tumor. These studies are summarized in Figure 1.
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Inhibition of Tumor Growth. The inhibition of tumor growth by MSCs has been observed in different types of animal models. Maestroni et al. first reported in experimental models of Lewis lung carcinoma and B16 melanoma that the coinjection of mouse MSCs with tumor cells inhibited primary tumor growth [51]. Although the factors mediating the antitumor activity of MSCs were not identified by the authors, data from that study suggested that they were distinct from inflammatory cytokines [51]. The antiproliferative action of MSCs was also reported in a model of colon carcinogenesis in rats, in which the coinjection of MSCs with tumor cells in a gelatin matrix implanted s.c. led to growth inhibition [52]. In addition, the coinjection of both cells triggered a more pronounced infiltration of monocytes and granulocytes [52].
Rat MSCs have the ability to migrate toward glioma cells, to inhibit their proliferation, and, when implanted into the contralateral hemisphere, to migrate to the hemisphere bearing the tumor [44]. When injected directly into the tumor, human skin-derived stem cells (hSDSCs) also reduce brain tumor size [53]. hSDSCs were also able to reduce tumor progression in Tyrp1-Tag mice [53].
In an experimental model of KS, the authors demonstrated that systematically injected primary human MSCs exerted a potent tumor-suppressive effect on KS in vivo, through direct cell contact [46]. The in vivo tumor-suppressive effects of MSCs correlate with their ability to inhibit KS cell Akt activity, as KS cells expressing a constitutively activated form of Akt are no longer sensitive to i.v. MSC administration [46]. Collectively, these findings suggest that human malignancies characterized by a deregulated Akt may be specific targets of the antitumorigenic properties of MSCs.
Enhancement of Tumor Growth and Development. Several studies show that MSCs can increase tumor growth. Fetal or adult MSCs injected s.c. together with tumor cells can favor tumor growth [54]. This is accompanied by extensive necrosis and angiogenesis compared with mice injected only with tumor cells [54]. Similar results have been obtained with Raji cells that were injected s.c. [55]. MSCs can also favor the growth of tumor cells within the bone. Indeed, multiple myeloma malignancy (MM) leads to the formation of osteolytic lesions in the bone, which is enhanced by the interaction of MM with MSCs [56].
Immunosuppression could also be one explanation for the enhancement of tumor growth by MSCs. We have shown that, when injected s.c. into an allogenic recipient, melanoma cells lead to tumor formation only in the presence of MSCs [22]. Interestingly, the action of MSCs could take place when MSCs were coinjected at the same site as tumor cells or when MSCs were injected at distance [57].
Only a few studies have begun to identify the molecules involved in the enhancement of cancer cell proliferation by MSCs. Indeed, coculture or indirect interaction of MSCs with breast cancer cells enhances tumor cell proliferation, which suggests that soluble factors are involved in this phenomenon [58]. MM secretes the Wnt inhibitor Dickkopf-1 (Dkk1), which in turn prevents MSCs from differentiating into osteoblasts. On the other hand, MSCs secrete IL-6, which stimulates MM proliferation [56]. Furthermore, Sasser et al. reported that MSCs secrete high levels of IL-6, which in turn leads to the phosphorylation of signal transducer and activator of transcription 3 (STAT3) through a paracrine effect [59]. Estrogen receptor (ER)-positive breast tumor cell lines display a low basal activation of STAT3 until exposed to MSCs, which induces a chronic phosphorylation of STAT3 on tyrosine-705 [59]. ER-negative breast cancer cells, on the other hand, express constitutively phosphorylated STAT3. IL-6 exposure, in either a paracrine or an autocrine manner, increases ER-positive cell line growth. In vivo, ER-positive breast cancer cells transfected with IL-6 show enhanced growth [59].
No Apparent Effect. Some studies reported no effect on tumor growth. This was the case in a model of ovarian cancer, in which intraperitoneally established xenografts were subsequently injected with bone marrow MSCs [48], and also of human AT-MSCs, which did not modify colon cancer cell growth in vitro [47]. Human MSCs also seem to have no effect in most cases on tumor growth of breast cancer cells implanted s.c. in athymic mice [60]. The action of MSCs on cancer cell growth can be even more difficult to interpret, as they can have opposite effects in vitro and in vivo. Indeed, when cocultured in vitro with hematopoietic and nonhematopoietic cancer cells, MSCs display antiproliferative properties by triggering a cell cycle arrest in G1 phase on tumor cells [61]. In addition, MSCs also reduce the apoptotic rate of cancer cells. This inhibition is reversible by removing MSCs and affects mainly cyclin D-dependent kinase levels. On the other hand, MSCs favor the in vivo tumor growth when coinjected s.c. to NOD/SCID mice [61]. One other critical parameter seems to be the ratio of MSCs to cancer cells. We observed that murine MSCs coinjected with Renca tumor cells in syngeneic immunocompetent mice displayed different effects on the kinetics of subcutaneous tumor growth, depending on the proportion of each cell type. Indeed, the growth of the tumor was not affected by the coinjection of the same amounts of MSCs, but was increased in the presence of 10-fold more MSCs, although 10-fold fewer MSCs completely abolished tumor formation [57].
MSCs and Metastasis. So far, very few studies have addressed the question of the effects of MSCs on metastasis. It was shown that murine MSC could reduce metastasis in a model of Lewis lung carcinoma and B16 melanoma [51]. A more recent study with human MSCs showed that in most cases, MSCs did not modify the growth of human breast cancer xenograft [60]. However, the most striking result of this study was the fact that MSCs could increase the metastasis rate of breast cancer cells through secretion of Rantes (CCL5) by MSCs, suggesting that the main adverse role of MSCs was its proinvasive potential [60]. It is likely that other molecules participate in the enhancement of metastasis by MSCs, and this will be the challenge of future studies.
In summary, depending on the nature of cancer cells and MSCs, on the integrity of the immune system of the mice that were injected, and on the sites of injections, studies have reported inhibition, enhancement, and no apparent effect on tumor growth. One example of this complexity is shown in the study by Karnoub et al., which showed that human MSCs did not affect tumor growth of MDA-MB-231 and MDA-MB-435 cells but increased the one of MCF-7/Ras cells [60], suggesting that the nature of cancer cells is critical. For these reasons, if one wants to use MSCs in anticancer therapies, it will be essential to identify the factors produced by MSCs cells responsible for the inhibition or the enhancement of tumor growth and those governing the response of tumor cells. It is also interesting to note that cancer cells can modify the growth or migration of MSCs, making the picture even more complex. Indeed, when coinjected s.c. to nude mice with melanoma cancer cells, MSCs display an increased proliferation [49]. In addition, it was shown recently that MCP-1 (CCL2) secreted by breast cancer cells [62, 63] increased the migration of MSCs [64].
MSCs and Their Impact on Tumoral Angiogenesis
Angiogenesis of the developing neoplasia is a key event required for the optimal growth of the tumor and metastasis. MSCs could modulate this phenomenon, as suggested by some reports. By attracting endothelial cells and stimulating their proliferation, MSCs could contribute to metastasis development. This effect is related to expression of proangiogenic factors induced by interaction between carcinoma cells and MSCs. Indeed, when human MSCs are injected i.v. to SCID mice engrafted with melanoma cells, they colonize tumor vessels, which suggests that they could participate in angiogenesis [65]. Indirect evidence suggests that MSCs increase tumor growth through an enhancement of angiogenesis, as MSCs expressing truncated soluble vascular endothelial growth factor decoy receptor (tsFlk-1) had no effect on tumor growth, whereas unmanipulated MSCs increased both tumor growth and angiogenesis [55]. The direct injection of hSDSCs in brain tumors has also been shown to reduce angiogenesis [53].
MSCs and Malignant Transformation
As MSCs have the ability to expand, one might wonder whether these cells may also be the seed for new tumors. A number of approaches have been used to begin to answer this question. In particular, several groups analyzed whether MSCs could undergo spontaneous transformation or have attempted to engineer MSCs to determine whether they could be transformed. On the other hand, tumor MSCs have been isolated that show differentiation abilities that are often close to those of original MSCs.
Are MSCs Able to Transform In Vitro? The issue of spontaneous transformation of MSCs is a matter of debate and, if it exists, seems to be an exceptional event. Rubio et al. have shown that human AT-MSCs isolated from adipose tissue undergo spontaneous transformation after long-term culture (4–5 months) [66]. This transformation takes place through two sequential steps, including the upregulation of c-myc and the downregulation of p16. Then, the cells display an increased telomerase activity, deletion of Ink4a/Arf locus, and retinoblastoma hyperphosphorylation [67]. Moreover, a cell population of human BM-MSCs cultured extensively, with a high telomerase activity, is capable of forming solid tumors in multiple organs in mice [68]. However, this issue remains controversial, as other studies did not observe transformation of human BM-MSCs [69]. Mouse bone-marrow MSCs are also able to undergo spontaneous transformation, but these cells are grown in the presence of a large number of hematopoietic cells and require many passages before obtaining a homogeneous population, which could explain why mouse cells undergo a higher rate of transformation compared with human MSCs [70, 71]. A previous study also reported that gastric cancer could originate from BM-derived cells, presumably MSCs [43]. In addition, it was shown that in vitro-transformed MSCs form tumors in vivo [72]. The transformation of MSCs is associated with chromosomal abnormalities, increased levels of telomerase activity, and c-myc expression. In addition, transformed MSCs display a higher sensitivity to anticancer drugs such as etoposide compared with nontransformed MSCs [71]. In conclusion, it is possible that the way MSCs are expanded and long-term culture lead to transformation. The safety of using MSCs in humans remains in question. The use of MSCs in patients should definitely require precise and limited procedures of expansion to avoid the risk of injecting transformed cells.
Factors Inducing Transformation of MSCs In Vitro. The immortalization and/or transformation of MSCs can also be triggered by the introduction of oncogenes. Indeed, human MSCs can be immortalized using HPV16 E6/E7 genes without neoplastic transformation, although the conditions of culture used by the authors could explain this result [73]. These cell lines retain the ability to differentiate into osteoblasts, chondroblasts, adipocytes, and neurons [73]. On the other hand, the transduction of MSCs with telomerase reverse transcriptase is sufficient to induce their transformation, leading to a population of cells with loss of contact inhibition, anchorage independence, and tumor formation in vivo [74, 75]. Human MSCs do not express human telomerase reverse transcriptase (hTERT). hTERT expression is indeed repressed in MSCs through hypoacetylation of hTERT promoter [76]. Furthermore, human MSCs immortalized with hTERT and Bmi1 (a repressor of p16INK4A) and then transformed with H-RAS display anchorage-independent growth and increased invasion ability [77]. They retain adipogenic and chondrogenic differentiation ability but not the osteogenic potential.
MSCs Are Targets of Oncogenic Processes. In patients, other oncogenes also have the potential to transform MSCs. This is the case for Ewing's sarcoma (EWS)-FLI1, which is involved in the etiology of Ewing tumors (ET). ET, a bone tumor observed in adolescents and young adults, harbors characteristic translocations that fuse a portion of the EWS gene with encoding DNA-binding domain of one of five E twenty-six (ETS) family genes [78]. The resulting EWS-FLI1 chimeric protein is thought to induce transformation. The introduction of EWS-FLI1 into MSCs is sufficient to transform them, and the resulting cells display the hallmarks of Ewing tumors [79]. Conversely, Tirode et al. have shown that Ewing cells, inhibited for EWS-FLI1 by a specific short hairpin RNA, display an MSC phenotype with the ability to differentiate into adipogenic and osteogenic lineages, suggesting that Ewing tumors could originate from MSC progenitors [80].
Are MSCs Found in Tumors Identical to Bone-Marrow MSCs? Several teams have compared the properties of nonpathological MSCs with those of tumor MSCs. MSCs from MM patients exhibited a normal phenotype and adipogenic and osteogenic differentiation capacity but a reduced efficiency to inhibit T-cell proliferation [81]. The comparison of bone marrow MSCs between healthy patients and MM patients showed a limited number of modifications, as only 145 genes, which are mainly involved in the tumor microenvironment (such as IL-1β, IL-6, SDF-1/CXCL12), were differentially expressed [81, 82]. Giant cell tumors of bone (GCT) cells can also differentiate into osteoblasts, as well as chondroblasts and adipocytes, suggesting that GCT stromal cells could originate from MSCs [83].
In summary, MSCs have the ability to transform spontaneously or to be transformed with natural oncogenes. This could represent a major limitation of their therapeutic use. Moreover, the comparison of MSCs found in healthy patients with those found in patients harboring a cancer indicates that these MSCs seem to have different transcriptomes. It will be essential to determine whether MSCs found in tumors originate from the site of the tumor itself or whether they come from the bone marrow.
Cross-Talk Between MSCs and Bone Cells
It appears very likely that MSCs could also affect metastasis development, in particular bone metastasis, because of their presence in great amounts in this location. Whether MSCs favors metastasis development or, on the contrary, could counteract osteolysis remains controversial. On the basis of several studies, it seems that cancer cells divert MSCs from their original functions to force them to participate in osteolysis. Sohara et al. showed that neuroblastoma cells could induce osteolytic lesions but that tumor cells could not directly activate osteoclasts [84]. This activation occurs through MSCs, but MSCs alone do not have bone-resorbing properties. In vitro, the activation of osteoclasts does not require a direct contact with tumor cells or MSCs, nor the direct interaction of tumor cells with MSCs. The coculture of tumor cells with MSCs dramatically increases the secretion of IL-6 by MSCs, which is an essential mediator of osteoclast activation. Cancer cells also secrete factors such as Dkk1, which in turn prevents MSCs from differentiating into osteoblasts [56]. On the other hand, it seems possible to use MSCs as cellular therapy to regenerate the bone. Indeed, MSC inoculation is associated with enhanced bone mineral density and the differentiation of MSCs in osteoblasts, even though these MSCs have mixed effects, as tumor growth decreased in some animals but not in others [85].
Innovative Cancer Therapy Through Engineering of MSCs
MSCs possess numerous properties that might make them an attractive choice as a cell-mediated gene therapy in human malignancies [46, 50]. MSCs have been shown to express transgenes efficiently and for an extended period without any defect in their stem cell properties [86]. If their ability to home to tumor sites is further demonstrated, MSCs might represent an attractive tool to deliver anticancer drugs to the carcinoma. To achieve this, MSCs have been engineered in a number of different ways, either to deliver cytotoxic drugs, to stimulate the immune response, or to block angiogenesis.
The first engineered MSCs were modified to express IFN-β and were able to inhibit the growth of melanoma cells in vitro and in vivo [49, 50]. Bone marrow MSCs engineered to express IFN- are also able to inhibit leukemia cell proliferation in vitro and to trigger their apoptosis [87]. Furthermore, MSCs infected with an adenovirus or retrovirus encoding IL-12 and injected i.p. to mice 1 week before s.c. injection of melanoma cells, hepatoma cells, or lung cancer cells are potent inhibitors of tumor growth [88, 89]. The observed antitumoral effect of MSCs-IL-12 was mediated primarily by activation of NK cells and CD8+ T cells in the inhibition of metastasis formation and primary tumor growth.
In a recent report, adenovirally engineered primary mouse MSCs used to express the immunostimulatory chemokine CX3CL1 were i.v. injected into syngeneic immunocompetent recipient bearing lung metastases of C26 colon carcinoma or B16 melanoma cells. These engineered MSCs were able to target tumoral but not normal tissue, inducing both innate and adaptive anticancer immunity response and thus prolonging the animals' survival [90]. Mouse MSCs adenovirally transduced to express human NK4, an antagonist of hepatocyte growth factor, also exert potent antitumorigenic effects by inhibiting tumor-associated angiogenesis and lymphoangiogenesis (two processes that are normally mediated by hepatocyte growth factor (HGF)-c-met signaling pathway) and by inducing tumor cell apoptosis [90].
A number of laboratories have used conditional replicative adenovirus (CRAds)-loaded MSCs to inhibit tumor growth. Stoff-Khalili et al. showed that i.v. injection of MSCs infected with CRAds (expressing E1A under the control of CXCR4 promoter) strongly decreased the development of pulmonary metastases of breast cancer cells [91]. On the other hand, MSCs alone had no effect on metastasis development [91]. In a model of ovarian cancer, intraperitoneally established xenografts were subsequently injected with MSCs [48]. MSCs were infected with an adenovirus (Ad5/3) that has a chimeric fiber where the knob of the Ad5 fiber is replaced by that of the Ad3. MSCs-Ad5/3 exert an oncolytic effect on ovarian cells in vitro and in vivo.
Interestingly, MSCs have been shown to be more resistant to irradiation compared with tumor cells [92]. They possess a better antioxidant reactive oxygen species-scavenging capacity and active double-strand break repair, which could facilitate their radioresistance. This could be of great interest for novel anticancer therapies. To use such properties, Kucerova et al. took advantage of human AT-MSCs, which were engineered to express cytosine deaminase (CD-AT-MSCs) [47]. Interestingly, AT-MSCs and, to a lesser degree, CD-AT-MSCs were less sensitive to 5-FU than cancer cells. In addition, CD-AT-MSCs inhibit the growth of colon carcinoma cells in vitro and in vivo in the presence of 5-fluorocytosine (5-FC), whereas AT-MSCs had no effect on cancer cells in the absence and the presence of 5-FC.
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CONCLUSION |
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TopFootnotesAbstractGeneral Properties of...Roles of Multipotent Stromal...ConclusionDisclosure of Potential...AcknowledgmentsReferences |
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST |
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TopFootnotesAbstractGeneral Properties of...Roles of Multipotent Stromal...ConclusionDisclosure of Potential...AcknowledgmentsReferences |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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