Peer-Reviewed Journal Details
Mandatory Fields
Ryan, AE,Colleran, A,O'Gorman, A,O'Flynn, L,Pindjacova, J,Lohan, P,O'Malley, G,Nosov, M,Mureau, C,Egan, LJ
2015
March
Oncogene
Targeting colon cancer cell NF-kappa B promotes an anti-tumour M1-like macrophage phenotype and inhibits peritoneal metastasis
Published
Optional Fields
TUMOR-ASSOCIATED MACROPHAGES COLORECTAL-CANCER CYTOREDUCTIVE SURGERY MOUSE MODEL T-CELLS INFLAMMATION ALPHA CARCINOMATOSIS MONOCYTES GROWTH
34
1563
1574
In a model of peritoneal metastasis in immune-competent mice, we show that nuclear factor (NF)-kappa B inhibition in CT26 colon cancer cells prevents metastasis. NF-kappa B inhibition, by stable overexpression of I kappa B-a super-repressor, induced differential polarization of co-cultured macrophages to an M1-like anti-tumour phenotype in vitro. NF-kappa B-deficient cancer cell-conditioned media (CT26/I kappa B-alpha 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/I kappa B-alpha SR cells and was positively associated with increased CD8(+)CD44(+)CD62L- and CD4(+)CD44(+)CD62L-effector T cells. Furthermore, inhibition of NF-kappa B 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/I kappa B-alpha 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/I kappa B-alpha SR cells compared with untreated tumours. Our data demonstrate, for the first time, that an important implication of targeting tumour cell NF-kappa B is skewing of macrophage polarization to an anti-tumour phenotype. This knowledge offers novel therapeutic opportunities for anticancer treatment.
10.1038/onc.2014.86
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