Macrophage migration inhibitory factor promotes intestinal tumorigenesis.
OBJECTIVE
The cytokine macrophage migration inhibitory factor (MIF) is expressed throughout the human gastrointestinal tract. Recently, protumorigenic activity of MIF has been described in several cancer models. Therefore, we investigated the expression and function of MIF during the early stages of intestinal tumorigenesis.


METHODS
MIF messenger RNA, protein, and tautomerase activity were measured in normal intestinal mucosa and adenomas from patients with sporadic colorectal adenomas and in the adenomatous polyposis coli (Apc)Min/+ mouse model of intestinal tumorigenesis. MIF function was investigated by using VACO-235 human colorectal adenoma cells in vitro and by testing the effect of genetic deletion of Mif on ApcMin/+ mouse intestinal tumorigenesis.


RESULTS
MIF expression and tautomerase activity were increased in human and ApcMin/+ mouse intestinal adenomas compared with adjacent normal mucosa. Up-regulation of MIF occurred mainly in epithelial cells (associated with an increasing grade of dysplasia), but also in stromal plasma cells. Exogenous MIF inhibited apoptosis and promoted anchorage-independent growth of VACO-235 cells (maximal at 100 ng/mL). Homozygous deletion of Mif was associated with a reduction in the number and size of ApcMin/+ mouse adenomas (P = .025 for the difference in large [>7-mm] tumors) and decreased angiogenesis (43% decrease in mean tumor microvessel density), but there was no alteration in epithelial cell apoptosis or proliferation.


CONCLUSIONS
MIF expression is increased in sporadic human colorectal adenomas, and exogenous MIF drives tumorigenic behavior of epithelial cells in vitro. Mif also promotes intestinal tumorigenesis (predominantly via angiogenesis) in the ApcMin/+ mouse. Therefore, MIF is a potential colorectal cancer chemoprevention target.
Wilson
Jonathan M
JM
Molecular Medicine Unit, University of Leeds, Leeds, United Kingdom.
Coletta
P Louise
PL
Cuthbert
Richard J
RJ
Scott
Nigel
N
MacLennan
Kenneth
K
Hawcroft
Gillian
G
Leng
Lin
L
Lubetsky
Jodi B
JB
Jin
Kai K
KK
Lolis
Elias
E
Medina
Francisco
F
Brieva
Jose A
JA
Poulsom
Richard
R
Markham
Alexander F
AF
Bucala
Richard
R
Hull
Mark A
MA
D000236:Adenoma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011125:Adenomatous Polyposis Coli / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
D008263:Macrophage Migration-Inhibitory Factors