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Interrelationship and expression profiling of cyclooxygenase and angiogenic factors in Indian patients with multiple myeloma

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Abstract

Multiple myeloma (MM) is classically illustrated by a desynchronized cytokine system with rise in inflammatory cytokines. There are recent reports which emphasized the potential role of angiogenesis in the development of MM. Role of cyclooxygenase 2 (COX-2) is well documented in the pathogenesis of solid tumors, but little is known about its occurrence and function in hematologic neoplasms. Involvement of neoangiogenesis is reported in the progression of MM, and angiopoietins probably contribute to this progression by enhancing neovascularization. Circulatory and mRNA levels of angiogenic factors and cyclooxygenase were determined in 125 subjects (75 MM patients and 50 healthy controls) by using enzyme-linked immunosorbent assay and quantitative PCR. We observed significant increase for angiogenic factors (Ang-1, Ang-2, hepatocyte growth factor, and vascular endothelial growth factor) and cyclooxygenase at circulatory level, as well as at mRNA level, as compared to healthy controls except insignificant increase for Ang-1 at circulatory level. We have also observed the significant positive correlation of all angiogenic factors with cyclooxygenase. The strong association found between angiogenic factors and COX-2 in this study may lead to the development of combination therapeutic strategy to treat MM. Therefore, targeting COX-2 by using its effective inhibitors demonstrating antiangiogenic and antitumor effects could be used as a new therapeutic approach for treatment of MM.

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References

  1. Bataille R, Harousseau J-L (1997) Multiple myeloma. N Engl J Med 336:1657–1664

    Article  PubMed  CAS  Google Scholar 

  2. Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC (2009) Multiple myeloma. Lancet 374(9686):324–339

    Article  PubMed  Google Scholar 

  3. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC (2004) Advances in biology of multiple myeloma: clinical applications. Blood 104:607–618

    Article  PubMed  CAS  Google Scholar 

  4. Rajkumar S-V, Mesa R-A, Fonseca R et al (2002) Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis. Clin Cancer Res 8:2210–2216

    PubMed  Google Scholar 

  5. Vacca A, Ribatti D, Presta M et al (1999) Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 93:3064–3073

    PubMed  CAS  Google Scholar 

  6. Vacca A, Ribatti D, Roccaro A-M, Frigeri A, Dammacco F (2001) Bone marrow angiogenesis in patients with active multiple myeloma. Semin Oncol 28:543–550

    Article  PubMed  CAS  Google Scholar 

  7. Munshi N-C, Wilson C (2001) Increased bone marrow microvessel density in newly diagnosed multiple myeloma carries a poor prognosis. Semin Oncol 28:565–569

    Article  PubMed  CAS  Google Scholar 

  8. Zha S, Yegnasubramanian V, Nelson WG, Isaacs WB, De Marzo AM (2004) Cyclooxygenases in cancer: progress and perspective. Cancer Lett 215:1–20

    Article  PubMed  CAS  Google Scholar 

  9. Salcedo R, Zhang X, Young HA et al (2003) Angiogenic effects of prostaglandin E2 are mediated by upregulation of CXCR4 on human microvascular endothelial cells. Blood 102:1966–1977

    Article  PubMed  CAS  Google Scholar 

  10. Majima M, Hayashi I, Muramatsu M, Katada J, Yamashina S, Katori M (2000) Cyclooxygenase-2 enhances basic fibroblast growth factor-induced angiogenesis through induction of vascular endothelial growth factor in rat sponge implants. Br J Pharmacol 130:641–649

    Article  PubMed  CAS  Google Scholar 

  11. Gately S, Li WW (2004) Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin Oncol 31:2–11

    Article  PubMed  CAS  Google Scholar 

  12. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN (1998) Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93:705–716

    Article  PubMed  CAS  Google Scholar 

  13. Ohsawa M, Fukushima H, Ikura Y, Inoue T, Shirai N, Sugama Y, Suekane T, Kitabayashi C, Nakamae H, Hino M, Ueda M (2006) Expression of cyclooxygenase-2 in Hodgkin’s lymphoma: its role in cell proliferation and angiogenesis. Leuk Lymphoma 47:1863–1871

    Article  PubMed  CAS  Google Scholar 

  14. Giulani N, Colla S, Lazzaretti M, Sala R, Roti G, Mancini C et al (2003) Proangiogenic properties of human myeloma cells: production of angiopoietin-1 and its potential relationship to myeloma-induced angiogenesis. Blood 102:638–645

    Article  Google Scholar 

  15. Zetterberg E, Lundberg LG, Palmblad J (2003) Expression of cox-2, tie-2 and glycodelin by megakaryocytes in patients with chronic myeloid leukaemia and polycythaemia vera. Br J Haematol 121:497–499

    Article  PubMed  CAS  Google Scholar 

  16. Zhang XH, Huang DP, Guo GL, Chen GR, Zhang HX, Wan L, Chen SY (2008) Co-expression of VEGF-C and COX-2 and its association with lymphangiogenesis in human breast cancer. BMC Cancer 8:4

    Article  PubMed  Google Scholar 

  17. Tang H, Wang J, Bai F, Zhai H, Gao J, Hong L, Xie H, Zhang F, Lan M, Yao W, Liu J, Wu K, Fan D (2008) Positive correlation of osteopontin, cyclooxygenase-2 and vascular endothelial growth factor in gastric cancer. Cancer Investig 26:60–67

    Article  CAS  Google Scholar 

  18. Payvandi F, Wu L, Haley M, Schafer PH, Zhang LH, Chen RS, Muller GW, Stirling DI (2004) Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF-alpha, IL-1beta, and LPS-stimulated human PBMC in a partially IL-10-dependent manner. Cell Immunol 230:81–88

    Article  PubMed  CAS  Google Scholar 

  19. Masferrer JL, Koki A, Seibert K (1999) COX-2 inhibitors: a new class of antiangiogenic agents. Ann NY Acad Sci 889:84–86

    Article  PubMed  CAS  Google Scholar 

  20. Jones MK, Wang H, Peskar BM, Levin E, Itani RM, Sarfeh IJ, Tarnawski AS (1999) Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med 5:1418–1423

    Article  PubMed  CAS  Google Scholar 

  21. Peters KG, De Vries C, Williams LT (1993) Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth. Proc Natl Acad Sci U S A 90:8915–8919

    Article  PubMed  CAS  Google Scholar 

  22. Trusolino L, Comoglio PM (2002) Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2:289–300

    Article  PubMed  CAS  Google Scholar 

  23. Rosario M, Birchmeier W (2003) How to make tubes: signaling by the Met receptor tyrosine kinase. Trends Cell Biol 13:328–335

    Article  PubMed  CAS  Google Scholar 

  24. Gerritsen ME, Tomlinson JE, Zlot C, Ziman M, Hwang S (2003) Using gene expression profiling to identify the molecular basis of the synergistic actions of hepatocyte growth factor and vascular endothelial growth factor in human endothelial cells. Br J Pharmacol 140:595–610

    Article  PubMed  CAS  Google Scholar 

  25. Derksen PW, de Gorter DJ, Meijer HP et al (2003) The hepatocyte growth factor/met pathway controls proliferation and apoptosis in multiple myeloma. Leukemia 17:764–774

    Article  PubMed  CAS  Google Scholar 

  26. Borset M, Hjorth-Hansen H, Seidel C, Sundan A, Waage A (1996) Hepatocyte growth factor and its receptor c-met in multiple myeloma. Blood 88:3998–4004

    PubMed  CAS  Google Scholar 

  27. Borset M, Lien E, Espevik T, Helseth E, Waage A, Sundan A (1996) Concomitant expression of hepatocyte growth factor/scatter factor and the receptor c-MET in human myeloma cell lines. J Biol Chem 271:24655–24661

    Article  PubMed  CAS  Google Scholar 

  28. Seidel C, Borset M, Turesson I, Abildgaard N, Sundan A, Waage A (1998) Elevated serum concentrations of hepatocyte growth factor in patients with multiple myeloma. The Nordic Myeloma Study Group. Blood 91:806–812

    PubMed  CAS  Google Scholar 

  29. Suri C, Jones PF, Patan S et al (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87:1171–1180

    Article  PubMed  CAS  Google Scholar 

  30. Maisonpierre PC, Suri C, Jones PF et al (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60

    Article  PubMed  CAS  Google Scholar 

  31. Holash J, Maisonpierre PC, Compton D et al (1999) Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284:1994–1998

    Article  PubMed  CAS  Google Scholar 

  32. Koga K, Todaka T, Morioka M, Hamada J, Kai Y, Yano S et al (2001) Expression of angiopoietin-2 in human glioma cells and its role for angiogenesis. Cancer Res 61:6248–6254

    PubMed  CAS  Google Scholar 

  33. Tait CR, Jones PF (2004) Angiopoietins in tumours: the angiogenic switch. J Pathol 204:1–10

    Article  PubMed  CAS  Google Scholar 

  34. Etoh T, Inoue H, Tanaka S, Barnard GF, Kitano S, Mori M (2001) Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. Cancer Res 61:2145–2153

    PubMed  CAS  Google Scholar 

  35. Tsutsui S, Inoue H, Yasuda K et al (2006) Angiopoietin 2 expression in invasive ductal carcinoma of the breast: its relationship to the VEGF expression and microvessel density. Breast Cancer Res Treat 98:261–266

    Article  PubMed  CAS  Google Scholar 

  36. Lind AJ, Wikstrom P, Granfors T, Egevad L, Stattin P, Bergh A (2005) Angiopoietin 2 expression is related to histological grade, vascular density, metastases, and outcome in prostate cancer. Prostate 62:394–399

    Article  PubMed  Google Scholar 

  37. Negaard HF, Iversen N, Bowitz-Lothe IM, Sandset PM, Steinsvik B, Ostenstad B, Iversen PO (2009) Increased bone marrow microvascular density in haematological malignancies is associated with differential regulation of angiogenic factors. Leukemia 23:162–169

    Article  PubMed  CAS  Google Scholar 

  38. Vacca A, Ria R, Ribatti D, Semeraro F, Djonov V et al (2003) A paracrine loop in the vascular endothelial growth factor pathway triggers tumor angiogenesis and growth in multiple myeloma. Haematologica 88:176–185

    PubMed  CAS  Google Scholar 

  39. Vacca A, Scavelli C, Montefusco V et al (2005) Thalidomide downregulates angiogenic genes in bone marrow endothelial cells of patients with active multiple myeloma. J Clin Oncol 23:5334–5346

    Article  PubMed  CAS  Google Scholar 

  40. Quartarone E, Alonci A, Allegra A, Bellomo G, Calabro L, D’ Angelo A et al (2006) Differential levels of soluble angiopoietin-2 and Tie-2 in patients with haematological malignancies. Eur J Haematol 77:480–485

    Article  PubMed  CAS  Google Scholar 

  41. Uneda S, Matsuno F, Sonoki T, Tniguchi I, Kawano F, Hata H (2003) Expression of vascular endothelial factor and angiopoietin-2 in myeloma cells. Haematologica 88:113–115

    PubMed  CAS  Google Scholar 

  42. Stratton MR (2011) Exploring the genomes of cancer cells: progress and promise. Science 331:1553–1558

    Article  PubMed  CAS  Google Scholar 

  43. Vacca A, Ribatti D, Roncali L, Dammacco F (1995) Angiogenesis in B cell lymphoproliferative diseases. Biological and clinical studies. Leuk Lymphoma 20:27–38

    Article  PubMed  CAS  Google Scholar 

  44. Rajkumar SV, Leong T, Roche PC, Fonseca R, Dispenzieri A, Lacy MQ, Lust JA, Witzig TE, Kyle RA, Gertz MA, Greipp PR (2000) Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res 6:3111–3116

    PubMed  CAS  Google Scholar 

  45. Kim HJ, Kim SM, Park KR, Jang HJ, Na YS, Ahn KS, Kim SH, Ahn KS (2011) Decursin chemosensitizes human multiple myeloma cells through inhibition of STAT3 signaling pathway. Cancer Lett 301:29–37

    Article  PubMed  CAS  Google Scholar 

  46. Zhu X, Giordano T, Yu QS, Holloway HW, Perry TA, Lahiri DK, Brossi A, Greig NH (2003) Thiothalidomides: novel isosteric analogues of thalidomide with enhanced TNF-alpha inhibitory activity. J Med Chem 46:5222–5229

    Article  PubMed  CAS  Google Scholar 

  47. Watanabe M, Dewan MZ, Okamura T, Sasaki M, Itoh K, Higashihara M, Mizoguchi H, Honda M, Sata T, Watanabe T, Yamamoto N, Umezawa K, Horie R (2005) A novel NF-kappaB inhibitor DHMEQ selectively targets constitutive NF-kappaB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo. Int J Cancer 114:32–38

    Article  PubMed  CAS  Google Scholar 

  48. Gao SJ, Li GL (2009) Expression of midkine and vascular endothelial growth factor in bone marrow of patients with multiple myeloma and its significance. Zhongguo Shi Yan Xue Ye Xue Za Zhi 17:1464–1467

    PubMed  CAS  Google Scholar 

  49. Liu JR, Luo SK, Li J, Su C (2007) Expression and clinical significance of vascular endothelial growth factor and its receptors in multiple myeloma. Ai Zheng 26:652–656

    PubMed  Google Scholar 

  50. Di Raimondo F, Azzaro MP, Palumbo G et al (2000) Angiogenic factors in multiple myeloma: higher levels in bone marrow than in peripheral blood. Haematologica 85:800–805

    PubMed  Google Scholar 

  51. Sezer O, Jakob C, Eucker J et al (2001) Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma. Eur J Haematol 66:83–88

    Article  PubMed  CAS  Google Scholar 

  52. Scudla V, Pika T, Budikova M, Petrova J, Minarik J, Bacovsky J, Langova K, Zivna J, Czech Myeloma Group (2010) The importance of serum levels of selected biological parameters in the diagnosis, staging and prognosis of multiple myeloma. Neoplasma 57:102–110

    Article  PubMed  CAS  Google Scholar 

  53. Urba ska-Rys H, Wierzbowska A, Robak T (2003) Circulating angiogenic cytokines in multiple myeloma and related disorders. Eur Cytokine Netw 14:40–51

    PubMed  Google Scholar 

  54. Iwasaki T, Hamano T, Ogata A et al (2002) Clinical significance of vascular endothelial growth factor and hepatocyte growth factor in multiple myeloma. Br J Haematol 116:796–802

    Article  PubMed  CAS  Google Scholar 

  55. Andersen NF, Standal T, Nielsen JL, Heickendorff L, Borset M, Sørensen FB, Abildgaard N (2005) Syndecan-1 and angiogenic cytokines in multiple myeloma: correlation with bone marrow angiogenesis and survival. Br J Haematol 128:210–217

    Article  PubMed  CAS  Google Scholar 

  56. Zdzisińska B, Bojarska-Junak A, Dmoszyńska A, Kandefer-Szerszeń M (2008) Abnormal cytokine production by bone marrow stromal cells of multiple myeloma patients in response to RPMI8226 myeloma cells. Arch Immunol Ther Exp (Warsz) 56:207–221

    Article  Google Scholar 

  57. Kara IO, Sahin B, Gunesacar R, Unsal C (2006) Clinical significance of hepatocyte growth factor, platelet-derived growth factor AB, and transforming growth factor-alpha in bone marrow and peripheral blood of patients with multiple myeloma. Adv Ther 23:635–645

    Article  PubMed  CAS  Google Scholar 

  58. Zhan F, Hardin J, Kordsmeier B et al (2000) Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood 99:1745–1757

    Article  Google Scholar 

  59. Anargyrou K, Terpos E, Vassilakopoulos TP, Pouli A, Sachanas S, Tzenou T, Masouridis S, Christoulas D, Angelopoulou MK, Dimitriadou EM, Kalpadakis C, Tsionos K, Panayiotidis P, Dimopoulos MA, Pangalis GA, Kyrtsonis MC, Greek Myeloma Study Group (2008) Normalization of the serum angiopoietin-1 to angiopoietin-2 ratio reflects response in refractory/resistant multiple myeloma patients treated with bortezomib. Haematologica 93:451–454

    Article  PubMed  CAS  Google Scholar 

  60. Joshi S, Khan R, Sharma M, Kumar L, Sharma A (2011) Angiopoietin-2: a potential novel diagnostic marker in multiple myeloma. Clin Biochem 44:590–595

    Article  PubMed  CAS  Google Scholar 

  61. Chen H, Shi L, Yang XY, Guo XL, Pan L (2010) Expression and clinical significance of angiopoietin-1 in multiple myeloma. Zhonghua Xue Ye Xue Za Zhi 31:654–658

    PubMed  Google Scholar 

  62. Roccaro AM, Hideshima T, Raje N, Kumar S, Ishitsuka K, Yasui H, Shiraishi N, Ribatti D, Nico B, Vacca A, Dammacco F, Richardson PG, Anderson KC (2006) Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells. Cancer Res 66:184–191

    Article  PubMed  CAS  Google Scholar 

  63. Oh H, Takagi H, Suzuma K, Otani A, Matsumura M, Honda Y (1999) Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem 274:15732–15739

    Article  PubMed  CAS  Google Scholar 

  64. Jones PF (2003) Not just angiogenesis—wider roles for the angiopoietins. J Pathol 201:515–527

    Article  PubMed  CAS  Google Scholar 

  65. Ladetto M, Vallet S, Trojan A, Dell’Aquila M, Monitillo L, Rosato R, Santo L, Drandi D, Bertola A, Falco P, Cavallo F, Ricca I, De Marco F, Mantoan B, Bode-Lesniewska B, Pagliano G, Francese R, Rocci A, Astolfi M, Compagno M, Mariani S, Godio L, Marino L, Ruggeri M, Omede P, Palumbo A, Boccadoro M (2005) Cyclooxygenase-2 (COX-2) is frequently expressed in multiple myeloma and is an independent predictor of poor outcome. Blood 105:4784–4791

    Article  PubMed  CAS  Google Scholar 

  66. Trojan A, Tinguely M, Vallet S, Seifert B, Jenni B, Zippelius A, Witzens-Harig M, Mechtersheimer G, Ho A, Goldschmidt H, Jager D, Boccadoro M, Ladetto M (2006) Clinical significance of cyclooxygenase-2 (COX-2) in multiple myeloma. Swiss Med Wkly 136:400–403

    PubMed  CAS  Google Scholar 

  67. Cetin M, Buyukberber S, Demir M, Sari I, Sari I, Deniz K, Eser B, Altuntas F, Camci C, Oztürk A, Turgut B, Vural O, Unal A (2005) Overexpression of cyclooxygenase-2 in multiple myeloma: association with reduced survival. Am J Hematol 80:169–173

    Article  PubMed  CAS  Google Scholar 

  68. Zhang M, Abe Y, Matsushima T, Nishimura J, Nawata H, Muta K (2005) Selective cyclooxygenase 2 inhibitor NS-398 induces apoptosis in myeloma cells via a Bcl-2 independent pathway. Leuk Lymphoma 46:425–433

    Article  PubMed  CAS  Google Scholar 

  69. Ding J, Tsuboi K, Hoshikawa H, Goto R, Mori N, Katsukawa M, Hiraki E, Yamamoto S, Abe M, Ueda N (2006) Cyclooxygenase isozymes are expressed in human myeloma cells but not involved in anti-proliferative effect of cyclooxygenase inhibitors. Mol Carcinog 45:250–259

    Article  PubMed  CAS  Google Scholar 

  70. Ryan EP, Pollock SJ, Kaur K, Felgar RE, Bernstein SH, Chiorazzi N, Phipps RP (2006) Constitutive and activation-inducible cyclooxygenase-2 expression enhances survival of chronic lymphocytic leukemia B cells. Clin Immunol 120:76–90

    Article  PubMed  CAS  Google Scholar 

  71. Paydas S, Ergin M, Erdogan S, Seydaoglu G (2007) Cyclooxygenase-2 expression in non-Hodgkin’s lymphomas. Leuk Lymphoma 48:389–395

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We acknowledge the Indian Council of Medical Research, New Delhi, India, for providing monetary support to carry out this study. We would like to thank Dr. Guresh Kumar, Department of Biostatistics, AIIMS, New Delhi, for the statistical analysis of data.

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The authors declare that they have no conflict of interest.

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Correspondence to Alpana Sharma.

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Khan, R., Sharma, M., Kumar, L. et al. Interrelationship and expression profiling of cyclooxygenase and angiogenic factors in Indian patients with multiple myeloma. Ann Hematol 92, 101–109 (2013). https://doi.org/10.1007/s00277-012-1572-5

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