Macrophage migration inhibitory factor promotes tumor growth in the context of lung injury and repair.
RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.
American journal of respiratory and critical care medicine
October 15, 2010
Agency: NCI NIH HHS, Id: CA46592
Agency: NIAMS NIH HHS, Id: R01-AR48267
Agency: NCI NIH HHS, Id: R01-CA94121
Agency: NIAMS NIH HHS, Id: R03 AR052482
Carcinoma, Lewis Lung
Disease Models, Animal
Macrophage Migration-Inhibitory Factors
Mice, Inbred C57BL
Tumor Cells, Cultured
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