Tissue-derived mesenchymal stromal cells used as vehicles for anti-tumor therapy exert different in vivo effects on migration capacity and tumor growth

BMC Medicine

Pilar Martin-Duque¹  Miguel Quintanilla²  Pilar Lopez-Larrubia²  Juan Carlos Ramirez⁵  Maite Iglesias⁷  Irene Cervello³  Carlos Simon³  Jerome Burnet⁴  Daniel Oberg⁶  Gracia Mendoza¹  Carolina Belmar-Lopez¹ 

[1]Instituto Aragones de Ciencias de la Salud-IIS Aragon, Zaragoza, Spain

[2]Instituto de Investigaciones Biomedicas Alberto Sols (CSIC-UAM), Madrid, Spain

[3]Fundacion IVI, Instituto Universitario IVI, University of Valencia, Institute of Health Research INCLIVA, Valencia, Spain

[4]Queen Mary, University of London/Cancer Research UK, London, UK

[5]Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain

[6]Department of Medical Biochemistry and Microbiology, The Biomedical Centre, Uppsala University, Uppsala, Sweden

[7]Facultad de Ciencias Biosanitarias, Universidad Francisco de Vitoria, Madrid, Spain

关键词: Pluripotency;    Tumor growth;    In vivo imaging;    Migration;    Mesenchymal stromal cells;   

Others  :  857010
DOI  :  10.1186/1741-7015-11-139

 received in 2012-07-24, accepted in 2013-04-19,  发布年份 2013

【 摘 要 】

Background

Mesenchymal stem cells (MSCs) have been promoted as an attractive option to use as cellular delivery vehicles to carry anti-tumor agents, owing to their ability to home into tumor sites and secrete cytokines. Multiple isolated populations have been described as MSCs, but despite extensive in vitro characterization, little is known about their in vivo behavior.

The aim of this study was to investigate the efficacy and efficiency of different MSC lineages derived from five different sources (bone marrow, adipose tissue, epithelial endometrium, stroma endometrium, and amniotic membrane), in order to assess their adequacy for cell-based anti-tumor therapies. Our study shows the crucial importance of understanding the interaction between MSCs and tumor cells, and provides both information and a methodological approach, which could be used to develop safer and more accurate targeted therapeutic applications.

Methods

We first measured the in vivo migration capacity and effect on tumor growth of the different MSCs using two imaging techniques: (i) single-photon emission computed tomography combined with computed tomography (SPECT-CT), using the human sodium iodine symporter gene (hNIS) and (ii) magnetic resonance imaging using superparamagnetic iron oxide. We then sought correlations between these parameters and expression of pluripotency-related or migration-related genes.

Results

Our results show that migration of human bone marrow-derived MSCs was significantly reduced and slower than that obtained with the other MSCs assayed and also with human induced pluripotent stem cells (hiPSCs). The qPCR data clearly show that MSCs and hiPSCs exert a very different pluripotency pattern, which correlates with the differences observed in their engraftment capacity and with their effects on tumor growth.

Conclusion

This study reveals differences in MSC recruitment/migration toward the tumor site and the corresponding effects on tumor growth. Three observations stand out: 1) tracking of the stem cell is essential to check the safety and efficacy of cell therapies; 2) the MSC lineage to be used in the cell therapy needs to be carefully chosen to balance efficacy and safety for a particular tumor type; and 3) different pluripotency and mobility patterns can be linked to the engraftment capacity of the MSCs, and should be checked as part of the clinical characterization of the lineage.

【 授权许可】

   
2013 Belmar-Lopez et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Kansas GS: Selectins and their ligands: current concepts and controversies. Blood 1996, 88:3259-3287.
• [2]Rüster B, Göttig S, Ludwig RJ, Bistrian R, Müller S, Seifried E, Gille J, Henschler R: Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells. Blood 2006, 108:3938-3944.
• [3]Schweitzer KM, Dräger AM, van der Valk P, Thijsen SF, Zevenbergen A, Theijsmeijer AP, van der Schoot CE, Langenhuijsen MM: Constitutive expression of E-selectin and vascular cell adhesion molecule-1 on endothelial cells of hematopoietic tissues. Am J Pathol 1996, 148:165-175.
• [4]De Miguel MP, Fuentes-Julian S, Blazquez-Martinez A, Pascual CY, Aller MA, Arias J, Arnalich-Montiel F: Immunosuppressive properties of mesenchymal stem cells: advances and applications. Curr Mol Med 2012, 12:574-591.
• [5]Salem HK, Thiemermann C: Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 2010, 28:585-596.
• [6]Kidd S, Caldwell L, Dietrich M, Samudio I, Spaeth EL, Watson K, Shi Y, Abbruzzese J, Konopleva M, Andreeff M, Marini FC: Mesenchymal stromal cells alone or expressing interferon-beta suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment. Cytotherapy 2010, 12:615-625.
• [7]Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M: Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res 2002, 62:3603-3608.
• [8]Yong RL, Shinojima N, Fueyo J, Gumin J, Vecil GG, Marini FC, Bogler O, Andreeff M, Lang FF: Human bone marrow-derived mesenchymal stem cells for intravascular delivery of oncolytic adenovirus Delta24-RGD to human gliomas. Cancer Res 2009, 69:8932-8940.
• [9]Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP: Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 1968, 6:230-247.
• [10]Friedenstein AJ, Piatetzky-Shapiro II, Petrakova KV: Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol 1966, 16:381-390.
• [11]Baksh D, Song L, Tuan RS: Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy. J Cell Mol Med 2004, 8:301-316.
• [12]Cervelló I, Gil-Sanchis C, Mas A, Delgado-Rosas F, Martínez-Conejero JA, Galán A, Martínez-Romero A, Martínez S, Navarro I, Ferro J, Horcajadas JA, Esteban FJ, O’Connor JE, Pellicer A, Simón C: Human endometrial side population cells exhibit genotypic, phenotypic and functional features of somatic stem cells. PLoS One 2010, 5:e10964.
• [13]Cervelló I, Mas A, Gil-Sanchis C, Peris L, Faus A, Saunders PT, Critchley HO, Simón C: Reconstruction of endometrium from human endometrial side population cell lines. PLoS One 2011, 6:e21221.
• [14]Chiu RC: Bone-marrow stem cells as a source for cell therapy. Heart Fail Rev 2003, 8:247-251.
• [15]Dubois SG, Floyd EZ, Zvonic S, Kilroy G, Wu X, Carling S, Halvorsen YD, Ravussin E, Gimble JM: Isolation of human adipose-derived stem cells from biopsies and liposuction specimens. Methods Mol Biol 2008, 449:69-79.
• [16]Gargett CE, Schwab KE, Zillwood RM, Nguyen HP, Wu D: Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol Reprod 2009, 80:1136-1145.
• [17]Shih YR, Kuo TK, Yang AH, Lee OK, Lee CH: Isolation and characterization of stem cells from the human parathyroid gland. Cell Prolif 2009, 42:461-470.
• [18]Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH: Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001, 7:211-228.
• [19]Zvaifler NJ, Marinova-Mutafchieva L, Adams G, Edwards CJ, Moss J, Burger JA, Maini RN: Mesenchymal precursor cells in the blood of normal individuals. Arthritis Res 2000, 2:477-488.
• [20]Bieback K, Klüter H: Mesenchymal stromal cells from umbilical cord blood. Curr Stem Cell Res Ther 2007, 2:310-323.
• [21]Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM: Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 2001, 98:2396-2402.
• [22]Gang EJ, Hong SH, Jeong JA, Hwang SH, Kim SW, Yang IH, Ahn C, Han H, Kim H: In vitro mesengenic potential of human umbilical cord blood-derived mesenchymal stem cells. Biochem Biophys Res Commun 2004, 321:102-108.
• [23]In’t Anker PS, Noort WA, Scherjon SA, Kleijburg-van der Keur C, Kruisselbrink AB, van Bezooijen RL, Beekhuizen W, Willemze R, Kanhai HH, Fibbe WE: Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. Haematologica 2003, 88:845-852.
• [24]Anker PS I’t, Scherjon SA, Kleijburg-van der Keur C, de Groot-Swings GM, Claas FH, Fibbe WE, Kanhai HH: Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells 2004, 22:1338-1345.
• [25]Zhang X, Hirai M, Cantero S, Ciubotariu R, Dobrila L, Hirsh A, Igura K, Satoh H, Yokomi I, Nishimura T, Yamaguchi S, Yoshimura K, Rubinstein P, Takahashi TA: Isolation and characterization of mesenchymal stem cells from human umbilical cord blood: reevaluation of critical factors for successful isolation and high ability to proliferate and differentiate to chondrocytes as compared to mesenchymal stem cells from bone marrow and adipose tissue. J Cell Biochem 2011, 112:1206-1218.
• [26]Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science 1999, 284:143-147.
• [27]Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8:315-317.
• [28]Klopp AH, Gupta A, Spaeth E, Andreeff M, Marini F 3rd: Concise review: Dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells 2011, 29:11-19.
• [29]Groot-Wassink T, Aboagye EO, Glaser M, Lemoine NR, Vassaux G: Adenovirus biodistribution and noninvasive imaging of gene expression in vivo by positron emission tomography using human sodium/iodide symporter as reporter gene. Hum Gene Ther 2002, 13:1723-1735.
• [30]Martin-Duque P, Jezzard S, Kaftansis L, Vassaux G: Direct comparison of the insulating properties of two genetic elements in an adenoviral vector containing two different expression cassettes. Hum Gene Ther 2004, 15:995-1002.
• [31]Martín-Duque P, Quintanilla M, McNeish I, Lopes R, Romero J, Romero D, Lemoine NR, Ramón y Cajal S, Vassaux G: Caspase-1 as a radio- and chemo-sensitiser in vitro and in vivo. Int J Mol Med 2006, 17:841-847.
• [32]Henning TD, Boddington S, Daldrup-Link HE: Labeling hESCs and MSCs with iron oxide nanoparticles for non-invasive in vivo tracking with MR imaging. J Vis Exp 2008, 13:685.
• [33]Loebinger MR, Janes SM: Stem cells as vectors for antitumor therapy. Thorax 2010, 65:362-369.
• [34]Pereboeva L, Komarova S, Mikheeva G, Krasnykh V, Curiel DT: Approaches to utilize mesenchymal progenitor cells as cellular vehicles. Stem Cells 2003, 21:389-404.
• [35]Dwyer RM, Potter-Beirne SM, Harrington KA, Lowery AJ, Hennessy E, Murphy JM, Barry FP, O’Brien T, Kerin MJ: Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin Cancer Res 2007, 13:5020-5027.
• [36]Khakoo AY, Pati S, Anderson SA, Reid W, Elshal MF, Rovira II, Nguyen AT, Malide D, Combs CA, Hall G, Zhang J, Raffeld M, Rogers TB, Stetler-Stevenson W, Frank JA, Reitz M, Finkel T: Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi’s sarcoma. J Exp Med 2006, 203:1235-1247.
• [37]Komarova S, Kawakami Y, Stoff-Khalili MA, Curiel DT, Pereboeva L: Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses. Mol Cancer Ther 2006, 5:755-766.
• [38]Loebinger MR, Eddaoudi A, Davies D, Janes SM: Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res 2009, 69:4134-4142.
• [39]Pereboeva L, Curiel DT: Cellular vehicles for cancer gene therapy: current status and future potential. Bio-Drugs 2004, 18:361-385.
• [40]Shinagawa K, Kitadai Y, Tanaka M, Sumida T, Kodama M, Higashi Y, Tanaka S, Yasui W, Chayama K: Mesenchymal stem cells enhance growth and metastasis of colon cancer. Int J Cancer 2010, 127:2323-2333.
• [41]Stoff-Khalili MA, Rivera AA, Mathis JM, Banerjee NS, Moon AS, Hess A, Rocconi RP, Numnum TM, Everts M, Chow LT, Douglas JT, Siegal GP, Zhu ZB, Bender HG, Dall P, Stoff A, Pereboeva L, Curiel DT: Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma. Breast Cancer Res Treat 2007, 105:157-167.
• [42]Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN, Champlin RE, Andreeff M: Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 2004, 96:1593-1603.
• [43]Eiró N, Vizoso FJ: Inflammation and cancer. World J Gastrointest Surg 2012, 4:62-72.
• [44]Dwyer RM, Ryan J, Havelin RJ, Morris JC, Miller BW, Liu Z, Flavin R, O’Flatharta C, Foley MJ, Barrett HH, Murphy JM, Barry FP, O’Brien T, Kerin MJ: Mesenchymal stem cell-mediated delivery of the sodium iodide symporter supports radionuclide imaging and treatment of breast cancer. Stem Cells 2011, 29:1149-1157.
• [45]Lin G, Yang R, Banie L, Wang G, Ning H, Li LC, Lue TF, Lin CS: Effects of transplantation of adipose tissue-derived stem cells on prostate tumor. Prostate 2010, 70:1066-1073.
• [46]Cousin B, Ravet E, Poglio S, De Toni F, Bertuzzi M, Lulka H, Touil I, André M, Grolleau JL, Péron JM, Chavoin JP, Bourin P, Pénicaud L, Casteilla L, Buscail L, Cordelier P: Adult stromal cells derived from human adipose tissue provoke pancreatic cancer cell death both in vitro and in vivo. PLoS One 2009, 4:e6278.
• [47]Secchiero P, Zorzet S, Tripodo C, Corallini F, Melloni E, Caruso L, Bosco R, Ingrao S, Zavan B, Zauli G: Human bone marrow mesenchymal stem cells display anti-cancer activity in SCID mice bearing disseminated non-Hodgkin’s lymphoma xenografts. PLoS One 2010, 5:e11140.
• [48]Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE: Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells 2006, 24:1030-1041.
• [49]Ponte AL, Marais E, Gallay N, Langonné A, Delorme B, Hérault O, Charbord P, Domenech J: The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells 2007, 25:1737-1745.
• [50]Ringe J, Strassburg S, Neumann K, Endres M, Notter M, Burmester GR, Kaps C, Sittinger M: Towards in situ tissue repair: human mesenchymal stem cells express chemokine receptors CXCR1, CXCR2 and CCR2, and migrate upon stimulation with CXCL8 but not CCL2. J Cell Biochem 2007, 101:135-146.
• [51]Sordi V, Malosio ML, Marchesi F, Mercalli A, Melzi R, Giordano T, Belmonte N, Ferrari G, Leone BE, Bertuzzi F, Zerbini G, Allavena P, Bonifacio E, Piemonti L: Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood 2005, 106:419-427.
• [52]Von Lüttichau I, Notohamiprodjo M, Wechselberger A, Peters C, Henger A, Seliger C, Djafarzadeh R, Huss R, Nelson PJ: Human adult CD34- progenitor cells functionally express the chemokine receptors CCR1, CCR4, CCR7, CXCR5, and CCR10 but not CXCR4. Stem Cells Dev 2005, 14:329-336.
• [53]Dai LJ, Moniri MR, Zeng ZR, Zhou JX, Rayat J, Warnock GL: Potential implications of mesenchymal stem cells in cancer therapy. Cancer Lett 2011, 305:8-20.
• [54]Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA: Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005, 121:335-348.
• [55]Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, Crystal RG, Besmer P, Lyden D, Moore MA, Werb Z, Rafii S: Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 2002, 109:625-637.
• [56]Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, Ponomaryov T, Taichman RS, Arenzana-Seisdedos F, Fujii N, Sandbank J, Zipori D, Lapidot T: G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol 2002, 3:687-694.
• [57]Kang NH, Hwang KA, Kim SU, Kim YB, Hyun SH, Jeung EB, Choi KC: Human amniotic fluid-derived stem cells expressing cytosine deaminase and thymidine kinase inhibits the growth of breast cancer cells in cellular and xenograft mouse models. Cancer Gene Ther 2012, 19:412-419.
• [58]Yang DY, Sheu ML, Su HL, Cheng FC, Chen YJ, Chen CJ, Chiu WT, Yiin JJ, Sheehan J, Pan HC: Dual regeneration of muscle and nerve by intravenous administration of human amniotic fluid-derived mesenchymal stem cells regulated by stromal cell-derived factor-1α in a sciatic nerve injury model. J Neurosurg 2012, 116:1357-1367.
• [59]Bhoopathi P, Chetty C, Gogineni VR, Gujrati M, Dinh DH, Rao JS, Lakka SS: MMP-2 mediates mesenchymal stem cell tropism towards medulloblastoma tumors. Gene Ther 2011, 18:692-701.
• [60]Dawson MR, Chae SS, Jain RK, Duda DG: Direct evidence for lineage-dependent effects of bone marrow stromal cells on tumor progression. Am J Cancer Res 2011, 1:144-154.
• [61]Kortesidis A, Zannettino A, Isenmann S, Shi S, Lapidot T, Gronthos S: Stromal-derived factor-1 promotes the growth, survival, and development of human bone marrow stromal stem cells. Blood 2005, 105:3793-3801.
• [62]Templin C, Zweigerdt R, Schwanke K, Olmer R, Ghadri JR, Emmert MY, Müller E, Küest SM, Cohrs S, Schibli R, Kronen P, Hilbe M, Reinisch A, Strunk D, Haverich A, Hoerstrup S, Lüscher TF, Kaufmann PA, Landmesser U, Martin U: Transplantation and tracking of human induced pluripotent stem cells in a pig model of myocardial infarction: assessment of cell survival, engraftment and distribution by hybrid SPECT-CT imaging of sodium iodide symporter trangene expression. Circulationin press
• [63]Vertelov G, Kharazi L, Muralidhar MG, Sanati G, Tankovich T, Kharazi A: High targeted migration of human mesenchymal stem cells grown in hypoxia is associated with enhanced activation of RhoA. Stem Cell Res Ther 2013, 4:5.
• [64]Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, García-Santos G, Ghajar C, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan J, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang Y, Bromberg J, Lyden D: Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012, 18:883-891.