Skip to main content

Advertisement

SpringerLink
Log in

Serum cytokines in follicular lymphoma. Correlation of TGF-β and VEGF with survival

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

The prognosis of follicular lymphoma could vary with the tumor immune microenvironment. We evaluated the prognostic value of serum levels of ten cytokines. Our study cohort included 60 follicular lymphoma patients and 20 controls. Serum was available at diagnosis in 31 patients, at first relapse in 18, and complete remission in 11. Bioplex technology was used for determination of nine cytokines [interleukin (IL)-1Ra, IL-6, IL-7, IL-10, IL-13, tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (b-FGF)]. Transforming growth factor beta (TGF-β) was measured by sandwich enzyme-linked immunosorbent assay. IL-1Ra, IL-6, IL-7, IL-10, IL-13, TNF-α, VEGF, and PDGF levels were found increased in follicular lymphoma patients compared to controls. Multivariate analysis identified early stage and high TGF-β levels as independent predictors of overall survival associated with improved outcome. High lactate dehydrogenase and VEGF levels were independently associated with poorer progression-free survival. These results show the prognostic value of TGF-β and VEGF in follicular lymphoma and suggest their contribution to tumor microenvironment alterations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Armitage JO, Weinsenburger DD (1998) New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 16:2780–2795

    CAS  PubMed  Google Scholar 

  2. Horning SJ (1993) Natural history of and therapy for the indolent non-Hodgkin's lymphomas. Semin Oncol 20:75–88

    CAS  PubMed  Google Scholar 

  3. Liu Q, Fayad L, Cabanillas F, Hagemeister FB, Ayers GD, Hess M et al (2006) Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol 24:1582–1589

    Article  PubMed  Google Scholar 

  4. Coiffier B, Brice P, Delarue R, Haioun C, Souleau B, Mounier N et al (2007) Effect of rituximab and/or high-dose therapy with autotransplant at time of relapse in patients with follicular lymphoma. Blood (ASH annual meeting abstracts) 110, Abstract 386

  5. Solal-Celigny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R et al (2004) Follicular lymphoma international prognostic index. Blood 104:1258–1265

    Article  CAS  PubMed  Google Scholar 

  6. Salles GA (2007) Clinical features, prognosis and treatment of follicular lymphoma. Hematology 2007:216–225

    Article  Google Scholar 

  7. De Jong D (2005) Molecular pathogenesis of follicular lymphoma: a cross talk of genetic and immunologic factors. J Clin Oncol 23:6358–6363

    Article  PubMed  Google Scholar 

  8. Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC et al (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351:2159–2169

    Article  CAS  PubMed  Google Scholar 

  9. Carreras J, Lopez-Guillermo A, Fox BC, Colomo L, Martinez A, Roncador G et al (2006) High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood 108:2957–2964

    Article  CAS  PubMed  Google Scholar 

  10. Lee AM, Clear AJ, Calaminici M, Davies AJ, Jordan S, MacDougall F et al (2006) Number of CD4+ cells and location of forkhead box protein P3-positive cells in diagnostic follicular lymphoma tissue microarrays correlates with outcome. J Clin Oncol 24:5052–5059

    Article  CAS  PubMed  Google Scholar 

  11. Farinha P, Masoudi H, Skinnider BF, Shumansky K, Spinelli JJ, Gill K et al (2005) Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). Blood 106:2169–2174

    Article  CAS  PubMed  Google Scholar 

  12. Canioni D, Salles G, Mounier N, Brousse N, Keuppens M, Morchhauser F et al (2008) High numbers of tumor-associated macrophages have an adverse prognostic value that can be circumvented by rituximab in patients with follicular lymphoma enrolled onto the GELA-GOELAMS FL-2000 trial. J Clin Oncol 26:440–446

    Article  CAS  PubMed  Google Scholar 

  13. Casanovas RO, Mounier N, Brice P, Divine M, Morschhauser F, Gabarre J et al (2007) Plasma cytokine and soluble receptor signature predicts outcome of patients with classical Hodgkin's lymphoma: a study from the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 25:1732–1740

    Article  Google Scholar 

  14. Blay JY, Burdin N, Rousset F, Lenoir G, Biron P, Philip T et al (1993) Serum interleukin-10 in non-Hodgkin's lymphoma: a prognostic factor. Blood 82:2169–2174

    CAS  PubMed  Google Scholar 

  15. Pedersen LM, Klausen TW, Davidsen UH, Johnsen HE (2005) Early changes in serum IL-6 and VEGF levels predict clinical outcome following first-line therapy in aggressive non-Hodgkin's lymphoma. Ann Hematol 84:510–516

    Article  CAS  PubMed  Google Scholar 

  16. Salven P, Orpana A, Teerenhovi L, Joensuu H (2000) Simultaneous elevation in the serum concentrations of the angiogenic growth factors VEGF and bFGF is an independent predictor of poor prognosis in non-Hodgkin lymphoma: a single-institution study of 200 patients. Blood 96:3712–3718

    CAS  PubMed  Google Scholar 

  17. Fayad L, Cabanillas F, Talpaz M, McLaughlin P, Kuzrock R (1998) High serum interleukin-6 levels correlate with a shorter failure-free survival in indolent lymphoma. Leuk Lymphoma 30:563–571

    CAS  PubMed  Google Scholar 

  18. Ansell SM, Novak AJ, Ziesmer S, LaPlant B, Cerhan JR, Yang ZZ et al (1997) Serum cytokine levels predict time to progression after rituximab as initial therapy in patients with follicular grade 1 non-Hodgkin lymphoma. Blood (ASH Annual Meeting Abstracts) 110, abstract 3410

  19. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M (1971) Report of the committee on Hodgkin's disease staging classification. Cancer Res 31:1860–1861

    CAS  PubMed  Google Scholar 

  20. Vignali DA (2000) Multiplexed particle-based flow cytometric assays. J Immunol Methods 243:243–255

    Article  CAS  PubMed  Google Scholar 

  21. Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481

    Article  Google Scholar 

  22. Therneau T, Grambsch P (2000) Modeling survival data: extending the Cox model. Springer, New York

    Google Scholar 

  23. Cerhan JR, Wang S, Maurer MJ, Ansell SM, Geyer SM, Cozen W et al (2007) Prognostic significance of host immune gene polymorphisms in follicular lymphoma survival. Blood 109:5439–5446

    Article  CAS  PubMed  Google Scholar 

  24. Khatri VP, Caligiuri MA (1998) A review of the association between interleukin-10 and human B-cell malignancies. Cancer Immunol Immunother 46:239–244

    Article  CAS  PubMed  Google Scholar 

  25. Levy Y, Brouet JC (1994) Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein. J Clin Invest 93:424–428

    Article  CAS  PubMed  Google Scholar 

  26. Lech-Maranda E, Baseggio L, Bienvenu J, Charlot C, Berger F, Rigal D et al (2004) Interleukin-10 gene promoter polymorphisms influence the clinical outcome of diffuse large B-cell lymphoma. Blood 103:3529–3534

    Article  CAS  PubMed  Google Scholar 

  27. Masood R, Zhang Y, Bond MW, Scadden DT, Moudgil T, Law RE et al (1995) Interleukin-10 is an autocrine growth factor for acquired immunodeficiency syndrome-related B-cell lymphoma. Blood 85:3423–3430

    CAS  PubMed  Google Scholar 

  28. Lebman DA, Edmiston JS (1999) The role of TGF-beta in growth, differentiation, and maturation of B lymphocytes. Microbes Infect 1:1297–1304

    Article  CAS  PubMed  Google Scholar 

  29. Golstein P, Wyllie AH (2001) T cell death and transforming growth factor beta1. J Exp Med 194:F19–F22

    Article  CAS  PubMed  Google Scholar 

  30. Tvrdik D, Dundr P, Povysil G, Pytlik R, Plankova M (2006) Up-regulation of p21WAF1 expression is mediated by Sp1/Sp3 transcription factors in TGFbeta1-arrested malignant B cells. Med Sci Monit 12:BR227–BR234

    CAS  PubMed  Google Scholar 

  31. Tvrdik D (2004) The effect of TGFbeta1 on the expression and phosphorylation of key cell-cycle regulators in malignant B cells. Med Sci Monit 10:BR447–BR454

    CAS  PubMed  Google Scholar 

  32. Husson H, Carideo EG, Neuberg D, Schultze J, Munoz A, Marks PW et al (2002) Gene expression profiling of follicular lymphoma and normal germinal center B cells using cDNA arrays. Blood 99:282–289

    Article  CAS  PubMed  Google Scholar 

  33. Huse K, Bakkebo M, Oksvold M, Smeland EB, Myklebust JH (2007) B cell lymphomas escape bone morphogenetic protein (BMP) induced growth inhibition: downregulation of BMP receptors and upregulation of inhibitory Smads. Blood (American Society of Hematology) 110, Abstract 2605

  34. Ganjoo K (2007) Antiangiogenesis: a new approach to the treatment of lymphoma. Leuk Lymphoma 48:454–455

    Article  PubMed  Google Scholar 

  35. Jorgensen JM, Sorensen FB, Bendix K, Nielsen JL, Olsen ML, Funder AM et al (2007) Angiogenesis in Non-Hodgkin Lymphoma: clinico-pathological correlations and prognostic significance in specific subtypes. Leuk Lymphoma 48:584–595

    Article  CAS  PubMed  Google Scholar 

  36. Stopeck AT, Bellamy W, Unger J, Rimsza L, Lannone M, Fisher RI et al (2005) Phase II trial of single agent bevacizumab (Avastin) in patients with relapsed, aggressive non-Hodgkin's lymphoma (NHL): Southwest Oncology Group Study S0108. J Clin Oncol (ASCO Annual Meeting), Abstract 6592

  37. Sorafenib in treating patients with recurrent diffuse large B-cell non-Hodgkin’s lymphoma (2008) http://clinicaltrials.gov/ct2/show/record/NCT00131937

Download references

Acknowledgments

The authors thank Damien Jeantet, Ecole Normale Superieure, Lyon, for technical assistance and Marie Dominique Reynaud, Centre Leon Berard, for editorial assistance.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Financial support

This study was supported in part by research funding from Roche France laboratories.

Authorship

Ghesquières, Blay, and Labidi made the design of the study. Ghesquières obtained funding. Labidi, Gargi, Sebban, and Biron obtained biological and clinical data. Chassagne carried out pathology revision. Labidi and Caux performed serum cytokine dosage. Chabaud made the statistical analysis. Labidi and Ghesquières drafted the manuscript. All authors revised the manuscript and have reviewed and approved the final manuscript.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Centre Léon Bérard, 28 Rue Laennec, 69008, Lyon, France

    Sana Intidhar Labidi, Catherine Sebban, Pierre Biron, Jean-Yves Blay & Hervé Ghesquières

  2. Inserm U590, Equipe Cytokines et Cancers, Centre Leon Berard, Lyon, France

    Christine Ménétrier-Caux & Jean-Yves Blay

  3. Department of Biostatistics, Centre Leon Berard, Lyon, France

    Sylvie Chabaud & Thérèse Gargi

  4. Department of Pathology, Centre Leon Berard, Lyon, France

    Catherine Chassagne

Authors
  1. Sana Intidhar Labidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christine Ménétrier-Caux
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sylvie Chabaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Catherine Chassagne
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Catherine Sebban
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thérèse Gargi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pierre Biron
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean-Yves Blay
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hervé Ghesquières
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sana Intidhar Labidi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Labidi, S.I., Ménétrier-Caux, C., Chabaud, S. et al. Serum cytokines in follicular lymphoma. Correlation of TGF-β and VEGF with survival. Ann Hematol 89, 25–33 (2010). https://doi.org/10.1007/s00277-009-0777-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-009-0777-8

Keywords

Search

Navigation