Tumor associated macrophages (TAMs) promote the metastasis and growth of non-small cell lung cancer (NSCLC) cells through NF-κB/PP2Ac positive feedback loop.

Non-small-cell lung cancer (NSCLC), with an aggressive biological behavior, is one of the most diagnosed cancers. Tumor-associated inflammatory cells play important roles in the interaction between chronic inflammation and lung cancer. However, the mechanisms involved are far from defined. In the present study, by developing an orthotopic NSCLC mouse model on the basis of chronic inflammation, we proved that inflammatory microenvironment accelerated growth of orthotopic xenografts in vivo. Tumor associated macrophages (TAMs) the most abundant population of inflammatory cells were identified. Treatment of macrophage conditional medium (MCM) promoted growth and migration of NSCLC cells. By using bioinformatics analysis, we identified down-regulated PP2Ac expression in NSCLC cells upon treatment of MCM. We further confirmed that this down-regulation was executed through NF-κB pathway dependent manner. Since IKK has been proved to be a substrate of PP2Ac, inhibition on PP2Ac could result in an amplification of NF-κB pathway signaling. Overexpression of PP2Ac, or the dominant negative forms of IKK or IκB, attenuated the acceleration on growth and metastasis by MCM. By using bioinformatics analysis, we further identified CXCL1 and COL6A1 could be downstreams of NF-κB/PP2Ac pathway. Luciferase assay and ChIP assay further confirmed location of response elements on the promoter regions of CXCL1 and COL6A1. Elevated CXCL1 facilitated angiogenesis, while up-regulated COL6A1 promoted proliferation and migration.