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      Mesenchymal stromal cells induce epithelial-to-mesenchymal transition in human colorectal cancer cells through the expression of surface-bound TGF-β

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          Abstract

          Mesenchymal stem/stromal cells (MSC) are multipotent precursors endowed with the ability to home to primary and metastatic tumor sites, where they can integrate into the tumor-associated stroma. However, molecular mechanisms and outcome of their interaction with cancer cells have not been fully clarified. In this study, we investigated the effects mediated by bone marrow-derived MSC on human colorectal cancer (CRC) cells in vitro and in vivo. We found that MSC triggered epithelial-to-mesenchymal transition (EMT) in tumor cells in vitro, as indicated by upregulation of EMT-related genes, downregulation of E-cadherin and acquisition of mesenchymal morphology. These effects required cell-to-cell contact and were mediated by surface-bound TGF-β newly expressed on MSC upon coculture with tumor cells. In vivo tumor masses formed by MSC-conditioned CRC cells were larger and characterized by higher vessel density, decreased E-cadherin expression and increased expression of mesenchymal markers. Furthermore, MSC-conditioned tumor cells displayed increased invasiveness in vitro and enhanced capacity to invade peripheral tissues in vivo. Thus, by promoting EMT-related phenomena, MSC appear to favor the acquisition of an aggressive phenotype by CRC cells.

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          Most cited references28

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          Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals.

          Mesenchymal stem cells (MSCs) are largely studied for their potential clinical use. Recently, they have gained further interest after demonstration of an immunosuppressive role. In this study, we investigated whether in vivo injection of MSCs could display side effects related to systemic immunosuppression favoring tumor growth. We first showed in vitro that the murine C3H10T1/2 (C3) MSC line and primary MSCs exhibit immunosuppressive properties in mixed lymphocyte reaction. We demonstrated that this effect is mediated by soluble factors, secreted only on "activation" of MSCs in the presence of splenocytes. Moreover, the immunosuppression is mediated by CD8+ regulatory cells responsible for the inhibition of allogeneic lymphocyte proliferation. We then demonstrated that the C3 MSCs expressing the human bone morphogenetic protein 2 (hBMP-2) differentiation factor were not rejected when implanted in various allogeneic immunocompetent mice and were still able to differentiate into bone. Importantly, using a murine melanoma tumor model, we showed that the subcutaneous injection of B16 melanoma cells led to tumor growth in allogeneic recipients only when MSCs were coinjected. Although the potential side effects of immunosuppression induced by MSCs have to be considered in further clinical studies, the usefulness of MSCs for various therapeutic applications still remains of great interest.
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            Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability.

            Transforming growth factor-beta (TGF-beta) is a potent inhibitor of epithelial cell growth. Human colon cancer cell lines with high rates of microsatellite instability were found to harbor mutations in the type II TGF-beta receptor (RII) gene. Eight such examples, due to three different mutations, were identified. The mutations were clustered within small repeated sequences in the RII gene, were accompanied by the absence of cell surface RII receptors, and were usually associated with small amounts of RII transcript. RII mutation, by inducing the escape of cells from TGF-beta-mediated growth control, links DNA repair defects with a specific pathway of tumor progression.
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              Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging.

              Multipotent mesenchymal stromal/stem cells (MSC) have shown potential clinical utility. However, previous assessments of MSC behavior in recipients have relied on visual detection in host tissue following sacrifice, failing to monitor in vivo MSC dispersion in a single animal and limiting the number of variables that can be observed concurrently. In this study, we used noninvasive, in vivo bioluminescent imaging to determine conditions under which MSC selectively engraft in sites of inflammation. MSC modified to express firefly luciferase (ffLuc-MSC) were injected into healthy mice or mice bearing inflammatory insults, and MSC localization was followed with bioluminescent imaging. The inflammatory insults investigated included cutaneous needle-stick and surgical incision wounds, as well as xenogeneic and syngeneic tumors. We also compared tumor models in which MSC were i.v. or i.p. delivered. Our results demonstrate that ffLuc-expressing human MSC (hMSC) systemically delivered to nontumor-bearing animals initially reside in the lungs, then egress to the liver and spleen, and decrease in signal over time. However, hMSC in wounded mice engraft and remain detectable only at injured sites. Similarly, in syngeneic and xenogeneic breast carcinoma-bearing mice, bioluminescent detection of systemically delivered MSC revealed persistent, specific colocalization with sites of tumor development. This pattern of tropism was also observed in an ovarian tumor model in which MSC were i.p. injected. In this study, we identified conditions under which MSC tropism and selective engraftment in sites of inflammation can be monitored by bioluminescent imaging over time. Importantly, these consistent findings were independent of tumor type, immunocompetence, and route of MSC delivery.
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                Author and article information

                Journal
                Int J Cancer
                Int. J. Cancer
                ijc
                International Journal of Cancer. Journal International du Cancer
                BlackWell Publishing Ltd (Oxford, UK )
                0020-7136
                1097-0215
                01 June 2014
                30 January 2014
                : 134
                : 11
                : 2583-2594
                Affiliations
                [1 ]Institute of Surgical Research and Hospital Management (ICFS) and Department of Biomedicine, University Hospital Basel, University of Basel Basel, Switzerland
                [2 ]Institute of Pathology, University of Basel Basel, Switzerland
                [3 ]Department of Biomedicine, University of Basel Basel, Switzerland
                [4 ]Department of Anatomy, University of Naples “Federico II” Naples, Italy
                [5 ]Department of Rheumatology, University of Basel Basel, Switzerland
                [6 ]Department of Surgery, University Hospital Basel Basel, Switzerland
                Author notes
                Correspondence to: Valentina Mele, Institute of Surgical Research and Hospital Management (ICFS) and Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland, Tel.: +41-61-265-2376, Fax: +41-61-265-3990, E-mail: valentina.mele@ 123456usb.ch
                Giandomenica Iezzi, Institute of Surgical Research and Hospital Management (ICFS) and Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland, Tel.: +41-61-265-2376, Fax: +41-61-265-3990, E-mail: giandomenica.iezzi@ 123456usb.ch

                Grant sponsor: Swiss National Science Foundation; Grant numbers: 31003A-122235, 310030-127490, PMPD33-118653 and PP00P3-133699; Grant sponsor: Freiwillige Akademische Gesellschaft (FAG); Grant sponsor: Kommission für Technologie und Innovation; Grant number: 10761

                Article
                10.1002/ijc.28598
                4338537
                24214914
                7c39872c-487e-42bf-9405-a4bd568b425e
                © 2013 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 22 January 2013
                : 22 October 2013
                Categories
                Cancer Cell Biology

                Oncology & Radiotherapy
                colorectal cancer,msc,emt,surface-bound tgf-β
                Oncology & Radiotherapy
                colorectal cancer, msc, emt, surface-bound tgf-β

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