Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Production of matrix metalloproteinase-9 in early stage B-CLL: suppression by interferons

Abstract

Besides vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), matrix metalloproteinases (MMPs) play critical roles in angiogenesis, tumor invasion and metastasis. Increased angiogenesis is observed in chronic B lymphocytic leukemia (B-CLL) and published data reported VEGF and bFGF production in this disease. The purpose of this study was to investigate MMP expression in early stage B-CLL. Elevated MMP-9 concentrations were detected by ELISA in the sera of B-CLL patients (median level 250 ng/ml) compared with healthy donors (67 ng/ml) (P < 0.0001), and immunostaining with antibodies against MMP-9 and B cell antigens (CD19, CD23) substantiated the presence of MMP-9 in tumoral B lymphocytes. By using RT-PCR, ELISA and zymography experiments, we confirmed that B-CLL cells expressed and released the pro-form of MMP-9 with Mr 92 kDa (158–1300 pg/ml/106 cells/48 h), p-aminophenylmercuric acetate generating a 82 kDa active form. In contrast, the production of MMP-9 by normal counterpart B cells was significantly low (28–169 pg/ml/106cells/48 h). Moreover, B-CLL culture supernatants contained bFGF (median levels 17 pg/ml/106 cells/48 h), VEGF (1.4 pg/ml/106 cells/48 h) and TNF-α (0.2 pg/ml/106 cells/48 h). TNF-α and VEGF antibodies blocked MMP-9 at the mRNA and protein levels. Interferons (IFNs) type I or type II repressed MMP-9 gelatinolytic activity in a dose and time dependency, and this was reflected by a parallel inhibition of MMP-9 mRNA and protein. IFNs however did not affect the production of bFGF, VEGF and TNF-α. Together, our data show that B-CLL lymphocytes synthesize MMP-9 and emphasize the specific inhibitory actions of IFNs on its expression.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Tomanek RJ, Schatteman GC . Angiogenesis: new insights and therapeutic potential Anat Record 2000 261: 126–135

    Article  CAS  Google Scholar 

  2. Tung-Ping Poon R, Fan ST, Wong J . Clinical implications of circulating angiogenic factors in cancer patients J Clin Oncol 2001 19: 1207–1225

    Article  Google Scholar 

  3. Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM . Matrix metalloproteinases: biologic activity and clinical implications J Clin Oncol 2000 18: 1135–1149

    Article  CAS  PubMed  Google Scholar 

  4. Moses MA . The regulation of neovascularization by matrix metalloproteinases and their inhibitors Stem Cells 1997 15: 180–189

    Article  CAS  PubMed  Google Scholar 

  5. Bertolini F, Mancuso P, Gobbi A, Pruneri G . The thin red line: angiogenesis in normal and malignant hematopoiesis Exp Hematol 2000 28: 993–1000

    Article  CAS  PubMed  Google Scholar 

  6. Aguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D, Koller C, Estrov Z, O'Brien S, Keating M, Freireich E, Albitar M . Angiogenesis in acute and chronic leukemias and myelodysplatic syndromes Blood 2000 96: 2240–2245

    CAS  PubMed  Google Scholar 

  7. Fiedler W, Graeven U, Ergun S, Verago S, Kilic N, Stockschlader M, Hossefeld DK . Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia Blood 1997 89: 1870–1875

    CAS  PubMed  Google Scholar 

  8. Salven P, Teerenhovi L, Joensuli H . A high pretreatment serum basic fibroblast growth factor concentration is an independent predictor of poor prognosis in non-Hodgkin's lymphoma Blood 1999 94: 3334–3339

    CAS  PubMed  Google Scholar 

  9. Vacca A, Ribatti D, Roncali L, Ranieri G, Serio G, Silvestris F, Dammacco F . Bone marrow angiogenesis and progression in multiple myeloma Br J Haematol 1994 87: 503–508

    Article  CAS  PubMed  Google Scholar 

  10. Vacca A, Di Loreto M, Ribatti D, Di Stefano R, Gadaleta-Caldarola G, Iodice G, Caloro D, Dammacco F . Bone marrow of patients with active multiple myeloma: angiogenesis and plasma cell adhesion molecules LFA-1, VLA-4, LAM-1, and CD44 Am J Hematol 1995 50: 9–14

    Article  CAS  PubMed  Google Scholar 

  11. Pruneri G, Bertolini F, Soligo D, Carboni N, Cortelezzi A, Ferrucci PF, Buffa R, Lambertenghi-Deliliers G, Pezzella F . Angiogenesis in myelodysplastic syndromes Br J Cancer 1999 81: 1398–1401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kini AR, Kay NE, Peterson LC . Increased bone marrow angiogenesis in B cell chronic lymphocytic leukemia Leukemia 2000 14: 1414–1418

    Article  CAS  PubMed  Google Scholar 

  13. Kalil N, Cheson BD . Management of chronic lymphocytic leukaemia Drugs Aging 2000 13: 9–27

    Article  Google Scholar 

  14. Aguayo A, O'Brien S, Keating M, Manshouri T, Gidel C, Barlogie B, Beran M, Kodler C, Kantarjan H, Albitar M . Clinical relevance of intracellular vascular endothelial growth factor levels in B-cell chronic lymphocytic leukemia Blood 2000 96: 768–770

    CAS  PubMed  Google Scholar 

  15. Chen H, Treweeke AT, West DC, Till KJ, Cawley JC, Zuzei M, Toh CH . In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells Blood 2000 96: 3181–3187

    CAS  PubMed  Google Scholar 

  16. Menzel T, Rahman Z, Calleja E, White K, Wilson EL, Wieder R, Gabrilove J . Elevated intracellular level of basic fibroblast growth factor correlates with stage of chronic lymphocytic leukemia and is associated with resistance to fludarabine Blood 1996 87: 1056–1063

    CAS  PubMed  Google Scholar 

  17. Stetler-Stevenson M, Mansoor A, Lim M, Fikushima P, Kehrl J, Mart G, Ptaszynski K, Wang J, Stetler-Stevenson WG . Expression of matrix metalloproteinases in reactive and neoplastic lymphoid cells Blood 1997 89: 1708–1715

    CAS  PubMed  Google Scholar 

  18. Trocmé C, Gaudin P, Berthier S, Barro C, Zaoui P, Morel F . Human B lymphocytes synthesize the 92-kDa gelatinase, matrix metalloproteinase-9 J Biol Chem 1998 273: 20677–20684

    Article  PubMed  Google Scholar 

  19. Kossakowska AE, Edwards DR, Prusinkiewicz C, Zhang MC, Guo D, Urbanski SJ, Grognan T, Marquez LA, Janowska-Wieczorek A . Interleukin-6 regulation of matrix metalloproteinase (MMP-2 and MMP-9) and tissue inhibitor of metalloproteinase (TIMP-1) expression in malignant non-Hodgkin's lymphomas Blood 1999 94: 2080–2089

    CAS  PubMed  Google Scholar 

  20. Kelly T, Borset M, Abe E, Gaddy-Kurten D, Sanderson RD . Matrix metalloproteinases in multiple myeloma Leuk Lymph 2000 37: 273–281

    Article  CAS  Google Scholar 

  21. Yoshizaki T, Sato H, Furukawa M, Pagano JS . The expression of matrix metalloproteinase 9 is enhanced by Epstein–Barr virus latent membrane protein 1 Proc Natl Acad Sci USA 1998 95: 3621–3626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Baron S, Tyring SK, Fleischmann WR, Coppenhaver DH, Niesel DW, Klimpel GR, Stanton GJ, Hughes TK . The interferons. Mechanisms of action and clinical applications JAMA 1991 266: 1375–1383

    Article  CAS  PubMed  Google Scholar 

  23. Strander H, Einhorn S . Interferons and the tumor cell Biotherapy 1996 8: 213–218

    Article  CAS  PubMed  Google Scholar 

  24. Corssmit EPM, De Metz J, Sauerwein HP, Romijn JA . Biologic responses to IFN-α administration in humans J Interfer Cyt Res 2000 20: 1039–1047

    Article  CAS  Google Scholar 

  25. Bauvois B, Djavaheri-Mergny M, Rouillard D, Dumont J, Wietzerbin J . Regulation of CD26/DPPIV gene expression by interferons and retinoic acid in tumor B cells Oncogene 2000 19: 265–272

    Article  CAS  PubMed  Google Scholar 

  26. Chintala SK, Sawaya R, Aggarwal BB, Majumder S, Giri DK, Kyritsis AP, Gokaslan ZL, Rao JS . Induction of matrix metalloproteinase-9 requires a polymerized actin cytoskeleton in human malignant glioma cells J Biol Chem 1998 273: 13545–13551

    Article  CAS  PubMed  Google Scholar 

  27. Westphal JR, Hullenaar RV, Pekk R, Willems RW, Crickard K, Crickard U, Askaa J, Clemmensen I, Ruiter DJ, De Waal MW . Angiogenic balance in human melanoma: expression of VEGF, bFGF, IL-8, PDGF and angiostatin in relation to vascular density of xenografts in vivo Int J Cancer 2000 86: 768–776

    Article  CAS  PubMed  Google Scholar 

  28. Cronauer MV, Stadlmann S, Klocker H, Abendstein B, Eder IE, Rogatsch H, Zeimet AG, Marth C, Offner FA . Basic fibroblast growth factor synthesis by human peritoneal mesothelial cells Am J Pathol 1999 155: 1977–1984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Opdenakker G, Van den Steen PE, Dubois B, Nelissen I, Van Coillie E, Masure S, Proost P, Van Damme J . Gelatinase B functions as regulator and effector in leukocyte biology J Leuk Biol 2001 69: 851–859

    CAS  Google Scholar 

  30. Wang He, Keiser JA . Vascular endothelial growth factor upregulates the expression of matrix metalloproteinases in vascular smooth muscle cells Cir Res 1998 83: 832–840

    Article  CAS  Google Scholar 

  31. Dias S, Hattori K, Zhu Z, Heissig B, Choy M, Lane W, Wu Y, Chadburn A, Hyjek E, Gill M, Hicklin DJ, Witte L, Moore MA, Rafii S . Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration J Clin Invest 2000 106: 511–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Schena M, Gaidano G, Gottardi D, Malavasi F, Larsson LG, Nilsson K, Caligaris-Cappio F . Molecular investigation of the cytokines produced by normal and malignant B lymphocytes Leukemia 1992 6: 120–125

    CAS  PubMed  Google Scholar 

  33. Rambaldi A, Bettoni S, Rossi V, Tini ML, Giudici G, Rizzo V, Bassan R, Mantovani A, Barbui T, Biondi A . Transcriptional and post-transcriptional regulation of IL1-beta, IL-6 and TNF-alpha genes in chronic lymphocytic leukemia Br J Haematol 1993 83: 204–211

    Article  CAS  PubMed  Google Scholar 

  34. Diaw L, Lefebvre d'Hellencour C, Cornillet I, Vuiller F, Guenounou M, Dighiero G . Expression and production of cytokines by heterohybrids and their parental B cells in CLL Leuk Lymph 1996 21: 281–291

    Article  CAS  Google Scholar 

  35. Di Girolamo N, Visvnathan K, Lloyd A, Wakefield D . Expression of TNF-alpha by human plasma cells in chronic inflammation J Leuk Biol 1997 61: 667–678

    Article  CAS  Google Scholar 

  36. Bond M, Rosalind P, Fabunmi P, Baker AH, Newby AC . Synergisitic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an abolute requirement for transcription factor NF-kB Biochem Biophys Res Comm 1998 435: 29–34

    CAS  Google Scholar 

  37. Furman RR, Asgary Z, Mascarenhas O, Liou H, Schattner EJ . Modulation of NF-κB activity and apoptosis in chronic lymphocytic leukemia B cells J Immunol 2000 164: 2200–2206

    Article  CAS  PubMed  Google Scholar 

  38. Bikfalvi A, Han ZC . Angiogenic factors are hematopoietic growth factors and vice versa Leukemia 1994 8: 523–529

    CAS  PubMed  Google Scholar 

  39. Ivanoff A, Ivanoff J, Hultenby K, Sundqvist KG . Infiltrative capacity of T leukemia cell lines: a distinct functional property coupled to expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) Clin Exp Metastasis 1999 17: 695–711

    Article  CAS  PubMed  Google Scholar 

  40. Engsig M, Chen Q, Vu TH, Pedersen AC, Therkidsen B, Lund LR, Henriksen K, Lenhard T, Foged NT, Werb Z, Delaissé JM . Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones J Cell Biol 2000 151: 879–889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tomanek RJ, Schatteman GC . Angiogenesis: new insights and therapeutic potential Anat Rec 2000 261: 126–135

    Article  CAS  PubMed  Google Scholar 

  42. Lienkens S, De Clercq E, Neyts J . Angiogenesis: regulators and clinical applications Biochem Pharmacol 2001 61: 253–270

    Article  Google Scholar 

  43. Dinney CP, Bielenberg DR, Perrotte P, Reich R, Eve BY, Bucana CD, Fidler IJ . Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration Cancer Res 1998 58: 808–814

    CAS  PubMed  Google Scholar 

  44. Lopez-Ocejo O, Perea SE, Bequet-Romero M, Arana MJ, Lopez-Saura P . Impaired angiogenic balance and suppression of tumorigenicity in HeLa cells chronically exposed to interferon-α Biochem Biophys Res Comm 2000 277: 410–416

    Article  CAS  PubMed  Google Scholar 

  45. Stüve O, Dooley NP, Uhm JH, Antel JP, Francis GS, Williams G, Yong VW . Interferon β-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9 Ann Neurol 1996 40: 853–863

    Article  PubMed  Google Scholar 

  46. Makela M, Salo T, Larjava H . MMP-9 from TNF alpha-stimulated keratinocytes binds to cell membranes and type I collagen: a cause for extended matrix degradation in inflammation? Biochem Biophys Res Commun 1998 18: 325–335

    Article  Google Scholar 

  47. Lou J, Gasche Y, Zheng L, Giroud C, Morel P, Clements J, Yhtier A, Grau GE . Interferon-beta inhibits activated leukocyte migration through human brain microvascular endothelial cell monolayer Lab Invest 1999 79: 1015–1025

    CAS  PubMed  Google Scholar 

  48. Ivanoff A, Ivanoff J, Hultenby K, Sundqvist KG . Infiltrative capacity of T leukemia cell lines: a distinct functional property coupled to expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) Clin Exp Metastasis 1999 17: 695–711

    Article  CAS  PubMed  Google Scholar 

  49. Bartholmé EJ, Van Aelst I, Koyen E, Kiss R, Willems F, Goldman M, Opdenakker G . Human monocyte-derived dendritic cells produce bioactive gelatinase B: inhibition by IFN-β J Interferon Cytokine Res 2001 21: 495–501

    Article  Google Scholar 

  50. Singh RK, Gutman M, Bucana CD, Sanchez R, Llansa N, Fidler IJ . Interferons α and β down-regulate the expression of basic fibroblast growth factor in human carcinomas Proc Natl Acad Sci USA 1995 92: 4562–4566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Riedel F, Gotte K, Berler W, Rojas W, Hormann K . Expression of basic fibroblast growth protein and its down regulation by interferons in head and neck cancer Head Neck 2000 22: 183–189

    Article  CAS  PubMed  Google Scholar 

  52. Kawano Y, Matsui N, Narahara H, Miyakawa I . Effects of interferon-gamma on secretion of vascular endothelial growth factor by endometrial stromal cells Am J Reprod Immunol 2000 43: 47–52

    Article  CAS  PubMed  Google Scholar 

  53. Salven P, Anttonen K, Repo H, Joensuu H, Orpana A . Endotoxins induce and interferon-alpha suppresses vascular endothelial growth factor (VEGF) production in human peripheral blood mononuclear cells Faseb J 2001 15: 1318–1320

    Article  CAS  PubMed  Google Scholar 

  54. Cheson BD . Chronic lymphoid leukemias Clin Oncol 2001 83: 1999–2022

    Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM), the Association pour la Recherche sur le Cancer (No. 9481) and the Fondation contre la Leucémie. The authors thank Roussel-Uclaf (Romainville, France) for supplying IFN-γ, Hoffman-La Roche (Basel, Switzerland) for supplying IFN-α2a, and Ares-Serono (Geneva, Switzerland) for supplying IFN-β. We are grateful to Dr J Sancéau (Institut Curie, Paris, France) for her invaluable help and suggestions, and to Mrs D Rouillard for her dedicated helpfulness in FACS.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bauvois, B., Dumont, J., Mathiot, C. et al. Production of matrix metalloproteinase-9 in early stage B-CLL: suppression by interferons. Leukemia 16, 791–798 (2002). https://doi.org/10.1038/sj.leu.2402472

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402472

Keywords

This article is cited by

Search

Quick links