Mesenchymal stem cells (MSC) have received much attention in the field of hematopoietic stem cell transplantation because not only do they support hematopoiesis but also exhibit a profound immunosuppressive activity that can be exploited to prevent undesired alloreactivity. We have previously shown that their immunosuppressive activity is mainly exerted at the level of T-cell proliferation. Here, we show that MSC exhibit a similar antiproliferative activity on tumor cells of hematopoietic and non hematopoietic origin. In vitro, MSC produced the transient arrest of tumor cells in the G1 phase of cell cycle; this was accompanied by a reduction in the apoptotic rate even when survival factors were limiting. However, when tumor cells were injected into non-obese diabetic–severe combined immunodeficient mice in conjunction with MSC, their growth was much faster as compared to the group receiving only tumor cells. To explain the discrepancy between the in vitro and in vivo behavior, we suggest that MSC have the ability to form a cancer stem cell niche in which tumor cells can preserve the potential to proliferate and sustain the malignant process. We conclude that the clinical use of MSC in conditions in which a malignant disease is involved should be handled with extreme caution.
Mesenchymal stem cells (MSC) constitute a rare non-hematopoietic population in the adult bone marrow (BM), which can be defined according to its ability to self-renew and differentiate into tissues of mesodermal origin (osteocytes, adipocytes, chondrocytes).1, 2 They are progenitors of bone marrow stroma and thus play a crucial role in supporting hematopoiesis3, 4 by providing hematopoietic progenitors, the necessary cytokines and cell contact-mediated signals to self-renew and/or differentiate.5 It has also been widely demonstrated that MSC exhibit a potent immunosuppressive activity, which targets virtually all types of immune cells of both lymphoid and myeloid lineage. There is evidence that such a broad activity results from a selective inhibition of cell cycle at early stages of cell commitment (G0/G1)6 and whereas cell proliferation is vigorously reduced, most of immune effectors functions are substantially preserved.
Because of these properties, MSC have been tested for therapeutic applications in the field of hemopoietic stem cell (HSC) transplantation whereby preliminary evidence suggests that they improve HSC engraftment7 and suppress graft-versus-host disease after allogeneic HSC transplantation.8, 9 Large unphysiological numbers of MSC are apparently required for clinical efficacy. As these therapeutic applications often involve malignant conditions, investigating the effect of MSC on tumor cells is mandatory. Furthermore, such a question becomes critical in view of the fact that the development and progression of some tumors depends on the surrounding stroma, which consists of cells deriving from bone marrow stromal precursors. Several studies have outlined a direct effect of stromal fibroblasts in cancer initiation and progression, especially in epithelial tumors.10, 11
Although some studies have observed that these cells inhibit tumor growth in murine12 and rat13, 14 models, others have demonstrated an opposite effect.15, 16 Depending on the system used, MSC have been shown to favor tumor growth either by promoting their invasive abilities via the activation of matrix metalloproteinases15 and neoangiogenesis16 or by preventing tumor cells recognition by the immune system.17 Regardless of the effect on tumor growth and progression, most studies have documented a selective migration of MSC to the tumor site and this property has been successfully exploited in animal models to deliver therapeutic molecules using MSC transduced with specific genes.18
Here, we show that although human MSC exhibit a potent antiproliferative activity in vitro on different tumor cell lines, this effect is transient and when assessed in vivo, it results in facilitation of tumor engraftment and growth. Similarly to what observed for T cells, MSC induce the downregulation of cyclin D2 and thus halt tumor cells in the G1 phase of the cell cycle. Such a effect is transient and reduces the proportion of spontaneous apoptosis associated with proliferation. Our findings suggest that MSC may preserve the self-renewal ability of cancer cells and a new mechanism by which stromal environment can influence the course of malignant diseases. The clinical use of large doses of MSC in the treatment strategies of malignant conditions might therefore favor the establishment of a tumor niche with long-term proliferative potential.
Materials and methods
Generation of MSC
Ten to 20 ml of BM suspensions cells were obtained from normal donors, ranging in age from 20 to 50 years. All samples were obtained with written, informed consent in accordance with the Hammersmith Hospital and Queen Charlotte's Hospital ethical committee requirements. To isolate MSC, ficolled BM mononuclear cells (Ficoll-Paque, Amersham-Phamarcia, Piscataway, NJ, USA) were plated in 25 cm2 flasks (Costar, Cambridge, MA, USA) at a concentration of 1 × 106/ml in Dulbecco's modified Eagle's medium (DMEM), with high glucose concentration, GLUTAMAX I (Gibco BRL, Gaitherburg, MD, USA), 10% fetal bovine serum (Stem Cell Technology Inc., London, UK), 100 U/ml penicillin and 100 μg/ml streptomycin (Gibco BRL). After 72 h incubation at 37°C in a 5% CO2 atmosphere, non-adherent cells were removed. When 70–80% confluent, adherent cells were trypsinized and expanded for 3–5 weeks. Before their use in the experiments, MSC were checked for positivity of CD105, CD106, CD73, HLA-class I, and the lack of expression of CD45.
Tumor cell lines
BV173 is derived from a lymphoid blast crisis of chronic myeloid leukemia (CML);19 K562 is an undifferentiated erythroleukemia cell line derived from a CML in blast crisis;20 KG1a is an undifferentiated blast cell line from acute myelogenous leukemia;21 the Jurkat cell is a human T-cell leukemia line22 and COLO 320DM (CC3) is a semi-adherent colon adenocarcinoma cell line.23 The Epstein–Barr virus -infected B cell line wS9-B-LCL/B was provided by G Lombardi (King's College, London, UK), whereas the small-cell lung cancer cell line UCH10 is a kind gift of P Beverley (Edward Janner Institute, Berkshire, UK). All cells were grown in Rosewell's Park Memorial Institute (RPMI) (Gibco, BRL) supplemented 10% fetal bovine serum (FBS) (Labtech International, Sussex, UK) and 1% antibiotic/antimycotic solution (Gibco, BRL). Cells were incubated at 37°C in 5% CO2 humidified cell culture incubator and fed every 2 days.
Cell proliferation assays were performed in round-bottom 96-well plates (Costar, Cambridge, MA, USA) in a total volume of 0.2 ml RPMI 1640 supplemented with 10% fetal calf serum (FCS), GLUTAMAX I (Gibco, BRL, Life Technologies Ltd, UK), 50 U/ml penicillin and 50 μg/ml streptomycin. A total of 0.5 μCi/well of [3H]-thymidine (ICN, Costa Mesa, CA, USA) was added after 5 days of culture and the cells were harvested 18 h later onto glass fiber filters using an LKB 96 well-harvester (Wallac Oy, Turku, Finland). [3H]thymidine uptake was measured on an LKB Betaplate counter (Wallac Oy). The results are expressed as mean count per minute for triplicate cultures (standard errors were routinely <10%).
For surface marker immunophenotyping, cells were incubated with the specific monoclonal antibody for 30′ at room temperature and then analyzed after extensive washing with phosphate-buffered saline (PBS). Background fluorescence was subtracted after analyzing unstained cells and cells stained with the relevant isotype control.
For cell cycle analysis, bromodeoxyuridine (BrDU; Sigma Aldrich, St Louis, MO, USA) was added to cell cultures for 1 h before cell harvest and fixed in 70% ethanol. Fixed cells were treated with 0.5% Triton-X-2M HCl (Sigma Aldrich) for 30 min to denature the DNA and neutralized by sodium tetraborate (Na2B4O7·10H2O, pH 8.5, Sigma Aldrich). Cells were stained with 5 μl of anti-BrDU-fluoroscein isothiocyanate antibody; after 30 min, 1 ml of PBS containing 5 μg/ml propidium iodide (PI; Sigma, St Louis, USA) was added before flow cytometry analysis using a fluorescence-activated cell sortiong (FACS) Calibur cytofluorimeter (Becton Dickinson, San Jose, CA, USA).
Non-obese diabetic–severe combined immunodeficient (NOD/SCID) mice used in vivo study were obtained from Jackson Laboratories (Bar Harbor, ME, USA), bred and maintained in a pathogen-free environment at Cancer Research UK Laboratories. Mice used were between 6 and 10 weeks of age and all procedures were carried out in accordance with the Home Office Animal (Scientific Procedures) Act of 1986. Mice did not receive any conditioning before receiving the cells that were administered subcutaneously in a total volume of 0.2 ml sterile phosphate-buffered saline (PBS). At autopsy, spleen, liver, BM, lymph nodes and the tumor (when applicable) were removed and fixed in 10% neutral buffered formalin solution for histologic preparations (BM was decalcified in 10% formalin/5% formic acid).
Cell suspensions were lysed in Nonidet P-40 lysis buffer (1% Nonidet P-40, 100 mM NaCl, 20 mM Tris-HCl pH 7.4, 10 mM NaF, 1 mM sodium orthovanadate, 30 nM Na-glycerophosphate) and protease inhibitors (Roche Applied Science, Basel, Switzerland) in ice for 15 min. Protein concentration was determined by Bio-Rad Dc protein assay (BioRad Lab Ltd, Hertfordshire, UK). Twenty five micro grams of proteins were electrophoretically separated by 7 and 10% SDS-polyacrylamide gel electrophoresis (SDS-PAGE) gels (Invitrogen-Novex, Carlsbad, CA, USA), transferred onto Protran Nitrocellulose transfer membranes (Schleicher and Schnell) and the membranes were incubated with the following primary antibodies: cdk4, cyclin D2, cyclin E, cyclin A, p27Kip1 and actin as control (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA). The immune complexes were detected using horseradish peroxidase-linked anti-mouse or anti-rabbit conjugates as appropriate (DAKO, Glostrup, Denmark) and visualized using enhanced chemiluminescence detection system (Amersham Biosciences, Amersham, UK).
MSC inhibit the proliferation of malignant cells of hematopoietic and non-hematopoietic origin
We studied the effect of MSC on the proliferative activity of malignant cells of different lineages. Tumor cell lines of hematopoietic (BV173, K562, Jurkat, KG1a and wS9-B-LCL) and non-hematopoietic (UCH10 and CC3) origin were cultivated, at different ratios, in the presence of MSC and tested for their proliferative activity after 3 days of co-culture. MSC exhibited a dose-dependent antiproliferative effect on all cell lines investigated (Figure 1a and b).
Soluble factors are involved into the anti-proliferative effect exerted by MSC
It has been shown that soluble factors contribute to the immunosuppressive effect of human MSC.24, 25 To examine whether the MSC-induced inhibition of tumor cells proliferation was mediated by soluble factors, MSC were cultured physically separated from BV173 cells using a transwell system or replaced by their culture supernatants. An inhibitory effect was detected in both conditions, although its magnitude was inferior as compared to the cultures in which MSC were in physical contact with the tumor cells (Figure 1c). The addition of escalating doses of anti-TGFβ blocking antibodies to the culture failed to restore tumor proliferation (data not shown), thus reasonably excluding a role of TGFβ in the MSC mediated inhibitory effect.
MSC favor tumor growth in vivo
To investigate the effect of MSC on the in vivo growth of tumor cells, we assessed in NOD-SCID mice the kinetic growth of tumor cells in presence of MSC. Mice received 106 BV173 cells with or without 0.5 × 106 MSC by subcutaneous injection. After 8 weeks, in three different experiments, the 75% of the mice co-injected with BV173 and MSC developed tumors at the site of injection, whereas only the 12% of animals receiving BV173 alone showed signs of tumor growth (Figure 2a). The tumor cell suspensions expressed the phenotype of human B cells and did not contain any detectable levels of MSC as assessed by CD105 staining (Figure 2b). BM from all mice was finally evaluated for the engraftment of tumor cells and MSC. Of the mice receiving MSC, only those which developed the tumor showed a small proportion of MSC in their BM as identified by the co-expression of CD105 and human major histocompatibility complex (MHC) class I. No presence of tumor cells (CD19+/human MHC class I+ coexpression) was detected in the BM of any of the animals, irrespective of whether they had developed the tumor (Figure 3a). However, when BM cells were cultivated for 2 weeks, a population with the phenotypic features of BV173 took over (Figure 3b). At subsequent analysis, these cells exhibiting indefinite self-renewal ability in vitro.
MSC transiently arrest tumor cells in the G1 phase of the cell cycle
In order to explain the discrepancy between the in vitro and in vivo findings, we characterized the effect of MSC on the cell cycle and survival of tumor cells. BV173 cells were cultured in the presence of MSC and tumor cells harvested for cell cycle analysis. BrDU incorporation of tumor cells was dramatically reduced in the presence of MSC (8 versus 29%) (Figure 4a and b), the analysis showed an accumulation of tumor cells predominantly in G1 phase (Figure 4c and d).
In order to determine the durability of the MSC-mediated inhibition of the proliferation, tumor cells were co-cultured with MSC for 48 h, then tumor cells were harvested, separated from MSC and re-plated for 24 or 48 h to be assessed for their proliferative ability. After MSC removal, BV173 cells recovered from the inhibitory effect by 40 and 90% at 24 and 48 h, respectively (Figure 5).
To identify the mechanism by which tumor cell cycle is arrested by MSC, we evaluated the expression of the principal molecules involved in cell cycle regulation. BV173 were cultured in the presence or absence of MSC; 48 and 72 h later the cells were examined by Western blotting for the expression of cyclin D2, cyclin A, cyclin E, cdk4 and p27Kip1 as G0/G1 and S phase specific markers, respectively. In the presence of MSC, the expression of positive cell cycle regulators, such as cyclin D2, were dramatically downregulated as compared to control cultures. Noticeably, the presence of MSC in culture determined a similar level of inhibition of p27Kip1 and was associated with a reduction in the expression of cdk4 (Figure 6). The removal of MSC and the subsequent culture of tumor cells in the absence of them restored the expression of the inhibited proteins at the normal levels.
MSC reduce the apoptosis of tumor cells
Our findings suggest that the inhibitory effect of MSC on tumor cell cycle is reversible. Although this may result from an insufficient exposure of tumor cells to MSC (48 h) and the lack of inhibitory effect in vivo appears to rule this out. However, the reversibility of the effect does not justify the better engraftment and faster in vivo growth. To address this issue, we looked at the effect of MSC on tumor cell apoptosis. When BV173 cells were co-cultured with MSC the proportion of apoptotic cells, as measured by Annexin-V and 7-ADD staining, was significantly reduced (Figure 7a). The effect was more dramatic when the experiment was repeated in conditions with low concentrations of FCS (2 and 1%) which favor apoptosis (Figure 7b and c).
Much attention has recently been paid to the ability of MSC to inhibit immune responses. The relative paucity of MSC even in the BM which is the major source of this cell type raises the issue of the physiological significance of their immunosuppressive effect. We have previously shown that MSC-mediated immunosuppression is produced via an antiproliferative effect whereby target cells are arrested at the early stages of cell cycle.6 In this study, we have tested the possibility that the described effects exerted by MSC on the cell cycle of immune cells can also be produced on other cell types. Our findings demonstrate that the ‘immunosuppressive’ effect mediated by MSC should be ascribed to a nonspecific anti-proliferative effect. In fact, human MSC inhibit the proliferation of cells of lymphoid, myeloid and erythroid origin as well as cells of non hematopoietic origin (Figure 1).
Another important conclusion is that MSC have the ability to interfere with the proliferation of tumor cells, in which the deregulation of cell cycle derive from very diverse pathways. Although an antitumor effect might have dramatic therapeutic implications, the results obtained from our animal studies apparently contradict the in vitro results (Figure 2). In fact, mice injected with the tumor in the presence of MSC had a much faster tumor growth than those which did not receive any MSC. Although the transient nature of the inhibitory effect of MSC on tumor cell proliferation might justify the discrepancy (Figure 5), the faster tumor growth observed in animals injected with MSC indicates that the MSC are not merely passive bystanders but actively promote tumor progression. In vivo results, similar to ours, have recently been described by Zhu et al.16; using immunodeficient BALB/c-nu/nu mice, they observed that mice which were injected with tumor cells and MSC had a much higher incidence of tumor formation as compared with controls.
A potential mechanism for tumor growth facilitation could be related to the systemic immunosuppression exerted by MSC.17 Although NOD/SCID mice are fairly good recipients for human cells, they still retain some residual immunity and the MSC-mediated immunosuppression might further improve the environmental conditions for engraftment.
However, MSC are precursors to BM stroma and there is evidence that they may contribute to tumor stroma. Tumor stroma plays a fundamental role in tumor growth, invasion and dissemination,26 and its characterization can be used as a prognostic factor in some cancer patients.27 During tumor progression, stromagenesis occur in parallel with tumorigenesis favoring tumor metastases by generating new vessels.28, 29 Although this is a valid and already recognized mechanism by which stroma supports tumor progression, it does not appear to be the predominant one in our model because the analysis of the tumor tissues failed to show the presence of MSC. Therefore, the effect of MSC responsible for tumor growth facilitation must have occurred at an earlier stage. The concentration and/or the half-life of the soluble factors responsible for the antiproliferative effect are probably not sufficient to maintain tumor cells in a quiescent state for a long time, but are adequate to initially confer the proliferative advantage. The in vitro molecular data showed that tumor cells that had been in contact with MSC were in a resting state (G0/G1) (Figure 4) and downregulated cyclin D2 (Figure 6). Because of its transient nature, such inhibition is likely to confer tumor cells a better survival by preserving their proliferative capacity and thus their self-renewal ability. This interpretation is consistent with our findings that the MSC-induced cell cycle arrest is accompanied by a substantial reduction of tumor cell apoptosis, particularly evident when growth and survival factors are limiting (Figure 7).
The quiescence of stem cells has been surmised to be of critical importance in protecting the stem cell compartment, because when they embark on a high proliferative activity their longevity is dramatically reduced.30 Cell cycle proteins have been shown to play a major role in the preservation of stem cell exhaustion and cyclin-dependent kinase inhibitors (CKI) appear to intervene in a cell-autonomous manner.31 The deficiency of the late G1-phase CKI protein P21cip1/waf1 results in increased cycling in hematopoietic stem cells with consequent reduction in their self-renewal ability.32 On the contrary, the upstream deletion of the early G1-phase CKI p18INK4C improves stem cell self-renewal.33 MSC seem to intervene at a very early stage of the cell cycle, thus supporting the notion that they favor long-term hematopoiesis. Considering the emerging evidence that not every cell within a cancer has tumor-initiating capacity, but that also tumors require a stem cell to be maintained, our findings suggest a completely new function of MSC, and possibly stroma, on tumor cells. This might account for the observation that, in some circumstances, tumor cells metastasizing to the BM remain dormant and can only be detected by sensitive methods.34
We suggest that MSC have the ability to form a cancer stem cell niche in which tumor cells preserve their self-renewal ability and thus the potential to proliferate and sustain the malignant process. Therefore, much caution should be used in the therapeutic exploitation of MSC in the context of malignant conditions.
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This work was funded by Leukemia Research Fund and Cancer Research-UK. R Ramasamy is supported by MOSTI Scholarship - University Putra Malaysia. I Soeiro is supported by a PhD studentship from Fundação para a Ciência e a Tecnologia, Portugal.
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Ramasamy, R., Lam, EF., Soeiro, I. et al. Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth. Leukemia 21, 304–310 (2007). https://doi.org/10.1038/sj.leu.2404489
- mesenchymal stem cells
- cell cycle
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