Lung cancer (LC) is the most common and lethal cancer worldwide and, in Australia, accounts for ~7,500 deaths annually. A causal correlation between LC and cigarette smoking is well established, however only 10-15% of smokers develop LC, suggesting there are other ill-defined genetic, epigenetic and/or environmental factors which predispose individuals to LC. Regarding the former, interleukin (IL)-6 signals via the gp130 signal-transducing receptor subunit to primarily activate the latent transcription factor STAT3, as such, the pro-inflammatory and oncogenic properties of the IL-6/gp130/STAT3 signalling axis can be established. Since IL-6 expression and STAT3 activity are up-regulated in human LC, we explored the downstream consequences of increased IL-6/STAT3 activity in the well documented Kras^G12D mouse LC model. For this purpose, we utilised gp130^F/F (FF) mice that carry a knock-in mutation in gp130 leading to deregulated IL-6/STAT3 signalling, and crossed these mice with the LoxP-Stop-LoxP Kras^G12D mice which harbour a conditionally-activated oncogenic Kras allele. Inhalation of FF:Kras^G12D and WT:Kras^G12D mice with a Cre recombinase adenovirus activated the Kras allele at 6 week of age, and mice were observed over 6 weeks.

There was a severe and diffuse development of invasive adenocarcinoma in situ (AIS) in the lungs of FF:Kras^G12D mice only. The percentage density of lesions in the lungs of FF:Kras^G12D mice was increased compared to WT:Kras^G12D littermate controls, and associated with an increase in the number of proliferative cells and inflammatory infiltrates (determined by immunohistochemistry). In contrast, partial suppression of deregulated IL-6/STAT3 signalling by crossing FF:Kras^G12D mice onto an IL-6^-/- or Stat3^-/+ background led to a recovery of normal lung tissue and a decrease of both proliferative and inflammatory cells.

These data show that deregulated gp130/STAT3 signalling in this mouse model drives the development of AIS and invasiveness in the lungs, and that this increased severity of AIS is proliferation-driven.