Deregulated GP130 signalling contributes to initiation of tumours and cancer-related cachexia in murine models.

Aim: To examine the role of deregulated gp130 signalling in the development of lung tumours and cancer-related cachexia in two models of lung cancer. Method(s): We used the gp130F/F (FF) mouse which carries a knock-in mutation in gp130, the critical co-receptor for the IL-6 cytokine family. These mice display elevated IL-6 levels and hyper-activated Stat3 in the absence of gp130-mediated PI3K/Akt and Mapk signalling. Two separate models were undertaken using FF and gp130+/+ (WT) mice commencing at 6 weeks of age. Model 1: Mice were exposed to a cigarette carcinogen (NKK) and observed over 16 weeks prior to the cellular and molecular evaluation of lung tumourigenesis. Model 2: FF and WT mice harbouring a conditionally activated oncogenic Kras allele were observed over 6 weeks after Kras activation. In addition to assessing development of lung tumours, mouse weight and muscle and fat mass were examined. Result(s): In NNK-treated animals there was a significant reduction in the number of tumours in FF mice compared to WT mice. This appeared to be independent of Stat3 as the number of tumours was unchanged from FF levels in mice with genetically normalized Stat3 levels. PI3K/Akt and Mapk pathway specific PCR arrays showed deregulation of a number of key oncogenes and tumour suppressor genes in the FF mouse suggesting a role for gp130- mediated PI3K/Akt and Mapk signalling. In the Kras model the key finding was marked weight loss in the FF mouse, with loss of both fat and lean tissue mass. This weight loss was attenuated by genetically normalizing Stat3. Conclusion(s): Our data suggest that deregulated IL-6/gp130 signalling contributes to both the development of lung cancer and its complications.