Expression of macrophage migration inhibitory factor relates to survival in high-grade osteosarcoma.
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.


METHODS
Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.
Department of Orthopaedic Surgery, Seoul National University College of Medicine, 101 Daehangno, Jongno-gu, 110-744 Seoul, Korea.
Ilkyu
I
Han
Mi Ra
MR
Lee
Kwang Woo
KW
Nam
Joo Han
JH
Oh
Kyung Chul
KC
Moon
Han-Soo
HS
Kim
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism* / Q000401:mortality*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism* / Q000401:mortality*; D011379:Prognosis; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D008263:Macrophage Migration-Inhibitory Factors; D042461:Vascular Endothelial Growth Factor A; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human