Fig. 2

COPD creates a favourable microenvironment for lung cancer initiation and progression. During COPD the p38 MAPK pathway is activated. P38 MAPK activates MK2, subsequently mediating the phosphorylation and thereby the inactivation of TTP. Therefore, TTP is unable to degrade the mRNA of proinflammatory cytokines (TNF, IL-6, IL-8), metalloproteinases 9 and 12 (MMP9 and MMP12), and cathepsin S (CTSS). Simultaneously endogenous inhibitors CIP2A and SET are upregulated and inhibit PP2A activity, reducing the dephosphorylation and thus activation of TTP. Cytokine secretion results in the recruitment of neutrophils and monocytes. All of the above collectively create a sustained chronic inflammatory environment, which feeds further secretion of MMP9, MMP12 and CTSS to promote proteolysis. These factors degrade the ECM in the lung parenchyma leading to subsequent airspace enlargement and rbm fragmentation. The expression of epithelial marker E-cadherin is decreased, whilst the expression of mesenchymal markers vimentin and S100A4 is increased, in conjunction with increased VEGF secretion. Chronic inflammation and high proteolytic activity collectively create an ideal niche for epithelial to mesenchymal transition (EMT), promoting the oncogenic transformation of resident cells of the lung, and encouraging LC initiation and progression