Deregulated gp130 signalling contributes to lung tumourigenesis and the development of cancer-related cachexia

Lung cancer is the leading cause of cancer death in Australia and worldwide, and is frequently associated with the devastating paraneoplastic syndrome of cachexia. While recent discoveries in the molecular foundations of lung cancer have produced specific, directed therapies with substantial benefit, these are effective in only a small proportion of patients with adenocarcinomas that demonstrate specific molecular characteristics. New therapies are desperately needed and the search for new molecular targets requires models with good translational potential. The potent immunomodulatory cytokine interleukin (IL)-6 has been linked with the development of lung cancer as well as cachexia, and presents a promising specific target in anti-cancer therapy. This thesis addresses the question of the role of IL-6 by utilising the FF mouse which, by virtue of a “knock in” substitution within the IL-6 family co-receptor gp130, displays endogenously elevated IL-6. As a consequence of this mutation, the FF mouse displays hyper-activation of the latent transcription factor STAT3 in the absence of gp130-driven PI3K/Akt and MAPK signalling. Importantly, STAT3, PI3K/Akt and MAPK have all been implicated in lung cancer development and the development of cachexia. Initial characterisation of the FF mouse lung demonstrated substantial pulmonary inflammation that is largely composed of B220+ cells. This inflammation is driven by IL-6 through STAT3 but not STAT1. Following this characterisation the FF mouse was used in two separate well-established lung cancer models; a cigarette carcinogen (NNK) model and a genetic (KrasG12D) model. In the cigarette carcinogen model there was a significant reduction in tumour number and size in FF mice, which appeared to be largely independent of STAT3. The difference seen is contributed to by the loss of gp130-driven PI3K/Akt and/or MAPK signalling as evidenced by upregulation of tumour suppressor genes and down-regulation of oncogenes in the FF mouse, downstream of both PI3K/Akt and MAPK. In the genetic model the key finding was of weight loss and early mortality in the absence of a significant change in tumour load in the FF:KrasG12D mice. Both the weight loss and early mortality were abrogated by genetically normalising STAT3 activation and ablating IL-6. Importantly, we also identified IL-6 trans-signalling as the signalling modality responsible for the cachexia by rescuing the weight loss using a monoclonal Ab targeting in the sIL6R.