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Isolation and Characterization of Dendritic Cells and Macrophages from the Mouse Intestine
Published on: May 21, 2012
Macrophage migration inhibitory factor promotes intestinal tumorigenesis
Jonathan M Wilson1, P Louise Coletta, Richard J Cuthbert
1Molecular Medicine Unit, University of Leeds, Leeds, United Kingdom.
Background & Aims:
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.
Insights
Macrophage migration inhibitory factor (MIF) promotes early intestinal tumor growth and angiogenesis. Inhibiting MIF may be a viable strategy for colorectal cancer chemoprevention.
Area of Science:
- Gastroenterology
- Oncology
- Molecular Biology
Background:
- Macrophage migration inhibitory factor (MIF) is present in the human gastrointestinal tract.
- MIF exhibits protumorigenic activity in various cancer models.
- Its role in early intestinal tumorigenesis requires investigation.
Purpose of the Study:
- To investigate the expression and function of MIF in early intestinal tumorigenesis.
- To determine if MIF is a potential target for colorectal cancer chemoprevention.
Main Methods:
- Measured MIF mRNA, protein, and activity in human colorectal adenomas and ApcMin/+ mice.
- Assessed MIF function using human colorectal adenoma cells in vitro.
- Evaluated the impact of genetic MIF deletion on ApcMin/+ mouse intestinal tumorigenesis.
Main Results:
- MIF expression and activity were elevated in intestinal adenomas from humans and ApcMin/+ mice.
- MIF promoted anchorage-independent growth and inhibited apoptosis of human adenoma cells in vitro.
- MIF deletion reduced tumor number/size and angiogenesis in ApcMin/+ mice, without affecting cell apoptosis or proliferation.
Conclusions:
- MIF expression increases in human colorectal adenomas.
- MIF promotes intestinal tumorigenesis, primarily through angiogenesis.
- MIF represents a potential therapeutic target for colorectal cancer chemoprevention.
