Increased plasma endostatin and GDF15 in indolent non-Hodgkin lymphoma
Keywords:
Growth differentiation factor 15, endostatin, matrix metalloproteinase 9, neutrophil gelatin-aseassociated lipocalin, non-Hodgkin lymphoma, angiogenesis
Abstract
Background: Increased microvascular density correlates with more advanced disease and unfavorable overall survival in non-Hodgkin lymphoma (NHL), suggesting that angiogenesis is important for disease progression. However, studies of anti-angiogenic agents in NHL patients, have generally not shown favorable outcomes. The aim of this study was to investigate whether plasma levels of a subset of angiogenesis-associated proteins are increased in indolent B-cell derived NHL (B-NHL) and to investigate whether the levels differ between patients with asymptomatic versus symptomatic disease.
Methods: Plasma levels of growth differentiation factor 15 (GDF15), endostatin, matrix metalloproteinase 9 (MMP9), neutrophil gelatinase-associated lipocalin (NGAL), long pentraxin 3 (PTX3), and galectin 3 (GAL-3) were measured by ELISA in 35 patients with symptomatic indolent B-NHL, 41 patients with asymptomatic disease, and 62 healthy controls. Bootstrap t-tests were used to assess the relative differences in biomarker levels between groups. Group differences were visualized using a principal component plot.
Results: Mean plasma endostatin and GDF15 levels were significantly higher in symptomatic and asymptomatic lymphoma patients than in controls. Symptomatic patients had higher mean MMP9 and NGAL than controls.
Conclusions: The finding of increased plasma endostatin and GDF15 in patients with asymptomatic indolent B-NHL suggests that increased angiogenic activity is an early event in indolent B-NHL disease progression.
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References
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34. Konstantinov KN, Robbins BA, Liu FT. Galectin-3, a beta-galactoside-binding animal lectin, is a marker of anaplastic large-cell lymphoma. Am J Pathol 1996; 148(1): 25–30.
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36. Leonard JP, Trneny M, Izutsu K, Fowler NH, Hong X, Zhu J, et al. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol 2019; 37(14): 1188–99. doi: 10.1200/JCO.19.00010
37. Hainsworth JD, Greco FA, Raefsky EL, Thompson DS, Lunin S, Reeves J, Jr., et al. Rituximab with or without bevacizumab for the treatment of patients with relapsed follicular lymphoma. Clin Lymphoma Myeloma Leuk 2014; 14(4): 277–83. doi: 10.1016/j.clml.2014.02.010
38. Guidetti A, Carlo-Stella C, Locatelli SL, Malorni W, Pierdominici M, Barbati C, et al. Phase II study of sorafenib in patients with relapsed or refractory lymphoma. Br J Haematol 2012; 158(1): 108–19. doi: 10.1111/j.1365-2141.2012.09139.x
2. Lumish M, Falchi L, Imber BS, Scordo M, Von Keudell G, Joffe E. How we treat mature B-cell neoplasms (indolent B-cell lymphomas). J Hematol Oncol 2021; 14(1): 5. doi: 10.1186/s13045-020-01018-6
3. Kurtin PJ. Indolent lymphomas of mature B lymphocytes. Hematol Oncol Clin North Am 2009; 23(4): 769–90. doi: 10.1016/j.hoc.2009.04.010
4. Freedman A, Jacobsen E. Follicular lymphoma: 2020 update on diagnosis and management. Am J Hematol 2020; 95(3): 316–27. doi: 10.1002/ajh.25696
5. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell 2019; 176(6): 1248–64. doi: 10.1016/j.cell.2019.01.021
6. Jiang L, Li N. B-cell non-Hodgkin lymphoma: importance of angiogenesis and antiangiogenic therapy. Angiogenesis 2020; 23(4): 515–29. doi: 10.1007/s10456-020-09729-7
7. Wu J, Ma S, Sun L, Qin Z, Wang Z, Wang N, et al. Prognostic value of microvessel density in non-hodgkin lymphoma: a meta-analysis. Acta Haematol 2021; 144(6): 603–12. doi: 10.1159/000515211
8. Marozzi M, Parnigoni A, Negri A, Viola M, Vigetti D, Passi A, et al. Inflammation, extracellular matrix remodeling, and proteostasis in tumor microenvironment. Int J Mol Sci 2021; 22(15): 8102. doi: 10.3390/ijms22158102
9. Mohan V, Das A, Sagi I. Emerging roles of ECM remodeling processes in cancer. Semin Cancer Biol 2020; 62: 192–200. doi: 10.1016/j.semcancer.2019.09.004
10. Menzel L, Höpken UE, Rehm A. Angiogenesis in lymph nodes is a critical regulator of immune response and lymphoma growth. Frontiers in Immunology 2020; 11: 591741. doi: 10.3389/fimmu.2020.591741
11. Hidman J, Larsson A, Thulin M, Karlsson T. Increased plasma GDF15 is associated with altered levels of soluble VEGF receptors 1 and 2 in symptomatic multiple myeloma. Acta Haematol 2021; 145(3): 326–333. doi: 10.1159/000519888
12. Larsson K, Höglund M, Larsson A, Thulin M, Karlsson T. Increased levels of the cardiovascular disease risk biomarkers GDF15 and myostatin in patients with chronic lymphocytic leukemia. Growth Factors 2020;38(3–4):189–96. doi: 10.1080/08977194.2021.1932870
13. Bono P, Teerenhovi L, Joensuu H. Elevated serum endostatin is associated with poor outcome in patients with non-Hodgkin lymphoma. Cancer 2003; 97(11): 2767–75. doi: 10.1002/cncr.11399
14. Bauvois B, Pramil E, Jondreville L, Chapiro E, Quiney C, Maloum K, et al. Relation of neutrophil gelatinase-associated lipocalin overexpression to the resistance to apoptosis of tumor B Cells in chronic lymphocytic leukemia. Cancers (Basel) 2020; 12(8): 2124. doi: 10.3390/cancers12082124
15. Zhou Z, Li Z, Xue W, Zhang X, Young KH, Wang Y, et al. Identification of PTX3 and S100A9 as serum diagnostic and therapeutic response biomarkers of NK/T cell lymphoma patients. Blood 2017; 130(Suppl 1): 2804.
16. Thulin M. Modern Statistics with R. Uppsala: Eos Chasma Press; 2021.
17. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B (Methodol) 1995;57(1):289-300. doi: 10.1111/j.2517-6161.1995.tb02031.x
18. Corre J, Hébraud B, Bourin P. Concise review: growth differentiation factor 15 in pathology: a clinical role? Stem Cells Transl Med 2013; 2(12): 946–52. doi: 10.5966/sctm.2013-0055
19. Ha G, De Torres F, Arouche N, Benzoubir N, Ferratge S, Hatem E, et al. GDF15 secreted by senescent endothelial cells improves vascular progenitor cell functions. PLoS One 2019; 14(5): e0216602. doi: 10.1371/journal.pone.0216602
20. Song H, Yin D, Liu Z. GDF-15 promotes angiogenesis through modulating p53/HIF-1α signaling pathway in hypoxic human umbilical vein endothelial cells. Mol Biol Rep 2012; 39(4): 4017–22. doi: 10.1007/s11033-011-1182-7
21. Dong G, Zheng QD, Ma M, Wu SF, Zhang R, Yao RR, et al. Angiogenesis enhanced by treatment damage to hepatocellular carcinoma through the release of GDF15. Cancer Med 2018; 7(3): 820–30. doi: 10.1002/cam4.1330
22. Westhrin M, Moen SH, Holien T, Mylin AK, Heickendorff L, Olsen OE, et al. Growth differentiation factor 15 (GDF15) promotes osteoclast differentiation and inhibits osteoblast differentiation and high serum GDF15 levels are associated with multiple myeloma bone disease. Haematologica 2015; 100(12): e511–4. doi: 10.3324/haematol.2015.124511
23. Corre J, Labat E, Espagnolle N, Hébraud B, Avet-Loiseau H, Roussel M, et al. Bioactivity and prognostic significance of growth differentiation factor GDF15 secreted by bone marrow mesenchymal stem cells in multiple myeloma. Cancer Res 2012; 72(6): 1395–406. doi: 10.1158/0008-5472.CAN-11-0188
24. Alaseem A, Alhazzani K, Dondapati P, Alobid S, Bishayee A, Rathinavelu A. Matrix metalloproteinases: a challenging paradigm of cancer management. Semin Cancer Biol 2019; 56: 100–15. doi: 10.1016/j.semcancer.2017.11.008
25. Haas TL, Milkiewicz M, Davis SJ, Zhou AL, Egginton S, Brown MD, et al. Matrix metalloproteinase activity is required for activity-induced angiogenesis in rat skeletal muscle. Am J Physio-Heart Circ Physio 2000; 279(4): H1540–H7. doi: 10.1152/ajpheart.2000.279.4.H1540
26. Sakata K, Satoh M, Someya M, Asanuma H, Nagakura H, Oouchi A, et al. Expression of matrix metalloproteinase 9 is a prognostic factor in patients with non-Hodgkin lymphoma. Cancer 2004; 100(2): 356–65. doi: 10.1002/cncr.11905
27. Seppinen L, Pihlajaniemi T. The multiple functions of collagen XVIII in development and disease. Matrix Biol 2011; 30(2): 83–92. doi: 10.1016/j.matbio.2010.11.001
28. Walia A, Yang JF, Huang YH, Rosenblatt MI, Chang JH, Azar DT. Endostatin’s emerging roles in angiogenesis, lymphangiogenesis, disease, and clinical applications. Biochim Biophys Acta 2015; 1850(12): 2422–38. doi: 10.1016/j.bbagen.2015.09.007
29. Santiago-Sánchez GS, Pita-Grisanti V, Quiñones-Díaz B, Gumpper K, Cruz-Monserrate Z, Vivas-Mejía PE. Biological functions and therapeutic potential of lipocalin 2 in cancer. Int J Mol Sci 2020; 21(12): 4365. doi: 10.3390/ijms21124365
30. Nakamura I, Hama S, Itakura S, Takasaki I, Nishi T, Tabuchi Y, et al. Lipocalin2 as a plasma marker for tumors with hypoxic regions. Sci Rep 2014; 4(1): 7235. doi: 10.1038/srep07235
31. Yang J, McNeish B, Butterfield C, Moses MA. Lipocalin 2 is a novel regulator of angiogenesis in human breast cancer. Faseb J 2013; 27(1): 45–50. doi: 10.1096/fj.12-211730
32. Wu L, Du Y, Lok J, Lo EH, Xing C. Lipocalin-2 enhances angiogenesis in rat brain endothelial cells via reactive oxygen species and iron-dependent mechanisms. J Neurochem 2015; 132(6): 622–8. doi: 10.1111/jnc.13023
33. Giacomini A, Ghedini GC, Presta M, Ronca R. Long pentraxin 3: a novel multifaceted player in cancer. Biochim Biophys Acta Rev Cancer 2018; 1869(1): 53–63. doi: 10.1016/j.bbcan.2017.11.004
34. Konstantinov KN, Robbins BA, Liu FT. Galectin-3, a beta-galactoside-binding animal lectin, is a marker of anaplastic large-cell lymphoma. Am J Pathol 1996; 148(1): 25–30.
35. Lu L, Payvandi F, Wu L, Zhang LH, Hariri RJ, Man HW, et al. The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. Microvasc Res 2009; 77(2): 78–86. doi: 10.1016/j.mvr.2008.08.003
36. Leonard JP, Trneny M, Izutsu K, Fowler NH, Hong X, Zhu J, et al. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol 2019; 37(14): 1188–99. doi: 10.1200/JCO.19.00010
37. Hainsworth JD, Greco FA, Raefsky EL, Thompson DS, Lunin S, Reeves J, Jr., et al. Rituximab with or without bevacizumab for the treatment of patients with relapsed follicular lymphoma. Clin Lymphoma Myeloma Leuk 2014; 14(4): 277–83. doi: 10.1016/j.clml.2014.02.010
38. Guidetti A, Carlo-Stella C, Locatelli SL, Malorni W, Pierdominici M, Barbati C, et al. Phase II study of sorafenib in patients with relapsed or refractory lymphoma. Br J Haematol 2012; 158(1): 108–19. doi: 10.1111/j.1365-2141.2012.09139.x
Published
2023-05-09
How to Cite
Hidman J., Larsson A., Thulin M., & Karlsson T. (2023). Increased plasma endostatin and GDF15 in indolent non-Hodgkin lymphoma. Upsala Journal of Medical Sciences, 128(1). https://doi.org/10.48101/ujms.v128.9392
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