Deregulated IL-6/gp130 signalling in lung cancer development

2017-02-13T04:19:25Z (GMT) by Gavin Brooks
Lung cancer is the most common and lethal form of cancer in Australia and worldwide, with lung adenocarcinoma (LAC) being the most common phenotype of lung cancer. LAC is strongly associated with chronic lung inflammation triggered by cigarette smoking, and one of the most established disease-associated consequences of the genotoxic effects of cigarette-derived carcinogens is activating mutations in the <i>Kras</i> proto-oncogene. The identification of activating mutations in a minority of LAC patients, mainly comprising never smokers, has paved the way for targeted therapies with substantial benefit. However, effective therapies for LAC with a more typical mutation profiles, especially those associated with smoking, are yet to be identified, thus highlighting the need for a better understanding of the molecular and genetic alterations involved in the initiation and progression of LAC. In this regard, components of the IL-6 cytokine family which signal through the shared gp130 signal-transducing receptor subunit, are commonly up-regulated in human lung cancer, and represents a promising target in anti-cancer therapy. Despite this, the molecular mechanisms associated with deregulated gp130 signalling in lung cancer has not been fully elucidated, largely due to the paucity of genetically defined pre-clinical mouse models that allow for identification of gp130 signalling pathway-related diseases. <br>     This thesis addresses the question whether gp130 signalling contributes to the initiation and maintenance of the malignant phenotype of LAC by enhancing the oncogenic effects of mutated <i>Kras.</i> We utilised our novel gp130<sup>F/F</sup> mouse model for upregulated endogenous IL-6 production and associated spontaneous pulmonary inflammation as a result of a “knock-in” substitution within the IL-6 family co-receptor gp130. These mice display augmented activation of the latent transcription factor Stat3 in the absence of gp130-driven PI3K/Akt and Mapk/Erk signalling. Importantly, Stat3, PI3K/Akt and Mapk/Erk have been implicated in lung cancer development. <br>     We used gp130<sup>F/F</sup> mice generated onto the lung cancer susceptible genetic background <i>Kras</i>(G12D) (gp130<sup>F/F</sup>:<i>Kras</i><sup>G12D</sup> mice) and elucidated for the first time that gp130 signalling driven cell proliferation augmented <i>Kras</i>-induced lung carcinogenesis. Importantly, we discovered a causal role for IL-6 via its pathogenic mode IL-6 trans signalling, as well as identify a potential therapeutic strategy to target discrete modes of IL-6 signalling in <i>Kras</i>-induced LAC. We also identified Stat3 as the downstream mediator of IL-6/gp130 driven inflammation associated with <i>Kras</i>-induced LAC. Furthermore, we validated above findings in clinical setting using lung cancer biopsies. <br>     These results will therefore provide a significant and original contribution to our fundamental understanding of the mechanisms involved in lung cancer that will potentially strengthen the translational impact of early detection and treatment of the disease in the clinic.