Abstract A26: IL-1β dependent epithelial-mesenchymal transition in non-small cell lung cancer

A26

Pulmonary diseases associated with a heightened risk of lung cancer, such as emphysema and pulmonary fibrosis, show both increased and deregulated inflammation. Tobacco smoke exposure is associated with chronic airway inflammation and is a strong risk factor for the development of lung cancer. Inflammatory mediators and inflammatory cells are over expressed in the pulmonary microenvironment of both smokers and patients with non-small cell lung cancer (NSCLC). Expression of interleukin 1β (IL-1β) is increased in a number of cancers, including lung cancer and is associated with tumor aggressiveness and poor patient outcomes. A chronic increase in inflammatory mediators in the lung tumor microenvironment can lead to increased tumor promotion, invasion, angiogenesis and metastasis; however the mechanism by which this occurs has yet to be elucidated.

We have found that IL-1β exposure leads to the down regulation of E-cadherin in NSCLC cell lines. Loss of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT) in which epithelial cells lose cell-cell junctions, undergo cytoskeletal reorganization and basement membrane degradation and switch from cadherin to integrin mediated adhesion. This transformation results in cells with a mesenchymal phenotype. An important feature of mesenchymal cells is their ability to migrate independently and invade locally - prerequisites for metastasis. Following IL-1β exposure we see, along with the loss of E-cadherin, changes in cellular morphology, down regulation of cytokeratin 18 and an up regulation of mesenchymal markers, particularly N-cadherin, vimentin and SNAI2 (Slug) - a transcriptional repressor of E-cadherin. Slug expression is increased at both the mRNA and protein levels and is found via chromatin immunoprecipitation to be bound to the E-cadherin promoter following IL-1β exposure. Further, in NSCLC cell lines which do not express E-cadherin, Slug expression is elevated. Blocking Slug expression using siRNA inhibits IL-1β mediated down regulation of E-cadherin

IL-1β has many well-characterized effects on signaling pathways and protein expression, including the up regulation of COX-2 which has been shown previously to decrease E-cadherin expression. However, the IL-1β mediated effects on E-cadherin expression are COX-2 independent. Blocking COX-2 activity with celecoxib does not abrogate the E-cadherin down regulation seen here. Additionally, others have found that loss of E-cadherin is associated with resistance to epidermal growth factor receptor tyrosine kinase inhibitors which are currently in use as treatment and have been suggested as prevention agents for NSCLC. Thus, the presence of inflammatory mediators in the pulmonary microenvironment may play a specific role in promoting resistance to targeted prevention and therapy.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A26.