Increased levels of a subset of angiogenesis-related plasma proteins in essential thrombocythemia
Keywords:
Essential thrombocythemia, angiogenesis, extracellular matrix, matrix metallopeptidase 9, endostatin
Abstract
Background: Increased local angiogenesis is important for the growth and dissemination of cancer. The myeloproliferative neoplasm essential thrombocythemia (ET) is known to involve increased bone marrow angiogenesis. Blood levels of several angiogenesis-related proteins are increased in different types of cancer. The aim of this study was to investigate whether a subset of such proteins was elevated in treatment-naïve ET patients.
Methods: Blood plasma from 41 ET patients and 43 healthy aged-matched controls was analyzed for eight different angiogenesis-related proteins.
Results: The ET cohort displayed a more homogenous expression pattern of these proteins compared with controls. Five of the eight proteins were significantly increased in ET patients.
Conclusion: Increased plasma levels of matrix metallopeptidase 9 (MMP9) and endostatin have not previously been reported in ET. In our patients, MMP9 levels correlated positively with Janus kinase 2 (JAK2) V617F allele burden and leukocyte count.
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References
1. Tefferi A, Pardanani A. Essential thrombocythemia. N Engl J Med. 2019;381:2135–44. doi: 10.1056/NEJMcp1816082
2. Panteli K, Zagorianakou N, Agnantis NJ, Bourantas KL, Bai M. Clinical correlation of bone marrow microvessel density in essential thrombocythemia. Acta Haematol. 2005;114:99–103. doi: 10.1159/000086583
3. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell. 2019;176:1248–64. doi: 10.1016/j.cell.2019.01.021
4. Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer. 2014;14:159–72. doi: 10.1038/nrc3677
5. Bowler E, Oltean S. Alternative splicing in angiogenesis. Int J Mol Sci. 2019;20:2067. doi: 10.3390/ijms20092067
6. 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
7. 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
8. Thulin M. Modern statistics with R. Uppsala: Eos Chasma Press; 2021. ISBN 9789152701515
9. 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;57:289–300. doi: 10.10.1111/j.2517-6161.1995.tb02031.x.x
10. Quintero-Fabian S, Arreola R, Beceril-Villanueva E, Torres-Romero JC, Arana-Argaez V, Lara-Riegos J, et al. Role of matrix metalloproteinases in angiogenesis and cancer. Front Oncol. 2019;9:1370. doi: 10.3389/fonc.2019.01370
11. Heljasvaara R, Nyberg P, Luostarinen J, Parikka M, Heikkilä P, Rehn M, et al. Generation of biologically active endostatin fragments from human collagen XVIII by distinct matrix metalloproteinases. Exp Cell Res. 2005;307:292–304. doi: 10.1016/j.yexcr.2005.03.021
12. Bendrik C, Robertson J, Gauldie J, Dabrosin C. Gene transfer of matrix metalloproteinase-9 induces tumor regression in breast cancer in vivo. Cancer Res. 2008;68:3405–412. doi: 10.1158/0008-5472.CAN-08-0295
13. Vu TH, Shipley M, Bergers G, Berger JE, Helms JA, Hanahan D, et al. MMP-9/Gelatinase-B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell. 1998;93:411–22. doi: 10.1016/S0092-8674(00)81169-1
14. 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 Physiol. Heart Circ Physiol. 2000;279:H1540–7. doi: 10.1152/ajpheart.2000.297.4.H1540
15. Walia A, Yang JF, Huang Y-H, Rosenblatt MI, Chang J-H, Azar DT. Endostatin’s emerging roles in angiogenesis, lymphangiogenesis, disease, and clinical applications. Biochim Biophys Acta. 2015;1850:2422–38. doi: 10.1016/j.bbagen2015.09.007
16. Maral S, Acar M, Balcik OS, Uctepe E, Hatipoglu OF, Akdeniz D, et al. Matrix metalloproteinase 2 and 9 polymorphism in patients with myeloproliferative diseases. A STROBE-compliant observational study. Medicine. 2015;94:e732. doi: 10.1097/MD.0000000000000732
17. Wang Y, Su Y, Xu Y, Pan S-H, Liu G-D. Genetic polymorphism c.1562C>T of the MMP9 is associated with macroangiopathy in type 2 diabetes mellitus. Biochem Biophys Res Comm. 2010;391:113–77. doi: 10.1016/j.bbrc.2009.11.012
18. Zhang B, Ye S, Herrmann S-M, Eriksson P, de Maat M, Evans A, at al. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation. 1999;99:1788–94. doi: 10.1161/01.CIR.99.14.1788
19. Deryugina EI, Zajac E, Juncker-Jensen A, Kupriyanova TA, Welter L, Quigley JP. Tissue-infiltrating neutrophils constitute the major in vivo source of angiogenesis-inducing MMP9 in the tumor microenvironment. Neoplasia. 2014;16:771–88. doi: 10.1016/j.neo.2014.08.013
20. Dale D. Neutropenia and neutrophilia. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. Williams hematology. 6th ed. New York: McGraw-Hill; 2001, pp. 823–34.
21. Akashi K, Draver D, Miyamoto T, Weissman IL. A clonogenic common myeloid precursor that gives rise to all myeloid lineages. Nature. 2000;404:193–7. doi: 10.1038/35004599
22. Petzold T, Zhang Z, Ballesteros I, Saleh I, Polzin A, Thienel M, et al. Neutrophil ‘plucking’ on megakaryocytes drives platelet production and boosts cardiovascular disease. Immunity. 2022;55:2885–99. doi: 10.1016/j.immuni.2022.10.001
23. Corre J, Hébraud B, Bourin P. Concise review: GDF15 in pathology: a clinical role? Stem Cells Translat Med. 2013;2:946–52. doi: 10.5966/sctm.2013-0055
24. 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/jouranl.pone.0216602
25. Park H, Nam K-S, Lee H-J, Kim KS. Ionizing radiation-induced GDF15 promotes angiogenesis in human glioblastoma models by promoting VEGFA expression through p-MAPK1/SP1 signaling. Front Oncol. 2022;12:801230. doi: 10.3389/fonc.2022.801230
26. Tarkun P, Mehtap O, Atesoglu E, Geduk A, Musul MM, Hacihanefioglu A. Serum hepcidin and growth differentiation factor-15 (GDF-15) levels in polycythemia vera and essential thrombocythemia. Eur J Haematol. 2013;91:228–35. doi: 10.1111/ejh.12150
27. Corre J, Labat E, Espagnolle N, Hebraud B, Avet-Loiseau H, Roussel M, et al. Bioactivity and prognostic significance of growth differentiation factor GDF 15 secreted by bone marrow mesenchymal stem cells in multiple myeloma. Cancer Res. 2012;72:1395–406. doi: 10.1158/0008-5472.CAN-11-0188
28. Tvaroska I, Selvaraj C, Koca J. Selectins – the two Dr. Jekyll and Mr. Hyde faces of adhesion molecules – a review. Molecules. 2020;25:2835. doi: 10.3390/molecules25122835
29. Koch AE, Halloran MM, Haskell CJ, Shah MR, Polverini PJ. Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature. 1995;376:517–9. doi: 10.1038/376517a0
30. Egami K, Murohara T, Aoki M, Matshuisi T. Ischemia-induced angiogenesis: role of inflammatory response mediated by P-selectin. J Leukocyte Biol. 2006;79:971–6. doi: 10.1189/jlb.0805448
31. Cella G, Marchetta M, Vianello F, Panova-Noeva M, Vignoli A, Russo L, et al. Nitric oxide derivatives and soluble plasma selectins in patients with myeloproliferative neoplasms. Thromb Haemost. 2010;104:151–6. doi: 10.1160/TH09-09-0663
32. Belotti A, Elli E, Speranza T, Lanzi E, Pioltelli P, Pogliani P. Circulating endothelial cells and endothelial activation in essential thrombocythemia: results from CD146+ immunomagnetic enrichment – flow cytometry and soluble E-selectin detection. Am J Hematol. 2011;87:319–20. doi: 10.1002/ajh.22264
33. Bilgir F, Bilgir O, Calan M, Sari F. The levels of adhesion molecules in essential thrombocythemia. Panminerva Med. 2013;55:385–90.
34. Ambati B, Nozaki M, Singh N, Takeda A, Jani P, Suthar T, et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature. 2006;443(26):993–7. doi: 10.1038/nature05249
35. Chappell JC, Taylor SM, Ferrara N, Bautch VL. Local guidance of emerging vessel sprouts requires soluble Flt-1 (VEGFR-1). Dev Cell. 2009;17(3):377–86. doi: 10.1016/j.devcel.2009.07.011
36. Trelinski J, Wierzbowska A, Krawzcynska A, Sakowicz A, Pietrucha T, Smolewski P, et al. Circulating endothelial cells in essential thrombocythemia and polycythemia vera: correlation with JAK2-V617F mutational status, angiogenic factors and coagulation activation markers. Int J Hematol. 2010;91:792–8. doi: 10.1007/s12185-010-0596-7
37. Gadomska G, Bartoszewska-Kubiak A, Boinska J, Matiakowska K, Ziolkowska K, Haus O, et al. Selected parameters of angiogenesis and the JAK2, CALR, and MPL mutations in patients with essential thrombocythemia. Clin Appl Thromb Haemostas. 2018;24:1056–60. doi: 10.1177/1076029617740222
38. Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, et al. Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors. Blood. 2010;95:952–8. doi: 10.1182/blood.V95.3.952.003k27_952_958
39. Ronca R, Taranto S, Corsini M, Tobia C, Ravelli C, Rezzola S, et al. Pentraxin 3 inhibits the angiogenic potential of multiple myeloma cells. Cancers. 2021;13:2255. doi: 10.3390/cancers13092255
40. Rodriguez-Grande B, Varghese L, Molina-Holgado F, Rajkovic O, Garlanda C, Denes A, et al. Pentraxin 3 mediates neurogenesis and angiogenesis after cerebral ischaemia. J Neuroinflamm. 2015;12:15. doi: 10.1186/s12974-014-0227-y
41. Abu Sabaa A, Shen Q, Bergfelt Lennmyr E, Enblad A P, Gammelgård G, Molin D, et al. Plasma protein biomarker profiling reveals major differences between acute leukaemia, lymphoma patients and controls. N Biotechnol. 2022;71:21–9. doi: 10.1016/j.nbt.2022.06.005
42. Gholiha A R, Hollander P, Löf L, Larsson A, Hashemi J, Mattsson Ulfstedt J, et al. Immune-proteome profiling in classical Hodgkin lymphoma tumor diagnostic tissue. Cancers. 2022;14:9. doi: 10.3390/cancers14010009
2. Panteli K, Zagorianakou N, Agnantis NJ, Bourantas KL, Bai M. Clinical correlation of bone marrow microvessel density in essential thrombocythemia. Acta Haematol. 2005;114:99–103. doi: 10.1159/000086583
3. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell. 2019;176:1248–64. doi: 10.1016/j.cell.2019.01.021
4. Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer. 2014;14:159–72. doi: 10.1038/nrc3677
5. Bowler E, Oltean S. Alternative splicing in angiogenesis. Int J Mol Sci. 2019;20:2067. doi: 10.3390/ijms20092067
6. 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
7. 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
8. Thulin M. Modern statistics with R. Uppsala: Eos Chasma Press; 2021. ISBN 9789152701515
9. 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;57:289–300. doi: 10.10.1111/j.2517-6161.1995.tb02031.x.x
10. Quintero-Fabian S, Arreola R, Beceril-Villanueva E, Torres-Romero JC, Arana-Argaez V, Lara-Riegos J, et al. Role of matrix metalloproteinases in angiogenesis and cancer. Front Oncol. 2019;9:1370. doi: 10.3389/fonc.2019.01370
11. Heljasvaara R, Nyberg P, Luostarinen J, Parikka M, Heikkilä P, Rehn M, et al. Generation of biologically active endostatin fragments from human collagen XVIII by distinct matrix metalloproteinases. Exp Cell Res. 2005;307:292–304. doi: 10.1016/j.yexcr.2005.03.021
12. Bendrik C, Robertson J, Gauldie J, Dabrosin C. Gene transfer of matrix metalloproteinase-9 induces tumor regression in breast cancer in vivo. Cancer Res. 2008;68:3405–412. doi: 10.1158/0008-5472.CAN-08-0295
13. Vu TH, Shipley M, Bergers G, Berger JE, Helms JA, Hanahan D, et al. MMP-9/Gelatinase-B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell. 1998;93:411–22. doi: 10.1016/S0092-8674(00)81169-1
14. 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 Physiol. Heart Circ Physiol. 2000;279:H1540–7. doi: 10.1152/ajpheart.2000.297.4.H1540
15. Walia A, Yang JF, Huang Y-H, Rosenblatt MI, Chang J-H, Azar DT. Endostatin’s emerging roles in angiogenesis, lymphangiogenesis, disease, and clinical applications. Biochim Biophys Acta. 2015;1850:2422–38. doi: 10.1016/j.bbagen2015.09.007
16. Maral S, Acar M, Balcik OS, Uctepe E, Hatipoglu OF, Akdeniz D, et al. Matrix metalloproteinase 2 and 9 polymorphism in patients with myeloproliferative diseases. A STROBE-compliant observational study. Medicine. 2015;94:e732. doi: 10.1097/MD.0000000000000732
17. Wang Y, Su Y, Xu Y, Pan S-H, Liu G-D. Genetic polymorphism c.1562C>T of the MMP9 is associated with macroangiopathy in type 2 diabetes mellitus. Biochem Biophys Res Comm. 2010;391:113–77. doi: 10.1016/j.bbrc.2009.11.012
18. Zhang B, Ye S, Herrmann S-M, Eriksson P, de Maat M, Evans A, at al. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation. 1999;99:1788–94. doi: 10.1161/01.CIR.99.14.1788
19. Deryugina EI, Zajac E, Juncker-Jensen A, Kupriyanova TA, Welter L, Quigley JP. Tissue-infiltrating neutrophils constitute the major in vivo source of angiogenesis-inducing MMP9 in the tumor microenvironment. Neoplasia. 2014;16:771–88. doi: 10.1016/j.neo.2014.08.013
20. Dale D. Neutropenia and neutrophilia. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. Williams hematology. 6th ed. New York: McGraw-Hill; 2001, pp. 823–34.
21. Akashi K, Draver D, Miyamoto T, Weissman IL. A clonogenic common myeloid precursor that gives rise to all myeloid lineages. Nature. 2000;404:193–7. doi: 10.1038/35004599
22. Petzold T, Zhang Z, Ballesteros I, Saleh I, Polzin A, Thienel M, et al. Neutrophil ‘plucking’ on megakaryocytes drives platelet production and boosts cardiovascular disease. Immunity. 2022;55:2885–99. doi: 10.1016/j.immuni.2022.10.001
23. Corre J, Hébraud B, Bourin P. Concise review: GDF15 in pathology: a clinical role? Stem Cells Translat Med. 2013;2:946–52. doi: 10.5966/sctm.2013-0055
24. 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/jouranl.pone.0216602
25. Park H, Nam K-S, Lee H-J, Kim KS. Ionizing radiation-induced GDF15 promotes angiogenesis in human glioblastoma models by promoting VEGFA expression through p-MAPK1/SP1 signaling. Front Oncol. 2022;12:801230. doi: 10.3389/fonc.2022.801230
26. Tarkun P, Mehtap O, Atesoglu E, Geduk A, Musul MM, Hacihanefioglu A. Serum hepcidin and growth differentiation factor-15 (GDF-15) levels in polycythemia vera and essential thrombocythemia. Eur J Haematol. 2013;91:228–35. doi: 10.1111/ejh.12150
27. Corre J, Labat E, Espagnolle N, Hebraud B, Avet-Loiseau H, Roussel M, et al. Bioactivity and prognostic significance of growth differentiation factor GDF 15 secreted by bone marrow mesenchymal stem cells in multiple myeloma. Cancer Res. 2012;72:1395–406. doi: 10.1158/0008-5472.CAN-11-0188
28. Tvaroska I, Selvaraj C, Koca J. Selectins – the two Dr. Jekyll and Mr. Hyde faces of adhesion molecules – a review. Molecules. 2020;25:2835. doi: 10.3390/molecules25122835
29. Koch AE, Halloran MM, Haskell CJ, Shah MR, Polverini PJ. Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature. 1995;376:517–9. doi: 10.1038/376517a0
30. Egami K, Murohara T, Aoki M, Matshuisi T. Ischemia-induced angiogenesis: role of inflammatory response mediated by P-selectin. J Leukocyte Biol. 2006;79:971–6. doi: 10.1189/jlb.0805448
31. Cella G, Marchetta M, Vianello F, Panova-Noeva M, Vignoli A, Russo L, et al. Nitric oxide derivatives and soluble plasma selectins in patients with myeloproliferative neoplasms. Thromb Haemost. 2010;104:151–6. doi: 10.1160/TH09-09-0663
32. Belotti A, Elli E, Speranza T, Lanzi E, Pioltelli P, Pogliani P. Circulating endothelial cells and endothelial activation in essential thrombocythemia: results from CD146+ immunomagnetic enrichment – flow cytometry and soluble E-selectin detection. Am J Hematol. 2011;87:319–20. doi: 10.1002/ajh.22264
33. Bilgir F, Bilgir O, Calan M, Sari F. The levels of adhesion molecules in essential thrombocythemia. Panminerva Med. 2013;55:385–90.
34. Ambati B, Nozaki M, Singh N, Takeda A, Jani P, Suthar T, et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature. 2006;443(26):993–7. doi: 10.1038/nature05249
35. Chappell JC, Taylor SM, Ferrara N, Bautch VL. Local guidance of emerging vessel sprouts requires soluble Flt-1 (VEGFR-1). Dev Cell. 2009;17(3):377–86. doi: 10.1016/j.devcel.2009.07.011
36. Trelinski J, Wierzbowska A, Krawzcynska A, Sakowicz A, Pietrucha T, Smolewski P, et al. Circulating endothelial cells in essential thrombocythemia and polycythemia vera: correlation with JAK2-V617F mutational status, angiogenic factors and coagulation activation markers. Int J Hematol. 2010;91:792–8. doi: 10.1007/s12185-010-0596-7
37. Gadomska G, Bartoszewska-Kubiak A, Boinska J, Matiakowska K, Ziolkowska K, Haus O, et al. Selected parameters of angiogenesis and the JAK2, CALR, and MPL mutations in patients with essential thrombocythemia. Clin Appl Thromb Haemostas. 2018;24:1056–60. doi: 10.1177/1076029617740222
38. Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, et al. Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors. Blood. 2010;95:952–8. doi: 10.1182/blood.V95.3.952.003k27_952_958
39. Ronca R, Taranto S, Corsini M, Tobia C, Ravelli C, Rezzola S, et al. Pentraxin 3 inhibits the angiogenic potential of multiple myeloma cells. Cancers. 2021;13:2255. doi: 10.3390/cancers13092255
40. Rodriguez-Grande B, Varghese L, Molina-Holgado F, Rajkovic O, Garlanda C, Denes A, et al. Pentraxin 3 mediates neurogenesis and angiogenesis after cerebral ischaemia. J Neuroinflamm. 2015;12:15. doi: 10.1186/s12974-014-0227-y
41. Abu Sabaa A, Shen Q, Bergfelt Lennmyr E, Enblad A P, Gammelgård G, Molin D, et al. Plasma protein biomarker profiling reveals major differences between acute leukaemia, lymphoma patients and controls. N Biotechnol. 2022;71:21–9. doi: 10.1016/j.nbt.2022.06.005
42. Gholiha A R, Hollander P, Löf L, Larsson A, Hashemi J, Mattsson Ulfstedt J, et al. Immune-proteome profiling in classical Hodgkin lymphoma tumor diagnostic tissue. Cancers. 2022;14:9. doi: 10.3390/cancers14010009
Published
2023-03-27
How to Cite
Vikman S., Larsson A., Thulin M., & Karlsson T. (2023). Increased levels of a subset of angiogenesis-related plasma proteins in essential thrombocythemia. Upsala Journal of Medical Sciences, 128(1). https://doi.org/10.48101/ujms.v128.9194
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