Suscripción a Biblioteca: Guest
Portal Digitalde Biblioteca Digital eLibros Revistas Referencias y Libros de Ponencias Colecciones
Critical Reviews™ in Eukaryotic Gene Expression
Factor de Impacto: 2.156 Factor de Impacto de 5 años: 2.255 SJR: 0.649 SNIP: 0.599 CiteScore™: 3

ISSN Imprimir: 1045-4403
ISSN En Línea: 2162-6502

Volumen 30, 2020 Volumen 29, 2019 Volumen 28, 2018 Volumen 27, 2017 Volumen 26, 2016 Volumen 25, 2015 Volumen 24, 2014 Volumen 23, 2013 Volumen 22, 2012 Volumen 21, 2011 Volumen 20, 2010 Volumen 19, 2009 Volumen 18, 2008 Volumen 17, 2007 Volumen 16, 2006 Volumen 15, 2005 Volumen 14, 2004 Volumen 13, 2003 Volumen 12, 2002 Volumen 11, 2001 Volumen 10, 2000 Volumen 9, 1999 Volumen 8, 1998 Volumen 7, 1997 Volumen 6, 1996 Volumen 5, 1995 Volumen 4, 1994

Critical Reviews™ in Eukaryotic Gene Expression

DOI: 10.1615/CritRevEukaryotGeneExpr.2019030483
pages 343-350

Programming hMSCs into Potential Genetic Therapy in Cancer

Nedime Serakinci
Near East University, Faculty of Medicine, Department of Medical Genetics, Near East Avenue, Nicosia 99138, Northern Cyprus; Near East University, Faculty of Arts and Sciences, Dept. of Molecular Biology and Genetics, Near East Avenue, Nicosia 99138, Northern Cyprus
Huseyin Cagsin
Near East University, Faculty of Medicine, Department of Medical Genetics, Nicosia, Turkish Republic of Northern Cyprus; Near East University, Faculty of Art and Sciences, Department of Molecular Biology and Genetics, Nicosia, Turkish Republic of Northern Cyprus


Based on their distinct characteristics, such as self-renewal and differentiation potential, human mesenchymal stem cells (hMSCs) have been proposed as a feasible tool for cancer therapy. The characteristic of hMSCs that can be used in cancer therapy is their ability to home to primary and metastatic tumor sites. Recent studies have shown that use of stem cells obtained from adult tissue may be a novel vehicle for stem cell–mediated cancer therapy with improved antitumor effects. Stem cells have been used as vehicles to deliver various agents to tumor sites in order to decrease the size of the tumor or increase the lifespan of the organism. Genetically modified MSCs have been shown to increase apoptosis and decrease growth and angiogenesis in solid tumors. In this review, we will focus on the potential of the genetically modified hMSC-based genetic therapy that is a combination of stem cell and gene therapy approaches and its potential advantages over current therapies.


  1. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002 Jul;418(6893):41-9.

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016 Jan;66(1):7-30.

  3. 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 May;105(10):3793-801.

  4. Ries C, Egea V, Karow M, Kolb H, Jochum M, Neth P. MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines. Blood. 2007 May;109(9):4055-63.

  5. Gonjalves RM, Antunes JC, Barbosa MA. Mesenchymal stem cell recruitment by stromal derived factor-1-delivery systems based on chitosan/poly(y-glutamic acid) polyelec-trolyte complexes. Eur Cell Mater. 2012 Apr;23:249-60.

  6. Wynn RF, Hart CA, Corradi-Perini C, O'Neill L, Evans CA, Wraith JE, Fairbairn LJ, Bellantuono I. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood. 2004 Nov;104(9):2643-5.

  7. Yang C, Lei D, Ouyang W, Ren J, Li H, Hu J, Huang SL. Conditioned media from human adipose tissue-derived mesenchymal stem cells and umbilical cord-derived mesenchymal stem cells efficiently induced the apoptosis and differentiation in human glioma cell lines in vitro. Biomed Res Int. 2014;2014:109389.

  8. Calio ML, Marinho DS, Ko GM, Ribeiro RR, Carbonel AF, Oyama LM, Ormanji M, Guirao TP, Calio PL, Reis LA, Simoes Mde J, Lisboa-Nascimento T, Ferreira AT, Bertoncini CR. Transplantation of bone marrow mesenchymal stem cells decreases oxidative stress, apoptosis, and hippocampal damage in brain of a spontaneous stroke model. Free Radic Biol Med. 2014 May;70:141-54.

  9. Yu B, Zhang X, Li X. Exosomes derived from mesenchymal stem cells. Int J Mol Sci. 2014 Mar;15(3):4142-57.

  10. Honoki K, Tsujiuchi T. Senescence bypass in mesenchymal stem cells: a potential pathogenesis and implications of pro-senescence therapy in sarcomas. Exp Rev Anticancer Ther. 2013 Aug;13(8):983-96.

  11. Serakinci N, Guldberg P, Burns JS, Abdallah B, Schredder H, Jensen T, Kassem M. Adult human mesenchymal stem cell as a target for neoplastic transformation. Oncogene. 2004 Jun;23(29):5095-8.

  12. Serakinci N, Christensen R, Fahrioglu U, Sorensen FB, Dagnss-Hansen F, Hajek M, Jensen TH, Kolvraa S, Keith NW. Mesenchymal stem cells as therapeutic delivery vehicles targeting tumor stroma. Cancer Biother Radiopharm. 2011 Dec;26(6):767-73.

  13. D'Souza A, Lacy M, Gertz M, Kumar S, Buadi F, Hayman S, Dingli D, Zeldenrust S, Kyle R, Ansell S, Inwards D, Johnston P, Micallef I, Porrata L, Litzow M, Gastineau D, Hogan W, Dispenzieri A. Long-term outcomes after autologous stem cell transplantation for patients with POEMS syndrome (osteosclerotic myeloma): a single-center experience. Blood. 2012 Jul;120(1):56-62.

  14. Sohni A, Verfaillie CM. Mesenchymal stem cells migration homing and tracking. Stem Cells Int. 2013;2013:1-8.

  15. Ajith TA. Strategies used in the clinical trials of gene therapy for cancer. J Exp Ther Oncol. 2015;11(1):33-9.

  16. Bowie C. Development of engineered cells for implantation in gene therapy. Adv Drug Deliv Rev. 1998 Aug;33(1- 2):31.

  17. Liu S-X, Xia Z-S, Zhong Y-Q. Gene therapy in pancreatic cancer. World J Gastroenterol. 2014 Oct;20(37):13343-68.

  18. Nayerossadat N, Ali P, Maedeh T. Viral and nonviral delivery systems for gene delivery. Adv Biomed Res. 2012;1(1):27.

  19. Lessard S, Francioli L, Alfoldi J, Tardif J, Ellinor PT. Human genetic variation alters CRISPR-Cas9 on- and off-targeting specificity at therapeutically implicated loci. Proc Natl Acad Sci. 2017;11257-66.

  20. Momin EN, Mohyeldin A, Zaidi HA, Vela G, Quinones-Hinojosa A. Mesenchymal stem cells: new approaches for the treatment of neurological diseases. Curr Stem Cell Res Ther. 2010 Dec;5(4):326-44.

  21. Aboody KS, Najbauer J, Danks MK. Stem and progenitor cell-mediated tumor selective gene therapy. Gene Ther. 2008 May;15(10):739-52.

  22. Mooney R, Weng Y, Tirughana-Sambandan R, Valenzuela V, Aramburo S, Garcia E, Li Z, Gutova M, Annala AJ, Berlin JM, Aboody KS. Neural stem cells improve intracranial nanoparticle retention and tumor-selective distribution. Future Oncol. 2014 Feb;10(3):401-15.

  23. Gao Z, Zhang L, Hu J, Sun Y. Mesenchymal stem cells: a potential targeted-delivery vehicle for anti-cancer drug, loaded nanoparticles. Nanomedicine. 2013 Feb;9(2):174- 84.

  24. Baglio SR, Rooijers K, Koppers-Lalic D, Verweij FJ, Perez Lanzon M, Zini N, Naaijkens B, Perut F, Niessen HW, Baldini N, Pegtel DM. Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res Ther. 2015 Jul;6(1):127.

  25. Bliss SA, Sinha G, Sandiford OA, Williams LM, Engelberth DJ, Guiro K, Isenalumhe LL, Greco SJ, Ayer S, Bryan M, Kumar R, Ponzio NM, Rameshwar P. Mesenchymal stem cell-derived exosomes stimulate cycling quiescence and early breast cancer dormancy in bone marrow. Cancer Res. 2016 Oct;76(19):5832-44.

  26. Zhu Y, Cheng M, Yang Z, Zeng C-Y, Chen J, Xie Y, Luo SW, Zhang KH, Zhou SF, Lu NH. Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts. Drug Des Devel Ther. 2014 Dec;8:2449-62.

  27. Niess H, Bao Q, Conrad C, Zischek C, Notohamiprodjo M, Schwab F, Schwarz B, Huss R, Jauch KW, Nelson PJ, Bruns CJ. Selective targeting of genetically engineered mesenchymal stem cells to tumor stroma microenvironments using tissue-specific suicide gene expression suppresses growth of hepatocellular carcinoma. Ann Surg. 2011 Nov;254(5):767-74.

  28. 28. Sage EK, Thakrar RM, Janes SM. Genetically modified mesenchymal stromal cells in cancer therapy. Cytotherapy. 2016 Nov;18(11):1435-45.

  29. Shah K. Encapsulated stem cells for cancer therapy. Biomatter. 2013 Jan;3(1):e24278.

  30. Menon LG, Kelly K, Yang HW, Kim S-K, Black PM, Carroll RS. Human bone marrow-derived mesenchymal stromal cells expressing S-TRAIL as a cellular delivery vehicle for human glioma therapy. Stem Cells. 2009 Sep;27(9):2320-30.

  31. 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 Jul;62(13):3603-8.

  32. 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 Nov;96(21):1593-603.

  33. Placencio VR, Li X, Sherrill TP, Fritz G, Bhowmick NA. Bone marrow derived mesenchymal stem cells incorporate into the prostate during regrowth. PLoS One. 2010 Sep;5(9):e12920.

  34. Seo SH, Kim KS, Park SH, Suh YS, Kim SJ, Jeun S-S, Sung YC. The effects of mesenchymal stem cells injected via different routes on modified IL-12-mediated antitumor activity. Gene Ther. 2011 May;18(5):488-95.

  35. Pacioni S, D'Alessandris QG, Giannetti S, Morgante L, Cocce V, Bonomi A, Buccarelli M, Pascucci L, Alessandri G, Pessina A, Ricci-Vitiani L, Falchetti ML, Pallini R. Human mesenchymal stromal cells inhibit tumor growth in orthotopic glioblastoma xenografts. Stem Cell Res Ther. 2017 Dec;8(1):53.

  36. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar;144(5):646-74.

  37. Serakinci N, Christensen R, Graakjaer J, Cairney CJ, Keith WN, Alsner J, Saretzki G, Kolvraa S. Ectopically hTERT expressing adult human mesenchymal stem cells are less radiosensitive than their telomerase negative counterpart. Exp Cell Res. 2007 Mar;313(5):1056-67.

  38. Serakinci N, Graakjaer J, Kolvraa S. Telomere stability and telomerase in mesenchymal stem cells. Biochimie. 2008 Jan;90(1):33-40.

  39. Furlani D, Ugurlucan M, Ong L, Bieback K, Pittermann E, Westien I, Wang W, Yerebakan C, Li W, Gaebel R, Li RK, Vollmar B, Steinhoff G, Ma N. Is the intravascular admin-istration of mesenchymal stem cells safe? Mesenchymal stem cells and intravital microscopy. Microvasc Res. 2009 May;77(3):370-6.

  40. Hiyama E, Hiyama K. Telomere and telomerase in stem cells. Br J Cancer. 2007 Apr;96(7):1020-4.

  41. Amariglio N, Hirshberg A, Scheithauer BW, Cohen Y, Loewenthal R, Trakhtenbrot L, Paz N, Koren-Michowitz M, Waldman D, Leider-Trejo L, Toren A, Constantini S, Rechavi G. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 2009 Feb;6(2):e1000029.

  42. Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K. Virus-free induction of pluripotency and sub-sequent excision of reprogramming factors. Nature. 2009 Apr;458(7239):771-5.

  43. Oricchio E, Papapetrou EP, Lafaille F, Ganat YM, Kriks S, Ortega-Molina A, Mark WH, Teruya-Feldstein J, Huse JT, Reuter V, Sadelain M, Studer L, Wendel HG. A cell engineering strategy to enhance the safety of stem cell therapies. Cell Rep. 2014 Sep;8(6):1677-85.

  44. Wang Y, Huso DL, Harrington J, Kellner J, Jeong DK, Turney J, McNiece IK. Outgrowth of a transformed cell population derived from normal human BM mesenchymal stem cell culture. Cytotherapy. 2005;7(6):509-19.

  45. Rubio D, Garcia S, De la Cueva T, Paz MF, Lloyd AC, Bernad A, Garcia-Castro J. Human mesenchymal stem cell transformation is associated with a mesenchymal-epithelial transition. Exp Cell Res. 2008 Feb;314(4):691-8.

  46. Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, Moretta A, Montagna D, Maccario R, Villa R, Daidone MG, Zuffardi O, Locatelli F. Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res. 2007 Oct;67(19):9142-9.

  47. Meza-Zepeda LA, Noer A, Dahl JA, Micci F, Myklebost O, Collas P. High-resolution analysis of genetic stability of human adipose tissue stem cells cultured to senescence. J Cell Mol Med. 2008 Apr;12(2):553-63.

  48. Burns JS, Abdallah BM, Guldberg P, Rygaard J, Schroder HD, Kassem M. Tumorigenic heterogeneity in cancer stem cells evolved from long-term cultures of telomerase-immortalized human mesenchymal stem cells. Cancer Res. 2005 Apr;65(8):3126-35.

  49. Scherzad A, Steber M, Gehrke T, Rak K, Froelich K, Schendzielorz P, Hagen R, Kleinsasser N, Hackenberg S. Human mesenchymal stem cells enhance cancer cell pro-liferation via IL-6 secretion and activation of ERK1/2. Int J Oncol. 2015 May;47(1):391-7.

  50. De Luca A, Lamura L, Gallo M, Maffia V, Normanno N. Mesenchymal stem cell-derived interleukin-6 and vascular endothelial growth factor promote breast cancer cell migration. J Cell Biochem. 2012 Nov;113(11):3363-70.

  51. Yi B, Kim SU, Kim Y, Lee HJUN, Cho M, Choi K. Antitumor effects of genetically engineered stem cells expressing yeast cytosine deaminase in lung cancer brain metastases via their tumor-tropic properties. Oncol Rep. 2012;1823-8.

  52. Yi B, Kang N, Hwang K, Kim SU, Jeung EB, Kim YB, Heo GJ, Choi KC. Genetically engineered stem cells expressing cytosine deaminase and interferon-P migrate to human lung cancer cells and have potentially therapeutic anti-tumor effects. Int J Oncol. 2011;(19):833-9.

  53. Qin J, Zhao Y, Wang Y, Betzler C, Popp FC, Augsburger D, Gupta AS, Augsburger D, Camaj P, Nelson PJ, Bruns CJl. Therapeutic potential of mesenchymal stem cells in gas-trointestinal cancers-current evidence. Gastrointestinal cancer: targets and therapy. Auckland, New Zealand: Dove Press; 2016. p. 41-7.

  54. Mavroudi M, Zarogoulidis P, Porpodis K, Kioumis I, Yarmus L, Malecki R,Zarogoulidis K, Malecki M. Stem cells' guided gene therapy of cancer: new frontier in personalized and targeted therapy. J Cancer Res Ther. 2014;2(1):22-33.

  55. Abdul-Ghani R, Ohana P, Matouk I, Ayesh S, Ayesh B, Laster M, Bibi O, Giladi H, Molnar-Kimber K, Sughayer MA, De Groot N. Use of transcriptional regulatory sequences of telomerase (hTER and hTERT) for selective killing of cancer cells. Mol Ther. 2000 Dec;2(6):539-44.

  56. Komata T, Koga S, Hirohata S, Takakura M, Germano IM, Inoue M, Kyo S, Kondo S, Kondo Y. A novel treatment of human malignant gliomas in vitro and in vivo: FADD gene transfer under the control of the human telomerase reverse transcriptase gene promoter. Int J Oncol. 2001 Nov;19(5):1015-20.

  57. Plumb JA, Bilsland A, Kakani R, Zhao J, Glasspool RM, Knox RJ, Evans TR, Keith WN. Telomerase-specific suicide gene therapy vectors expressing bacterial nitroreductase sensitize human cancer cells to the prodrug CB1954. Oncogene. 2001 Nov;20(53):7797-803.

  58. Yashima K, Piatyszek MA, Saboorian HM, Virmani AK, Brown D, Shay JW, Gazdar AF. Telomerase activity and in situ telomerase RNA expression in malignant and non-malignant lymph nodes. J Clin Pathol. 1997 Feb;50(2):110-7.

  59. Joseph I, Tressler R, Bassett E, Harley C, Buseman CM, Pattamatta P, Wright WE, Shay JW, Go NF. The telo-merase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines. Cancer Res. 2010 Nov;70(22):9494-504.

  60. Resnick IB, Barkats C, Shapira MY, Stepensky P, Bloom AI, Shimoni A, Mankuta D, Varda-Bloom N, Rheingold L, Yeshurun M, Bielorai B, Toren A, Zuckerman T, Nagler A, Or R. Treatment of severe steroid resistant acute GVHD with mesenchymal stromal cells (MSC). Am J Blood Res. 2013;3(3):225-38.

  61. Barkholt L, Flory E, Jekerle V, Lucas-Samuel S, Ahnert P, Bisset L, Buscher D, Fibbe W, Foussat A, Kwa M, Lantz O, Maciulaitis R, Palomaki T, Schneider CK, Sensebe L, Tachdjian G, Tarte K, Tosca L, Salmikangas P. Risk of tumorigenicity in mesenchymal stromal cell-based therapies-bridging scientific observations and regulatory viewpoints. Cytotherapy. 2013 Jul;15(7):753-9.

Articles with similar content:

Bone Tissue Engineering: Recent Advances and Challenges
Critical Reviews™ in Biomedical Engineering, Vol.40, 2012, issue 5
Syam P. Nukavarapu, Cato T. Laurencin, Ami R. Amini
Adipose-Derived Adult Stem Cells: Available Technologies for Potential Clinical Regenerative Applications in Dentistry
Critical Reviews™ in Biomedical Engineering, Vol.41, 2013, issue 6
Elena Varoni, Andrea Cochis, Barbara Azzimonti, Lia Rimondini, Enrico Catalano, Antonio Carrassi
Recent Advances in Cancer Stem Cell Targeted Therapy
Critical Reviews™ in Oncogenesis, Vol.24, 2019, issue 1
Muge Ocal, Hakan Akbulut, Samira Abdi Abgarmi, Merve Besler, Cansu Babahan
Gain of Antitumor Functions and Induction of Differentiation in Cancer Stem Cells Contribute to Complete Cure and No Relapse
Critical Reviews™ in Oncogenesis, Vol.15, 2009, issue 1-2
Minal Garg
Characteristics and Tissue Regeneration Properties of Gingiva-Derived Mesenchymal Stem Cells
Critical Reviews™ in Eukaryotic Gene Expression, Vol.25, 2015, issue 2
Dehua Li, Zhengze Guo, Zhang Wu, Lei Qin, Ningbo Zhao