Advertisement

Tumor Biology

, Volume 37, Issue 8, pp 10745–10752 | Cite as

Bone marrow stromal cells induced activation of nuclear factor κB signaling protects non-Hodgkin’s B lymphoma cells from apoptosis

  • Tuo Su
  • Jiakai Li
  • Mingming Meng
  • Sheng Zhao
  • Yali Xu
  • Xinmin Ding
  • Hong Jiang
  • Xiaorong Ma
  • Jin Qian
  • Wei Han
  • Lixin Sun
  • Xiaobin Li
  • Zuojun Liu
  • Lei Pan
  • Xinying Xue
Original Article

Abstract

The microenvironment encompassing a variety of non-malignant cells in close proximity with malignant tumor cells has been well known to significantly affect the behavior of tumor cells. In this study, we therefore studied the mechanism of bone marrow stromal cells in protection of lymphoma cells from spontaneous apoptosis. We demonstrated that adhesion of the freshly isolated lymphoma B cells to bone marrow stromal cells or freshly isolated lymphoma stromal cells inhibited B cell spontaneous apoptosis in culture. This inhibition of apoptosis correlated with decreased cleavage of caspase-3/8 and increased activation of canonical and non-canonical NF-κB signaling pathway. In addition to BAFF signaling which has been reported as a functional determinant for B lymphoma cell survival in the bone marrow environment, we demonstrated RANKL from BMSCs works synergistically with BAFF to activate NF-κB signaling pathway and thus protects lymphoma B cells from spontaneous apoptosis.

Keywords

Bone marrow stromal cells Nuclear factor κB signaling Non-Hodgkin’s B lymphoma cells Apoptosis 

Notes

Acknowledgments

This study was supported by the fund of special fund, railway head corporation (No. J2015c001-B), and the Young Doctorial Foundation of Beijing Shijitan Hospital (No. 2016-QB10).

This study was supported by the fund of special fund, railway head corporation. Project number is J2015C001-B.

References

  1. 1.
    Kuppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer. 2005;5:251–62. doi: 10.1038/nrc1589.CrossRefPubMedGoogle Scholar
  2. 2.
    Campo E et al. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011;117:5019–32. doi: 10.1182/blood-2011-01-293050.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Alizadeh AA et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–11. doi: 10.1038/35000501.CrossRefPubMedGoogle Scholar
  4. 4.
    Kuppers R, Klein U, Hansmann ML, Rajewsky K. Cellular origin of human B-cell lymphomas. N Engl J Med. 1999;341:1520–9. doi: 10.1056/NEJM199911113412007.CrossRefPubMedGoogle Scholar
  5. 5.
    Shaffer 3rd AL, Young RM, Staudt LM. Pathogenesis of human B cell lymphomas. Annu Rev Immunol. 2012;30:565–610. doi: 10.1146/annurev-immunol-020711-075027.CrossRefPubMedGoogle Scholar
  6. 6.
    Kuppers R. The biology of Hodgkin’s lymphoma. Nat Rev Cancer. 2009;9:15–27. doi: 10.1038/nrc2542.CrossRefPubMedGoogle Scholar
  7. 7.
    Schmitz R et al. TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med. 2009;206:981–9. doi: 10.1084/jem.20090528.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Compagno M et al. Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature. 2009;459:717–21. doi: 10.1038/nature07968.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Kato M et al. Frequent inactivation of A20 in B-cell lymphomas. Nature. 2009;459:712–6. doi: 10.1038/nature07969.CrossRefPubMedGoogle Scholar
  10. 10.
    Honma K et al. TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas. Blood. 2009;114:2467–75. doi: 10.1182/blood-2008-12-194852.CrossRefPubMedGoogle Scholar
  11. 11.
    Lenz G et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science. 2008;319:1676–9. doi: 10.1126/science.1153629.CrossRefPubMedGoogle Scholar
  12. 12.
    Sun L, Deng L, Ea CK, Xia ZP, Chen ZJ. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell. 2004;14:289–301.CrossRefPubMedGoogle Scholar
  13. 13.
    Suarez F, Lortholary O, Hermine O, Lecuit M. Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood. 2006;107:3034–44. doi: 10.1182/blood-2005-09-3679.CrossRefPubMedGoogle Scholar
  14. 14.
    Davis RE et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463:88–92. doi: 10.1038/nature08638.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Ye BH et al. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science. 1993;262:747–50.CrossRefPubMedGoogle Scholar
  16. 16.
    Basso K, Dalla-Favera R. BCL6: master regulator of the germinal center reaction and key oncogene in B cell lymphomagenesis. Adv Immunol. 2010;105:193–210. doi: 10.1016/S0065-2776(10)05007-8.CrossRefPubMedGoogle Scholar
  17. 17.
    Mandelbaum J et al. BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. Cancer Cell. 2010;18:568–79. doi: 10.1016/j.ccr.2010.10.030.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Pasqualucci L et al. Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J Exp Med. 2006;203:311–7. doi: 10.1084/jem.20052204.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Tam W et al. Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas. Blood. 2006;107:4090–100. doi: 10.1182/blood-2005-09-3778.CrossRefPubMedGoogle Scholar
  20. 20.
    Iida S et al. Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma. Nat Genet. 1997;17:226–30. doi: 10.1038/ng1097-226.CrossRefPubMedGoogle Scholar
  21. 21.
    Chapman MA et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471:467–72. doi: 10.1038/nature09837.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Salaverria I et al. Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood. 2011;118:139–47. doi: 10.1182/blood-2011-01-330795.CrossRefPubMedGoogle Scholar
  23. 23.
    DeClerck YA et al. Proteases, extracellular matrix, and cancer: a workshop of the path B study section. Am J Pathol. 2004;164:1131–9. doi: 10.1016/S0002-9440(10)63200-2.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Dave SS et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med. 2004;351:2159–69. doi: 10.1056/NEJMoa041869.CrossRefPubMedGoogle Scholar
  25. 25.
    Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009;114:3367–75. doi: 10.1182/blood-2009-06-225326.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Do RK et al. Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response. J Exp Med. 2000;192:953–64.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lwin T et al. Lymphoma cell adhesion-induced expression of B cell-activating factor of the TNF family in bone marrow stromal cells protects non-Hodgkin’s B lymphoma cells from apoptosis. Leukemia. 2009;23:170–7. doi: 10.1038/leu.2008.266.CrossRefPubMedGoogle Scholar
  28. 28.
    Lwin T et al. Bone marrow stromal cells prevent apoptosis of lymphoma cells by upregulation of anti-apoptotic proteins associated with activation of NF-kappaB (RelB/p52) in non-Hodgkin’s lymphoma cells. Leukemia. 2007;21:1521–31. doi: 10.1038/sj.leu.2404723.CrossRefPubMedGoogle Scholar
  29. 29.
    Lwin T et al. Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas. Blood. 2007;110:1631–8. doi: 10.1182/blood-2006-11-060350.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Mudaliar MA et al. Comparative gene expression profiling identifies common molecular signatures of NF-kappaB activation in canine and human diffuse large B cell lymphoma (DLBCL). PLoS One. 2013;8:e72591. doi: 10.1371/journal.pone.0072591.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Steidl C et al. Gene expression profiling of microdissected Hodgkin Reed-Sternberg cells correlates with treatment outcome in classical Hodgkin lymphoma. Blood. 2012;120:3530–40. doi: 10.1182/blood-2012-06-439570.CrossRefPubMedGoogle Scholar
  32. 32.
    Claudio E, Brown K, Park S, Wang H, Siebenlist U. BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. Nat Immunol. 2002;3:958–65. doi: 10.1038/ni842.CrossRefPubMedGoogle Scholar
  33. 33.
    Dougall WC et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 1999;13:2412–24.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Senftleben U et al. Activation by IKKalpha of a second, evolutionary conserved. NF-kappa B signaling pathway. Science. 2001;293:1495–9. doi: 10.1126/science.1062677.CrossRefPubMedGoogle Scholar
  35. 35.
    Franzoso G et al. Mice deficient in nuclear factor (NF)-kappa B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. J Exp Med. 1998;187:147–59.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Shinkura R et al. Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase. Nat Genet. 1999;22:74–7. doi: 10.1038/8780.CrossRefPubMedGoogle Scholar
  37. 37.
    Yamaoka S et al. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell. 1998;93:1231–40.CrossRefPubMedGoogle Scholar
  38. 38.
    Sun SC. The noncanonical NF-kappaB pathway. Immunol Rev. 2012;246:125–40. doi: 10.1111/j.1600-065X.2011.01088.x.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Tuo Su
    • 1
  • Jiakai Li
    • 2
  • Mingming Meng
    • 3
  • Sheng Zhao
    • 4
  • Yali Xu
    • 5
  • Xinmin Ding
    • 5
  • Hong Jiang
    • 5
  • Xiaorong Ma
    • 5
  • Jin Qian
    • 5
  • Wei Han
    • 1
  • Lixin Sun
    • 1
  • Xiaobin Li
    • 1
  • Zuojun Liu
    • 1
  • Lei Pan
    • 5
  • Xinying Xue
    • 5
  1. 1.Department of General Surgery, Beijing Luhe HospitalCapital Medical UniversityBeijingChina
  2. 2.Department of Radiology of Chinese PLA General HospitalBeijingChina
  3. 3.Department of Gastroenterology, Beijing Shijitan HospitalCapital Medical UniversityBeijingChina
  4. 4.Department of CardiologyPeking University Ninth School of Clinical Medicine, Beijing Shijitan HospitalBeijingChina
  5. 5.Department of Special Medical Treatment, Beijing Shijitan HospitalCapital Medical UniversityBeijingChina

Personalised recommendations