Promotion of a cancer-like phenotype, through chronic exposure to inflammatory cytokines and hypoxia in a bronchial epithelial cell line model.

Anne-Marie Baird,Derek J Richard,Kenneth J O’Byrne,Steven G Gray

doi:10.1038/srep18907

Abstract

Globally, lung cancer accounts for approximately 20% of all cancer related deaths. Five-year survival is poor and rates have remained unchanged for the past four decades. There is an urgent need to identify markers of lung carcinogenesis and new targets for therapy. Given the recent successes of immune modulators in cancer therapy and the improved understanding of immune evasion by tumours, we sought to determine the carcinogenic impact of chronic TNF-α and IL-1β exposure in a normal bronchial epithelial cell line model. Following three months of culture in a chronic inflammatory environment under conditions of normoxia and hypoxia (0.5% oxygen), normal cells developed a number of key genotypic and phenotypic alterations. Important cellular features such as the proliferative, adhesive and invasive capacity of the normal cells were significantly amplified. In addition, gene expression profiles were altered in pathways associated with apoptosis, angiogenesis and invasion. The data generated in this study provides support that TNF-α, IL-1β and hypoxia promotes a neoplastic phenotype in normal bronchial epithelial cells. In turn these mediators may be of benefit for biomarker and/or immune-therapy target studies. This project provides an important inflammatory in vitro model for further immuno-oncology studies in the lung cancer setting.

Highlights

Lung cancer accounts for approximately 20% of all cancer related deaths
The reduction in angiogenic potential was significant in TNF-α /IL-1β compared to Empty vector control (EVC) (p < 0.01) (Fig. 7D). These results suggest that the HBEC4 ctl and EVC secrete different angiogenic mediators depending on oxygen concentration, and that TNF-α and IL-1β are produced at a level, which promotes an anti-angiogenic response
An increase was observed in the MMP gene family, which are critical in hypoxia mediated invasion of lung adenocarcinoma[40]

Summary

Introduction

Lung cancer accounts for approximately 20% of all cancer related deaths. Five-year survival is poor and rates have remained unchanged for the past four decades. The data generated in this study provides support that TNF-α, IL-1β and hypoxia promotes a neoplastic phenotype in normal bronchial epithelial cells In turn these mediators may be of benefit for biomarker and/or immune-therapy target studies. It is acknowledged that chronic inflammation plays an important role in cancer initiation and progression in a variety of solid cancers[4,5,6,7] This includes lung cancer[8,9,10,11], as individuals with inflammatory lung conditions are at an increased risk of lung cancer development even in the absence of tobacco use[10]. IL-1β serum concentrations are significantly higher in lung cancer patients compared with controls and levels are associated with a worse prognosis[22] High levels of this cytokine are linked to shorter progression free survival and overall survival in the disease[26]

Methods

Results

Conclusion