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Role of Tumor Necrosis Factor-Producing Mesenchymal Stem Cells on Apoptosis of Chronic B-lymphocytic Tumor Cells Resistant to Fludarabine-based Chemotherapy

  • Valizadeh, Armita (Physiology Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences) ;
  • Ahmadzadeh, Ahmad (Thalassemia and Hemoglobinopathies Research Center, Shafa Hospital, Ahvaz Jundishapur University of Medical Sciences) ;
  • Saki, Ghasem (Physiology Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences) ;
  • Khodadadi, Ali (Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences) ;
  • Teimoori, Ali (Cancer, Petroleum and Environmental Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences)
  • Published : 2016.01.11

Abstract

Background: B-cell chronic lymphocytic leukemia B (B-CLL), the most common type of leukemia, may be caused by apoptosis deficiency in the body. Adipose tissue-derived mesenchymal stem cells (AD-MSCs) as providers of pro-apoptotic molecules such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), can be considered as an effective anti-cancer therapy candidate. Therefore, in this study we assessed the role of tumor necrosis factor-producing mesenchymal stem cells oin apoptosis of B-CLL cells resistant to fludarabine-based chemotherapy. Materials and Methods: In this study, after isolation and culture of AD-MSCs, a lentiviral LeGO-iG2-TRAIL-GFP vector containing a gene producing the ligand pro-apoptotic with plasmid PsPAX2 and PMDG2 virus were transfected into cell-lines to generate T293HEK. Then, T293HEK cell supernatant containing the virus produced after 48 and 72 hours was collected, and these viruses were transduced to reprogram AD-MSCs. Apoptosis rates were separately studied in four groups: group 1, AD-MSCs-TRAIL; group 2, AD-MSCs-GFP; group 3, AD-MSCs; and group 4, CLL. Results: Observed apoptosis rates were: group 1, $42{\pm}1.04%$; group 2, $21{\pm}0.57%$; group 3, $19{\pm}2.6%$; and group 4, % $0.01{\pm}0.01$. The highest rate of apoptosis thus occurred ingroup 1 (transduced TRAIL encoding vector). In this group, the average medium-soluble TRAIL was 72.7pg/m and flow cytometry analysis showed a pro-apoptosis rate of $63{\pm}1.6%$, which was again higher than in other groups. Conclusions: In this study we have shown that tumor necrosis factor (TNF) secreted by AD-MSCs may play an effective role in inducing B-CLL cell apoptosis.

Keywords

B-cell chronic lymphocytic leukemia B cells;mesenchymal stem cells;TNF;chemotherapy resistance

References

  1. Abdul Halim NS, Fakiruddin KS, Ali SA, et al (2014). A comparative study of non-viral gene delivery techniques to human adipose-derived mesenchymal stem cell. Int J Mol Sci, 15, 15044-60. https://doi.org/10.3390/ijms150915044
  2. Ashkenazi A, Holland P, Eckhardt SG (2008). 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, 26, 3621-30. https://doi.org/10.1200/JCO.2007.15.7198
  3. Balakrishnan K, Burger JA, Quiroga MP, et al (2010). Influence of bone marrow stromal microenvironment on forodesineinduced responses in CLL primary cells. Blood, 116, 1083-91. https://doi.org/10.1182/blood-2009-10-246199
  4. Batsali AK, Kastrinaki MC, Papadaki HA, et al (2013). Mesenchymal stem cells derived from Wharton's Jelly of the umbilical cord: biological properties and emerging clinical applications. Curr Stem Cell Res Ther, 8, 144-55. https://doi.org/10.2174/1574888X11308020005
  5. Calon A, Espinet E, Palomo-Ponce S, et al (2012). Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell, 22, 571-584. https://doi.org/10.1016/j.ccr.2012.08.013
  6. de Vries EG, Timmer T, Mulder NH, et al (2003). Modulation of death receptor pathways in oncology. Drugs Today (Barc), 39, 95-109.
  7. Foss DL, Murtaugh MP (2000). Mechanisms of vaccine adjuvanticity at mucosal surfaces. Anim Health Res Rev, 1, 3-24. https://doi.org/10.1017/S1466252300000025
  8. Grisendi G, Bussolari R, Cafarelli L, et al (2010). Adiposederived mesenchymal stem cells as stable source of tumor necrosis factor-related apoptosis-inducing ligand delivery for cancer therapy. Cancer Res, 70, 3718-29. https://doi.org/10.1158/0008-5472.CAN-09-1865
  9. Hallek M (2015). Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment. Am J Hematol, 90, 446-60. https://doi.org/10.1002/ajh.23979
  10. Hallek M, Cheson BD, Catovsky D, et al (2008). Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the international workshop on chronic lymphocytic leukemia updating the national cancer institute-working group 1996 guidelines. Blood, 111, 5446-5456. https://doi.org/10.1182/blood-2007-06-093906
  11. Hoch AI, Leach JK (2014). Concise review: optimizing expansion of bone marrow mesenchymal stem/stromal cells for clinical applications. Stem Cells Transl Med, 3, 643-652. https://doi.org/10.5966/sctm.2013-0196
  12. Kay NE, Shanafelt TD, Strege AK, et al (2007). Bone biopsy derived marrow stromal elements rescue chronic lymphocytic leukemia B-cells from spontaneous and drug induced cell death and facilitates an "angiogenic switch". Leuk Res, 31, 899-906. https://doi.org/10.1016/j.leukres.2006.11.024
  13. Kojima K, McQueen T, Chen Y, et al (2011). p53 activation of mesenchymal stromal cells partially abrogates microenvironment-mediated resistance to FLT3 inhibition in AML through HIF-1alpha-mediated down-regulation of CXCL12. Blood, 118, 4431-9. https://doi.org/10.1182/blood-2011-02-334136
  14. Loebinger MR, Janes SM (2010). Stem cells as vectors for antitumour therapy. Thorax, 65, 362-9. https://doi.org/10.1136/thx.2009.128025
  15. Mahalingam D, Szegezdi E, Keane M, et al (2009). TRAIL receptor signalling and modulation: Are we on the right TRAIL? Cancer Treat Rev, 35, 280-8. https://doi.org/10.1016/j.ctrv.2008.11.006
  16. Pachon-Pena G, Yu G, Tucker A, et al (2011). Stromal stem cells from adipose tissue and bone marrow of age-matched female donors display distinct immunophenotypic profiles. J Cell Physiol, 226, 843-51. https://doi.org/10.1002/jcp.22408
  17. Sadighi S, Khoshzban A, Tavakoli A, et al (2014). Isolation, amplification and identification of mesenchymal stem cells de-rived from human adipose tissue. Tehran Univ Med J, 72, 27-32.
  18. Sen A, Lea-Currie YR, Sujkowska D, et al (2001). Adipogenic potential of human adipose derived stromal cells from multiple donors is heterogeneous. J Cell Biochem, 81, 312-9. https://doi.org/10.1002/1097-4644(20010501)81:2<312::AID-JCB1046>3.0.CO;2-Q
  19. Sharma RR, Pollock K, Hubel A, et al (2014). Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices. Transfusion, 54, 1418-37. https://doi.org/10.1111/trf.12421
  20. Tiscornia G, Singer O, Verma IM (2006). Production and purification of lentiviral vectors. Nat Protoc, 1, 241-5. https://doi.org/10.1038/nprot.2006.37
  21. Walczak H, Haas TL (2008). Biochemical analysis of the native TRAIL death-inducing signaling complex. Methods Mol Biol, 414, 221-39.
  22. Whiteside TL (2008). The tumor microenvironment and its role in promoting tumor growth. Oncogene, 27, 5904-12. https://doi.org/10.1038/onc.2008.271
  23. Wiley SR, Schooley K, Smolak PJ, et al (1995). Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity, 3, 673-82. https://doi.org/10.1016/1074-7613(95)90057-8
  24. Wu J, Li J, Salcedo R, et al (2012). The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Cancer Res, 72, 3977-86. https://doi.org/10.1158/0008-5472.CAN-12-0938