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Expression of Macrophage Migration Inhibitory Factor Relates to Survival in High-grade Osteosarcoma

  • Ilkyu Han
  • Mi Ra Lee
  • Kwang Woo Nam
  • Joo Han Oh
  • Kyung Chul Moon
  • Han-Soo Kim
Symposium: Molecular Genetics in Sarcoma

Abstract

Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is implicated in many aspects of tumor progression, including cell proliferation, invasion, and angiogenesis. We asked if MIF expression predicts survival and if it is associated with angiogenesis and cell invasion in osteosarcoma. We performed immunohistochemistry for MIF expression in prechemotherapy biopsy specimens of 58 patients with osteosarcoma. To investigate the role of MIF in angiogenesis, microvessel density was measured and compared with MIF expression. We also treated osteosarcoma cell lines (U2-OS and MG63) with MIF and measured vascular endothelial growth factor, a potent proangiogenic factor, by enzyme-linked immunosorbent assay. To study the role of MIF in cell invasion, Boyden chamber assay was performed after knockdown of MIF by short interfering RNA. MIF independently predicted overall survival and metastasis-free survival. MIF expression correlated with microvessel density and induced a dose-dependent increase in vascular endothelial growth factor. Knockdown of MIF by short interfering RNA resulted in decreased cell invasion. These results suggest MIF could serve as a prognostic marker and a potential therapeutic target for osteosarcoma.

Level of Evidence: Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.

Keywords

Vascular Endothelial Growth Factor Osteosarcoma Migration Inhibitory Factor Microvessel Density Osteosarcoma Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Bacher M, Schrader J, Thompson N, Kuschela K, Gemsa D, Waeber G, Schlegel J. Up-regulation of macrophage migration inhibitory factor gene and protein expression in glial tumor cells during hypoxic and hypoglycemic stress indicates a critical role for angiogenesis in glioblastoma multiforme. Am J Pathol. 2003;162:11–17.PubMedGoogle Scholar
  2. 2.
    Davis AM, Bell RS, Goodwin PJ. Prognostic factors in osteosarcoma: a critical review. J Clin Oncol. 1994;12:423–431.PubMedGoogle Scholar
  3. 3.
    Ek ET, Dass CR, Contreras KG, Choong PF. Pigment epithelium-derived factor overexpression inhibits orthotopic osteosarcoma growth, angiogenesis and metastasis. Cancer Gene Ther. 2007;14:616–626.PubMedCrossRefGoogle Scholar
  4. 4.
    Enneking W. Staging musculoskeletal tumors. In: Enneking W, ed. Musculoskeletal Tumor Surgery. New York: Churchill Livingstone; 1983:69–88.Google Scholar
  5. 5.
    Gorlick R, Anderson P, Andrulis I, Arndt C, Beardsley GP, Bernstein M, Bridge J, Cheung NK, Dome JS, Ebb D, Gardner T, Gebhardt M, Grier H, Hansen M, Healey J, Helman L, Hock J, Houghton J, Houghton P, Huvos A, Khanna C, Kieran M, Kleinerman E, Ladanyi M, Lau C, Malkin D, Marina N, Meltzer P, Meyers P, Schofield D, Schwartz C, Smith MA, Toretsky J, Tsokos M, Wexler L, Wigginton J, Withrow S, Schoenfeldt M, Anderson B. Biology of childhood osteogenic sarcoma and potential targets for therapeutic development: meeting summary. Clin Cancer Res. 2003;9:5442–5453.PubMedGoogle Scholar
  6. 6.
    Hira E, Ono T, Dhar DK, El-Assal ON, Hishikawa Y, Yamanoi A, Nagasue N. Overexpression of macrophage migration inhibitory factor induces angiogenesis and deteriorates prognosis after radical resection for hepatocellular carcinoma. Cancer. 2005;103:588–598.PubMedCrossRefGoogle Scholar
  7. 7.
    Hoang BH, Kubo T, Healey JH, Sowers R, Mazza B, Yang R, Huvos AG, Meyers PA, Gorlick R. Expression of LDL receptor-related protein 5 (LRP5) as a novel marker for disease progression in high-grade osteosarcoma. Int J Cancer. 2004;109:106–111.PubMedCrossRefGoogle Scholar
  8. 8.
    Kager L, Zoubek A, Potschger U, Kastner U, Flege S, Kempf-Bielack B, Branscheid D, Kotz R, Salzer-Kuntschik M, Winkelmann W, Jundt G, Kabisch H, Reichardt P, Jurgens H, Gadner H, Bielack SS. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol. 2003;21:2011–2018.PubMedCrossRefGoogle Scholar
  9. 9.
    Kamimura A, Kamachi M, Nishihira J, Ogura S, Isobe H, Dosaka-Akita H, Ogata A, Shindoh M, Ohbuchi T, Kawakami Y. Intracellular distribution of macrophage migration inhibitory factor predicts the prognosis of patients with adenocarcinoma of the lung. Cancer. 2000;89:334–341.PubMedCrossRefGoogle Scholar
  10. 10.
    Kaya M, Wada T, Akatsuka T, Kawaguchi S, Nagoya S, Shindoh M, Higashino F, Mezawa F, Okada F, Ishii S. Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis. Clin Cancer Res. 2000;6:572–577.PubMedGoogle Scholar
  11. 11.
    Kreuter M, Bieker R, Bielack SS, Auras T, Buerger H, Gosheger G, Jurgens H, Berdel WE, Mesters RM. Prognostic relevance of increased angiogenesis in osteosarcoma. Clin Cancer Res. 2004;10:8531–8537.PubMedCrossRefGoogle Scholar
  12. 12.
    Laverdiere C, Hoang BH, Yang R, Sowers R, Qin J, Meyers PA, Huvos AG, Healey JH, Gorlick R. Messenger RNA expression levels of CXCR4 correlate with metastatic behavior and outcome in patients with osteosarcoma. Clin Cancer Res. 2005;11:2561–2567.PubMedCrossRefGoogle Scholar
  13. 13.
    Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, Memon MA, Weeden S, Uscinska BM, van Glabbeke M, Kirkpatrick A, Hauben EI, Craft AW, Taminiau AH. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007;99:112–128.PubMedCrossRefGoogle Scholar
  14. 14.
    Luu HH, Zhou L, Haydon RC, Deyrup AT, Montag AG, Huo D, Heck R, Heizmann CW, Peabody TD, Simon MA, He TC. Increased expression of S100A6 is associated with decreased metastasis and inhibition of cell migration and anchorage independent growth in human osteosarcoma. Cancer Lett. 2005;229:135–148.PubMedCrossRefGoogle Scholar
  15. 15.
    Marina N, Gebhardt M, Teot L, Gorlick R. Biology and therapeutic advances for pediatric osteosarcoma. Oncologist. 2004;9:422–441.PubMedCrossRefGoogle Scholar
  16. 16.
    Meyer-Siegler K, Hudson PB. Enhanced expression of macrophage migration inhibitory factor in prostatic adenocarcinoma metastases. Urology. 1996;48:448–452.PubMedCrossRefGoogle Scholar
  17. 17.
    Meyer-Siegler KL, Iczkowski KA, Vera PL. Further evidence for increased macrophage migration inhibitory factor expression in prostate cancer. BMC Cancer. 2005;5:73.PubMedCrossRefGoogle Scholar
  18. 18.
    Meyer-Siegler KL, Leifheit EC, Vera PL. Inhibition of macrophage migration inhibitory factor decreases proliferation and cytokine expression in bladder cancer cells. BMC Cancer. 2004;4:34.PubMedCrossRefGoogle Scholar
  19. 19.
    Mitchell RA. Mechanisms and effectors of MIF-dependent promotion of tumourigenesis. Cell Signal. 2004;16:13–19.PubMedCrossRefGoogle Scholar
  20. 20.
    Munaut C, Boniver J, Foidart JM, Deprez M. Macrophage migration inhibitory factor (MIF) expression in human glioblastomas correlates with vascular endothelial growth factor (VEGF) expression. Neuropathol Appl Neurobiol. 2002;28:452–460.PubMedCrossRefGoogle Scholar
  21. 21.
    Nishihira J, Ishibashi T, Fukushima T, Sun B, Sato Y, Todo S. Macrophage migration inhibitory factor (MIF): its potential role in tumor growth and tumor-associated angiogenesis. Ann NY Acad Sci. 2003;995:171–182.PubMedCrossRefGoogle Scholar
  22. 22.
    Ren Y, Law S, Huang X, Lee PY, Bacher M, Srivastava G, Wong J. Macrophage migration inhibitory factor stimulates angiogenic factor expression and correlates with differentiation and lymph node status in patients with esophageal squamous cell carcinoma. Ann Surg. 2005;242:55–63.PubMedCrossRefGoogle Scholar
  23. 23.
    Ren Y, Tsui HT, Poon RT, Ng IO, Li Z, Chen Y, Jiang G, Lau C, Yu WC, Bacher M, Fan ST. Macrophage migration inhibitory factor: roles in regulating tumor cell migration and expression of angiogenic factors in hepatocellular carcinoma. Int J Cancer. 2003;107:22–29.PubMedCrossRefGoogle Scholar
  24. 24.
    Rosen G, Caparros B, Huvos AG, Kosloff C, Nirenberg A, Cacavio A, Marcove RC, Lane JM, Mehta B, Urban C. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer. 1982;49:1221–1230.PubMedCrossRefGoogle Scholar
  25. 25.
    Sun B, Nishihira J, Yoshiki T, Kondo M, Sato Y, Sasaki F, Todo S. Macrophage migration inhibitory factor promotes tumor invasion and metastasis via the Rho-dependent pathway. Clin Cancer Res. 2005;11:1050–1058.PubMedGoogle Scholar
  26. 26.
    Vermeulen PB, Gasparini G, Fox SB, Colpaert C, Marson LP, Gion M, Belien JA, de Waal RM, Van Marck E, Magnani E, Weidner N, Harris AL, Dirix LY. Second international consensus on the methodology and criteria of evaluation of angiogenesis quantification in solid human tumours. Eur J Cancer. 2002;38:1564–1579.PubMedCrossRefGoogle Scholar
  27. 27.
    Ward WG, Mikaelian K, Dorey F, Mirra JM, Sassoon A, Holmes EC, Eilber FR, Eckardt JJ. Pulmonary metastases of stage IIB extremity osteosarcoma and subsequent pulmonary metastases. J Clin Oncol. 1994;12:1849–1858.PubMedGoogle Scholar
  28. 28.
    White ES, Flaherty KR, Carskadon S, Brant A, Iannettoni MD, Yee J, Orringer MB, Arenberg DA. Macrophage migration inhibitory factor and CXC chemokine expression in non-small cell lung cancer: role in angiogenesis and prognosis. Clin Cancer Res. 2003;9:853–860.PubMedGoogle Scholar
  29. 29.
    Wilson JM, Coletta PL, Cuthbert RJ, Scott N, MacLennan K, Hawcroft G, Leng L, Lubetsky JB, Jin KK, Lolis E, Medina F, Brieva JA, Poulsom R, Markham AF, Bucala R, Hull MA. Macrophage migration inhibitory factor promotes intestinal tumorigenesis. Gastroenterology. 2005;129:1485–1503.PubMedCrossRefGoogle Scholar
  30. 30.
    Yao K, Shida S, Selvakumaran M, Zimmerman R, Simon E, Schick J, Haas NB, Balke M, Ross H, Johnson SW, O’Dwyer PJ. Macrophage migration inhibitory factor is a determinant of hypoxia-induced apoptosis in colon cancer cell lines. Clin Cancer Res. 2005;11:7264–7272.PubMedCrossRefGoogle Scholar

Copyright information

© The Association of Bone and Joint Surgeons 2008

Authors and Affiliations

  • Ilkyu Han
    • 1
  • Mi Ra Lee
    • 1
    • 2
  • Kwang Woo Nam
    • 3
  • Joo Han Oh
    • 1
    • 4
  • Kyung Chul Moon
    • 5
  • Han-Soo Kim
    • 1
  1. 1.Department of Orthopaedic SurgerySeoul National University College of MedicineSeoulKorea
  2. 2.Clinical Research Institute of Seoul National University HospitalSeoulKorea
  3. 3.Department of Orthopedic SurgeryCheju National UniversityJeju-siKorea
  4. 4.Seoul National University Bundang HospitalSeongnam-siKorea
  5. 5.Department of PathologySeoul National University College of MedicineSeoulKorea

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