Macrophage migration inhibitory factor promotes tumor growth in the context of lung injury and repair.
BACKGROUND
Tissue injury and repair involve highly conserved processes governed by mechanisms that can be co-opted in tumors. We hypothesized that soluble factors released during the repair response to lung injury would promote orthotopic tumor growth.


OBJECTIVE
To determine whether lung injury promoted growth of orthotopic lung tumors and to study the molecular mechanisms.


METHODS
We initiated lung injury in C57Bl6 mice using different stimuli, then injected Lewis lung carcinoma cells during the repair phase. We assessed tumor growth 14 days later. We measured tumor angiogenesis, cytokine expression, proliferation, and apoptosis.


RESULTS
Regardless of the mechanism, injured lungs contained more numerous and larger tumors than sham-injured lungs. Tumors from injured lungs were no more vascular, but had higher levels of proliferation and reduced rates of apoptosis. The cytokine macrophage migration inhibitory factor (MIF) was highly expressed in both models of tissue injury. We observed no increase in tumor growth after lung injury in MIF knockout mice. We induced lung-specific overexpression of MIF in a double-transgenic mouse, and observed that MIF overexpression by itself was sufficient to accelerate the growth of orthotopic Lewis lung carcinoma tumors.


CONCLUSIONS
Lung injury leads to increased expression of the cytokine MIF, which results in protection from apoptosis and increased proliferation in orthotopic tumors injected after the acute phase of injury.
Arenberg
Douglas
D
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0642, USA. darenber@umich.edu
Luckhardt
Tracy R
TR
Carskadon
Shannon
S
Zhao
Liujian
L
Amin
Mohammad A
MA
Koch
Alisa E
AE
D000818:Animals; D017209:Apoptosis; D018827:Carcinoma, Lewis Lung; D049109:Cell Proliferation; D002908:Chronic Disease; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D055370:Lung Injury / Q000276:immunology* / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D014407:Tumor Cells, Cultured
D016207:Cytokines; D008263:Macrophage Migration-Inhibitory Factors