Targeting colon cancer cell NF-κB promotes an anti-tumour M1-like macrophage phenotype and inhibits peritoneal metastasis.
In a model of peritoneal metastasis in immune-competent mice, we show that nuclear factor (NF)-κB inhibition in CT26 colon cancer cells prevents metastasis. NF-κB inhibition, by stable overexpression of IκB-α super-repressor, induced differential polarization of co-cultured macrophages to an M1-like anti-tumour phenotype in vitro. NF-κB-deficient cancer cell-conditioned media (CT26/IκB-α SR) induced interleukin (IL)-12 and nitric oxide (NO) synthase (inducible NO synthase (iNOS)) expression in macrophages. Control cell (CT26/EV) conditioned media induced high levels of IL-10 and arginase in macrophages. In vivo, this effect translated to reduction in metastasis in mice injected with CT26/ IκB-α SR cells and was positively associated with increased CD8(+)CD44(+)CD62L(-) and CD4(+)CD44(+)CD62L(-) effector T cells. Furthermore, inhibition of NF-κB activity induced high levels of NO in infiltrating immune cells and decreases in matrix metalloproteinase-9 expression, simultaneous with increases in tissue inhibitor of metalloproteinases 1 and 2 within tumours. CT26/IκB-α SR tumours displayed increased pro-inflammatory gene expression, low levels of angiogenesis and extensive intratumoral apoptosis, consistent with the presence of an anti-tumour macrophage phenotype. Macrophage depletion reduced tumour size in CT26/EV-injected animals and increased tumour size in CT26/IκB-α SR cells compared with untreated tumours. Our data demonstrate, for the first time, that an important implication of targeting tumour cell NF-κB is skewing of macrophage polarization to an anti-tumour phenotype. This knowledge offers novel therapeutic opportunities for anticancer treatment.
1] Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland [2] Regenerative Medicine Institute (REMEDI), NCBES, School of Medicine, National University of Ireland, Galway, Ireland.
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Ryan
Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland.
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Colleran
Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland.
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O'Gorman
Regenerative Medicine Institute (REMEDI), NCBES, School of Medicine, National University of Ireland, Galway, Ireland.
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O'Flynn
Regenerative Medicine Institute (REMEDI), NCBES, School of Medicine, National University of Ireland, Galway, Ireland.
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Pindjacova
Regenerative Medicine Institute (REMEDI), NCBES, School of Medicine, National University of Ireland, Galway, Ireland.
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Lohan
1] Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland [2] Regenerative Medicine Institute (REMEDI), NCBES, School of Medicine, National University of Ireland, Galway, Ireland.
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O'Malley
Regenerative Medicine Institute (REMEDI), NCBES, School of Medicine, National University of Ireland, Galway, Ireland.
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Nosov
Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland.
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Mureau
Discipline of Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland.
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Egan
D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology; D017077:Culture Media, Conditioned; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009569:Nitric Oxide / Q000378:metabolism; D010534:Peritoneal Neoplasms / Q000378:metabolism* / Q000556:secondary*; D015398:Signal Transduction
D017077:Culture Media, Conditioned; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide