Sustained exposure to TNF-α and IL-1β increases the invasion, adhesion and proliferative potential of a normal bronchial epithelial cell line  — ASN Events
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Sustained exposure to TNF-α and IL-1β increases the invasion, adhesion and proliferative potential of a normal bronchial epithelial cell line  (#296)

Anne-Marie Baird 1 2 , Steven Gray 1 , Derek Richard 2 , Kenneth O'Byrne 2 3 4
  1. Thoracic Oncology Research Group, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
  2. Cancer and Ageing Research Program, Queensland University of Technology, Brisbane, QLD, Australia
  3. Thoracic Oncology Research Group, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
  4. Divison of Cancer Services , Princess Alexandra Hospital, Brisbane, QLD, Australia

Aims

Hypoxia and chronic inflammation are key triggers in the transformation process with at least 20% of all malignancies initiated or exacerbated by inflammation. The aim of this study was to examine inflammation as a contributory factor in non-small cell lung cancer (NSCLC) carcinogenesis, concentrating primarily on the pathological involvement of the pro-inflammatory cytokines, TNF-α/IL-1β, and hypoxia.

Methods

A normal bronchial epithelial cell line was modified to stably and functionally over-express TNF-α and IL-1β (alone or in combination). Cells were cultured continuously for three months under normoxic and hypoxic conditions. Functional assays were performed to assess cellular change: transformation assay (soft agar), proliferation (BrdU ELISA), invasion (matrigel), adhesion (FACS) and angiogenesis (endothelial tube formation). Gene expression alterations were also assessed using qPCR Cancer PathwayFinder arrays.

Results

Although anchorage independent growth was not evident by soft agar, the expression of ICAM and VCAM were up regulated and the cellular proliferative rate has increased. Under normoxia, the IL-1β and TNF-α/IL-1β clones displayed an increased invasive capacity compared with the empty vector control (p<0.05). Differences were also detected in the gene expression profile implicated in pathways involved in the hallmarks of cancer - cell signalling (FOS, JUN), apoptosis (BAD, BAX, BCL2), angiogenesis (CXCL8), adhesion, invasion and cell cycle regulation (p53, c-myc).

Conclusion

This study provides a valuable isogenic cell line model in which to study the effect of prolonged chronic inflammation. Although the cells have not developed anchorage independent growth, there are distinct indications that phenotypic changes occurred within the three-month time frame. As pro-longed chronic exposure to inflammation is a pre-requisite for many disease states, these results warrant extended growth studies to further delineate the complex roles of TNF-α, IL-1β and hypoxia in the process of lung carcinogenesis. This will assist in the development of novel targeted therapeutics and clinically relevant biomarkers.    

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