Macrophage migration inhibitory factor stimulates angiogenic factor expression and correlates with differentiation and lymph node status in patients with esophageal squamous cell carcinoma.
OBJECTIVE
The objectives of this study were: 1) to examine the expression of macrophage migration inhibitory factor (MIF) in esophageal squamous cell carcinoma (ESCC); 2) to see if a relationship exists between MIF expression, clinicopathologic features, and long-term prognosis; and 3) to ascertain the possible biologic function of MIF in angiogenesis.


BACKGROUND
MIF has been linked to fundamental processes such as those controlling cell proliferation, cell survival, angiogenesis, and tumor progression. Its role in ESCC, and the correlation of MIF expression and tumor pathologic features in patients, has not been elucidated.


METHODS
The expression of MIF in tumor and nontumor tissues was examined by immunohistochemical staining. Concentrations of MIF, vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) in patients' sera and in the supernatant of tumor cells culture were examined by ELISA. Correlations with clinicopathologic factors were made.


RESULTS
In 72 patients with ESCC, intracellular MIF was overexpressed in esophagectomy specimens. The expression of MIF correlated with both tumor differentiation and lymph node status. The median survival in the low-MIF expression group (<50% positively stained cancer cells on immunohistochemistry) and high expression group (>/=50% positively stained cancer cells) was 28.3 months and 15.8 months, respectively (P = 0.03). The 3-year survival rates for the 2 groups were 37.7% and 12.1%, respectively. MIF expression was related to microvessel density; increased MIF serum levels also correlated with higher serum levels of VEGF. In addition, in vitro MIF stimulation of esophageal cancer cell lines induced a dose-dependent increase in VEGF and IL-8 secretion.


CONCLUSIONS
These results demonstrate, for the first time, that human esophageal carcinomas express and secrete large amounts of MIF. Through its effects on VEGF and IL-8, MIF may serve as an autocrine factor in angiogenesis and thus play an important role in the pathogenesis of ESCC.
Ren
Yi
Y
Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong. yren@hkucc.hku.hk
Law
Simon
S
Huang
Xin
X
Lee
Ping Yin
PY
Bacher
Michael
M
Srivastava
Gopesh
G
Wong
John
J
D014408:Biomarkers, Tumor / Q000032:analysis; D001707:Biopsy, Needle; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D015331:Cohort Studies; D004938:Esophageal Neoplasms / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D016629:Esophagectomy / Q000379:methods; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000097:blood / Q000378:metabolism*; D008198:Lymph Nodes / Q000473:pathology*; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood / Q000378:metabolism*; D008297:Male; D009367:Neoplasm Staging; D011336:Probability; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism*
D014408:Biomarkers, Tumor; D016209:Interleukin-8; D008263:Macrophage Migration-Inhibitory Factors; D042461:Vascular Endothelial Growth Factor A