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Human umbilical cord mesenchymal stem cells delivering sTRAIL home to lung cancer mediated by MCP-1/CCR2 axis and exhibit antitumor effects

Tumor Biology

Abstract

Mesenchymal stem cells (MSCs) are believed to be a potential vehicle delivering antitumor agents for their tumor-homing capacity, while the underlying mechanism is yet to be explored. The apoptotic ligand TNF-related apoptosis-inducing ligand (TRAIL) has been suggested as a promising candidate for cancer gene therapy owing to its advantage of selectively inducing apoptosis in cancer cells while sparing normal cells. An isoleucine zipper (ISZ) added to the N-terminal of secretable soluble TRAIL (sTRAIL) can generate the trimeric form of TRAIL (ISZ-sTRAIL) and increase its antitumor potential. However, the inefficient delivery and toxicity are still obstacles for its use. In this study, the migration of human umbilical cord mesenchymal stem cells (HUMSCs) to lung cancer was observed through transwell migration assay and animal bioluminescent imaging both in vitro and in vivo. We found that the homing ability of HUMSCs was suppressed after either knocking down the expression of monocyte chemoattractant protein-1(MCP-1) in lung cancer cells or blocking CCR2 expressed on the surface of HUMSCs, indicating the important role of MCP-1/CCR2 axis in the tropism of HUMSCs to lung cancer. Furthermore, we genetically modified HUMSCs to deliver ISZ-sTRAIL to tumor sites specifically. This targeted therapeutic system exhibited promising apoptotic induction and antitumor potential in a xenograft mouse model without obvious side effects. In conclusion, HUMSCs expressing ISZ-sTRAIL might be an efficient therapeutic approach against lung cancer and MCP-1/CCR2 axis is essential for the tumor tropism of HUMSCs.

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References

  1. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7. doi:10.1080/14653240600855905.

    Article  CAS  PubMed  Google Scholar 

  2. Kidd S, Caldwell L, Dietrich M, Samudio I, Spaeth EL, Watson K, et al. Mesenchymal stromal cells alone or expressing interferon-beta suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment. Cytotherapy. 2010;12(5):615–25. doi:10.3109/14653241003631815.

    Article  CAS  PubMed  Google Scholar 

  3. Mader EK, Butler G, Dowdy SC, Mariani A, Knutson KL, Federspiel MJ, et al. Optimizing patient derived mesenchymal stem cells as virus carriers for a phase I clinical trial in ovarian cancer. J Transl Med. 2013;11:20. doi:10.1186/1479-5876-11-20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Choi SA, Lee JY, Wang KC, Phi JH, Song SH, Song J, et al. Human adipose tissue-derived mesenchymal stem cells: characteristics and therapeutic potential as cellular vehicles for prodrug gene therapy against brainstem gliomas. Eur J Cancer. 2012;48(1):129–37. doi:10.1016/j.ejca.2011.04.033.

    Article  CAS  PubMed  Google Scholar 

  5. Sordi V, Malosio ML, Marchesi F, Mercalli A, Melzi R, Giordano T, et al. Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood. 2005;106(2):419–27. doi:10.1182/blood-2004-09-3507.

    Article  CAS  PubMed  Google Scholar 

  6. Ponte AL, Marais E, Gallay N, Langonne A, Delorme B, Herault O, et al. The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells (Dayton, Ohio). 2007;25(7):1737–45. doi:10.1634/stemcells.2007-0054.

    Article  CAS  Google Scholar 

  7. Wang L, Li Y, Chen J, Gautam SC, Zhang Z, Lu M, et al. Ischemic cerebral tissue and MCP-1 enhance rat bone marrow stromal cell migration in interface culture. Exp Hematol. 2002;30(7):831–6.

    Article  CAS  PubMed  Google Scholar 

  8. Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med. 1999;5(2):157–63. doi:10.1038/5517.

    Article  CAS  PubMed  Google Scholar 

  9. Kim MH, Billiar TR, Seol DW. The secretable form of trimeric TRAIL, a potent inducer of apoptosis. Biochem Biophys Res Commun. 2004;321(4):930–5. doi:10.1016/j.bbrc.2004.07.046.

    Article  CAS  PubMed  Google Scholar 

  10. Yan C, Li S, Li Z, Peng H, Yuan X, Jiang L, et al. Human umbilical cord mesenchymal stem cells as vehicles of CD20-specific TRAIL fusion protein delivery: a double-target therapy against non-Hodgkin’s lymphoma. Mol Pharm. 2013;10(1):142–51. doi:10.1021/mp300261e.

    Article  CAS  PubMed  Google Scholar 

  11. Ashkenazi A, Holland P, Eckhardt SG. Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/Tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). J Clin Oncol. 2008;26(21):3621–30. doi:10.1200/jco.2007.15.7198.

    Article  CAS  PubMed  Google Scholar 

  12. Kelley SK, Harris LA, Xie D, Deforge L, Totpal K, Bussiere J, et al. Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety. J Pharmacol Exp Ther. 2001;299(1):31–8.

    CAS  PubMed  Google Scholar 

  13. Ma L, Feng XY, Cui BL, Law F, Jiang XW, Yang LY, et al. Human umbilical cord Wharton’s jelly-derived mesenchymal stem cells differentiation into nerve-like cells. Chin Med J (Engl). 2005;118(23):1987–93.

    CAS  Google Scholar 

  14. Danielyan L, Beer-Hammer S, Stolzing A, Schafer R, Siegel G, Fabian C, et al. Intranasal delivery of bone marrow-derived mesenchymal stem cells, macrophages, and microglia to the brain in mouse models of Alzheimer’s and Parkinson’s disease. Cell Transplant. 2014;23 Suppl 1:S123–39. doi:10.3727/096368914x684970.

    Article  PubMed  Google Scholar 

  15. Prabakar KR, Dominguez-Bendala J, Molano RD, Pileggi A, Villate S, Ricordi C, et al. Generation of glucose-responsive, insulin-producing cells from human umbilical cord blood-derived mesenchymal stem cells. Cell Transplant. 2012;21(6):1321–39. doi:10.3727/096368911x612530.

    Article  PubMed  Google Scholar 

  16. Kang BJ, Kim H, Lee SK, Kim J, Shen Y, Jung S, et al. Umbilical-cord-blood-derived mesenchymal stem cells seeded onto fibronectin-immobilized polycaprolactone nanofiber improve cardiac function. Acta Biomater. 2014;10(7):3007–17. doi:10.1016/j.actbio.2014.03.013.

    Article  CAS  PubMed  Google Scholar 

  17. Nakamura K, Ito Y, Kawano Y, Kurozumi K, Kobune M, Tsuda H, et al. Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther. 2004;11(14):1155–64. doi:10.1038/sj.gt.3302276.

    Article  CAS  PubMed  Google Scholar 

  18. Ren C, Kumar S, Chanda D, Chen J, Mountz JD, Ponnazhagan S. Therapeutic potential of mesenchymal stem cells producing interferon-alpha in a mouse melanoma lung metastasis model. Stem Cells (Dayton, Ohio). 2008;26(9):2332–8. doi:10.1634/stemcells.2008-0084.

    Article  CAS  Google Scholar 

  19. Kanehira M, Xin H, Hoshino K, Maemondo M, Mizuguchi H, Hayakawa T, et al. Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells. Cancer Gene Ther. 2007;14(11):894–903. doi:10.1038/sj.cgt.7701079.

    Article  CAS  PubMed  Google Scholar 

  20. Kim SM, Woo JS, Jeong CH, Ryu CH, Lim JY, Jeun SS. Effective combination therapy for malignant glioma with TRAIL-secreting mesenchymal stem cells and lipoxygenase inhibitor MK886. Cancer Res. 2012;72(18):4807–17. doi:10.1158/0008-5472.can-12-0123.

    Article  CAS  PubMed  Google Scholar 

  21. Reagan MR, Seib FP, McMillin DW, Sage EK, Mitsiades CS, Janes SM, et al. Stem cell implants for cancer therapy: TRAIL-expressing mesenchymal stem cells target cancer cells in situ. J Breast Cancer. 2012;15(3):273–82. doi:10.4048/jbc.2012.15.3.273.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Mohr A, Albarenque SM, Deedigan L, Yu R, Reidy M, Fulda S, et al. Targeting of XIAP combined with systemic mesenchymal stem cell-mediated delivery of sTRAIL ligand inhibits metastatic growth of pancreatic carcinoma cells. Stem Cells (Dayton, Ohio). 2010;28(11):2109–20. doi:10.1002/stem.533.

    Article  CAS  Google Scholar 

  23. Akimoto K, Kimura K, Nagano M, Takano S, To’a Salazar G, Yamashita T, et al. Umbilical cord blood-derived mesenchymal stem cells inhibit, but adipose tissue-derived mesenchymal stem cells promote, glioblastoma multiforme proliferation. Stem Cells Dev. 2013;22(9):1370–86. doi:10.1089/scd.2012.0486.

    Article  CAS  PubMed  Google Scholar 

  24. Chao KC, Yang HT, Chen MW. Human umbilical cord mesenchymal stem cells suppress breast cancer tumourigenesis through direct cell-cell contact and internalization. J Cell Mol Med. 2012;16(8):1803–15. doi:10.1111/j.1582-4934.2011.01459.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kucerova L, Matuskova M, Hlubinova K, Altanerova V, Altaner C. Tumor cell behaviour modulation by mesenchymal stromal cells. Mol Cancer. 2010;9:129. doi:10.1186/1476-4598-9-129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Waterman RS, Henkle SL, Betancourt AM. Mesenchymal stem cell 1 (MSC1)-based therapy attenuates tumor growth whereas MSC2-treatment promotes tumor growth and metastasis. PLoS One. 2012;7(9):e45590. doi:10.1371/journal.pone.0045590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PLoS One. 2010;5(4):e10088. doi:10.1371/journal.pone.0010088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ringe J, Strassburg S, Neumann K, Endres M, Notter M, Burmester GR, et al. 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(1):135–46. doi:10.1002/jcb.21172.

    Article  CAS  PubMed  Google Scholar 

  29. Takano T, Li YJ, Kukita A, Yamaza T, Ayukawa Y, Moriyama K, et al. Mesenchymal stem cells markedly suppress inflammatory bone destruction in rats with adjuvant-induced arthritis. Lab Invest. 2014;94(3):286–96. doi:10.1038/labinvest.2013.152.

    Article  CAS  PubMed  Google Scholar 

  30. Guo J, Zhang H, Xiao J, Wu J, Ye Y, Li Z, et al. Monocyte chemotactic protein-1 promotes the myocardial homing of mesenchymal stem cells in dilated cardiomyopathy. Int J Mol Sci. 2013;14(4):8164–78. doi:10.3390/ijms14048164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Boomsma RA, Geenen DL. Mesenchymal stem cells secrete multiple cytokines that promote angiogenesis and have contrasting effects on chemotaxis and apoptosis. PLoS One. 2012;7(4):e35685. doi:10.1371/journal.pone.0035685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ryan CM, Brown JA, Bourke E, Prendergast AM, Kavanagh C, Liu Z, et al. ROCK activity and the Gbetagamma complex mediate chemotactic migration of mouse bone marrow-derived stromal cells. Stem Cell Res Ther. 2015;6(1):136. doi:10.1186/s13287-015-0125-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dwyer RM, Potter-Beirne SM, Harrington KA, Lowery AJ, Hennessy E, Murphy JM, et al. Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin Cancer Res. 2007;13(17):5020–7. doi:10.1158/1078-0432.ccr-07-0731.

    Article  CAS  PubMed  Google Scholar 

  34. Belema-Bedada F, Uchida S, Martire A, Kostin S, Braun T. Efficient homing of multipotent adult mesenchymal stem cells depends on FROUNT-mediated clustering of CCR2. Cell Stem Cell. 2008;2(6):566–75. doi:10.1016/j.stem.2008.03.003.

    Article  CAS  PubMed  Google Scholar 

  35. Rombouts WJ, Ploemacher RE. Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia. 2003;17(1):160–70. doi:10.1038/sj.leu.2402763.

    Article  CAS  PubMed  Google Scholar 

  36. Shi M, Li J, Liao L, Chen B, Li B, Chen L, et al. Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment: role in homing efficiency in NOD/SCID mice. Haematologica. 2007;92(7):897–904.

    Article  PubMed  Google Scholar 

  37. Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, et al. Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med. 2003;198(9):1391–402. doi:10.1084/jem.20030267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Eggenhofer E, Benseler V, Kroemer A, Popp FC, Geissler EK, Schlitt HJ, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol. 2012;3:297. doi:10.3389/fimmu.2012.00297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Walczak P, Zhang J, Gilad AA, Kedziorek DA, Ruiz-Cabello J, Young RG, et al. Dual-modality monitoring of targeted intraarterial delivery of mesenchymal stem cells after transient ischemia. Stroke. 2008;39(5):1569–74. doi:10.1161/strokeaha.107.502047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by grants from the Natural Science Foundation of China (No. 81401887), Tianjin Natural Science Foundation (No. 14JCQNJC11500), Science Foundation of Tianjin Medical University (No. 2012KYM03), and National Basic Research Program of China (973 Program) (No. 2012CB9333004).

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Correspondence to Xinwei Zhang or Xiubao Ren.

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Cihui Yan and Xinmiao Song contributed equally to this work.

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Yan, C., Song, X., Yu, W. et al. Human umbilical cord mesenchymal stem cells delivering sTRAIL home to lung cancer mediated by MCP-1/CCR2 axis and exhibit antitumor effects. Tumor Biol. 37, 8425–8435 (2016). https://doi.org/10.1007/s13277-015-4746-7

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  • DOI: https://doi.org/10.1007/s13277-015-4746-7

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