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      Growth inhibition of colorectal carcinoma by lentiviral TRAIL-transgenic human mesenchymal stem cells requires their substantial intratumoral presence

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          Abstract

          Colorectal carcinoma (CRC) constitutes a common malignancy with limited therapeutic options in metastasized stages. Mesenchymal stem cells (MSC) home to tumours and may therefore serve as a novel therapeutic tool for intratumoral delivery of antineoplastic factors. Tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) which promises apoptosis induction preferentially in tumour cells represents such a factor. We generated TRAIL-MSC by transduction of human MSC with a third generation lentiviral vector system and analysed their characteristics and capacity to inhibit CRC growth. (1) TRAIL-MSC showed stable transgene expression with neither changes in the defining MSC characteristics nor signs of malignant transformation. (2) Upon direct in vitro coculture TRAIL-MSC induced apoptosis in TRAIL-sensitive CRC-cell lines (DLD-1 and HCT-15) but also in CRC-cell lines resistant to soluble TRAIL (HCT-8 and SW480). (3) In mixed subcutaneous (s.c.) xenografts TRAIL-MSC inhibited CRC-tumour growth presumably by apoptosis induction but a substantial proportion of TRAIL-MSC within the total tumour cell number was needed to yield such anti-tumour effect. (4) Systemic application of TRAIL-MSC had no effect on the growth of s.c. DLD-1 xenografts which appeared to be due to a pulmonary entrapment and low rate of tumour integration of TRAIL-MSC. Systemic TRAIL-MSC caused no toxicity in this model. (5) Wild-type MSC seemed to exert a tumour growth-supporting effect in mixed s.c. DLD-1 xenografts. These novel results support the idea that lentiviral TRAIL-transgenic human MSC may serve as vehicles for clinical tumour therapy but also highlight the need for further investigations to improve tumour integration of transgenic MSC and to clarify a potential tumour-supporting effect by MSC.

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          Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone.

          Edwin M Horwitz, Patricia L Gordon, Winston K K Koo … (2002)
          Treatment with isolated allogeneic mesenchymal cells has the potential to enhance the therapeutic effects of conventional bone marrow transplantation in patients with genetic disorders affecting mesenchymal tissues, including bone, cartilage, and muscle. To demonstrate the feasibility of mesenchymal cell therapy and to gain insight into the transplant biology of these cells, we used gene-marked, donor marrow-derived mesenchymal cells to treat six children who had undergone standard bone marrow transplantation for severe osteogenesis imperfecta. Each child received two infusions of the allogeneic cells. Five of six patients showed engraftment in one or more sites, including bone, skin, and marrow stroma, and had an acceleration of growth velocity during the first 6 mo postinfusion. This improvement ranged from 60% to 94% (median, 70%) of the predicted median values for age- and sex-matched unaffected children, compared with 0% to 40% (median, 20%) over the 6 mo immediately preceding the infusions. There was no clinically significant toxicity except for an urticarial rash in one patient just after the second infusion. Failure to detect engraftment of cells expressing the neomycin phosphotransferase marker gene suggested the potential for immune attack against therapeutic cells expressing a foreign protein. Thus, allogeneic mesenchymal cells offer feasible posttransplantation therapy for osteogenesis imperfecta and likely other disorders originating in mesenchymal precursors.
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            Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma

            Aarif Khakoo, Shibani Pati, Stasia A. Anderson … (2006)
            Emerging evidence suggests that both human stem cells and mature stromal cells can play an important role in the development and growth of human malignancies. In contrast to these tumor-promoting properties, we observed that in an in vivo model of Kaposi's sarcoma (KS), intravenously (i.v.) injected human mesenchymal stem cells (MSCs) home to sites of tumorigenesis and potently inhibit tumor growth. We further show that human MSCs can inhibit the in vitro activation of the Akt protein kinase within some but not all tumor and primary cell lines. The inhibition of Akt activity requires the MSCs to make direct cell–cell contact and can be inhibited by a neutralizing antibody against E-cadherin. We further demonstrate that in vivo, Akt activation within KS cells is potently down-regulated in areas adjacent to MSC infiltration. Finally, the in vivo tumor-suppressive effects of MSCs correlates with their ability to inhibit target cell Akt activity, and KS tumors engineered to express a constitutively activated Akt construct are no longer sensitive to i.v. MSC administration. These results suggest that in contrast to other stem cells or normal stromal cells, MSCs possess intrinsic antineoplastic properties and that this stem cell population might be of particular utility for treating those human malignancies characterized by dysregulated Akt.
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              Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents.

              Matus Studeny, Frank C. Marini, Jennifer L. Dembinski … (2004)
              High concentrations of interferon beta (IFN-beta) inhibit malignant cell growth in vitro. However, the therapeutic utility of IFN-beta in vivo is limited by its excessive toxicity when administered systemically at high doses. Mesenchymal stem cells (MSC) can be used to target delivery of agents to tumor cells. We tested whether MSC can deliver IFN-beta to tumors, reducing toxicity. Human MSC were transduced with an adenoviral expression vector carrying the human IFN-beta gene (MSC-IFN-beta cells). Flow cytometry was used to measure tumor cell proliferation among in vitro co-cultures of MSC-IFN-beta cells and human MDA 231 breast carcinoma cells or A375SM melanoma cells. We used a severe combined immunodeficiency mouse xenograft model (4-10 mice per group) to examine the effects of injected MSC-IFN-beta cells and human recombinant IFN-beta on the growth of MDA 231- and A375SM-derived pulmonary metastases in vivo and on survival. All statistical tests were two-sided. Co-culture of MSC-IFN-beta cells with A375SM cells or MDA 231 cells inhibited tumor cell growth as compared with growth of the tumor cells cultured alone (differences in mean percentage of control cell growth: -94.0% [95% confidence interval [CI] = -81.2% to -106.8%; P<.001] and -104.8% [95% CI = -82.1% to -127.5%; P<.001], respectively). Intravenous injection of MSC-IFN-beta cells into mice with established MDA 231 or A375SM pulmonary metastases led to incorporation of MSC in the tumor architecture and, compared with untreated control mice, to prolonged mouse survival (median survival for MDA 231-injected mice: 60 and 37 days for MSC-injected and control mice, respectively [difference = 23.0 days (95% CI = 14.5 to 34.0 days; P<.001]; median survival for A375SM-injected mice: 73.5 and 30.0 days for MSC-injected and control mice, respectively [difference = 43.5 days (95% CI = 37.0 to 57.5 days; P<.001]). By contrast, intravenous injection of recombinant IFN-beta did not prolong survival in the same models (median survival for MDA 231-injected mice: 41.0 and 37.0 days for IFN-beta-injected and control mice, respectively [difference = 4 days, 95% CI = -5 to 10 days; P = .308]; median survival for A375SM-injected mice: 32.0 and 30.0 days for IFN-beta-injected and control mice, respectively [difference = 2 days, 95% CI = 0 to 4.5 days; P = .059]). Injected MSC-IFN-beta cells suppressed the growth of pulmonary metastases, presumably through the local production of IFN-beta in the tumor microenvironment. MSC may be an effective platform for the targeted delivery of therapeutic proteins to cancer sites.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cell Mol Med
                Journal ID (iso-abbrev): J. Cell. Mol. Med
                Journal ID (publisher-id): jcmm
                Title: Journal of Cellular and Molecular Medicine
                Publisher: Blackwell Publishing Ltd (Oxford, UK )
                ISSN (Print): 1582-1838
                ISSN (Electronic): 1582-4934
                Publication date (Print): September 2010
                Publication date (Electronic): 05 June 2009
                Volume: 14
                Issue: 9
                Pages: 2292-2304
                Affiliations
                Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg Halle, Germany
                Author notes
                *Correspondence to: Lutz P. MUELLER, Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, D-06120 Halle, Germany. Tel: +49-345-557 7278 Fax: +49-345-557 7279 E-mail: lutz.mueller@ 123456medizin.uni-halle.de
                [#]

                These authors have contributed equally to this work.

                Article
                DOI: 10.1111/j.1582-4934.2009.00794.x
                PMC ID: 3822570
                PubMed ID: 19508388
                SO-VID: 9f24be72-cd33-44e9-a53b-542b87b7a03b
                Copyright © © 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
                History
                Date received : 19 January 2009
                Date accepted : 13 May 2009
                Categories
                Subject: Articles

                ScienceOpen disciplines: Molecular medicine
                Keywords: msc,trail,gene therapy,lentiviral,resistance,colorectal carcinoma
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: msc, trail, gene therapy, lentiviral, resistance, colorectal carcinoma

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