Combined activation of IGF signaling and CREB phosphorylation is important for lung tumourigenesis
The insulin-like growth factor (IGF) family has been implicated in growth, development and metastasis in many different types of cancer. Our previous in vivo studies have demonstrated that overexpression of IGF-II in lung epithelium of MMTV-IGF-II transgenic mice is sufficient to induce lung tumours. Further examination of these tumours revealed high levels of phosphorylated cAMP response element binding protein (CREB). This thesis investigated the role IGF signaling and CREB activation plays in lung tumourigenesis. Up to 80% of human lung tumours overexpress the IGF-IR and there have been a number of IGF-IR therapies developed to target this receptor. Initially, I examined the importance of IGF-IR overexpression in lung tumourigenesis using two inducible transgenic mouse models. Insulin-like growth factor receptor 1 induced lung tumours were detectable as early as 30 days of treatment and tumours were macroscopically visible by 90 days. Further examination of the IGF-IR signaling pathways showed that Akt, p38 MAPK, Stat3 and CREB were activated in the transgenic lung tumours. Overexpression of CREB in a normal lung cell line induced anchorage-independent colony growth in soft agar while suppression of CREB expression in two lung cancer cell lines diminished colony growth in soft agar. In order to determine whether CREB overexpression is sufficient to transform lung cells and whether CREB is directly capable of inducing lung tumours, tetracycline inducible transgenic mice were generated. Induction of CREB in these mice resulted in cell specific expression of CREB but no hyperplasia or tumour formation after 10 months of CREB overeexpression. Therefore, we concluded that overexpression of CREB alone was insufficient to induce lung hyperplasia and tumour development. Previously, CREB had not been examined in human lung tumour biopsies, so immunohistochemistry for CREB and phosphorylated CREB was performed on lung tumour tissue arrays. We observed high levels of CREB and phosphorylated CREB in all types of human lung tumour samples. As well, CREB expression was more consistently elevated in the early stage samples than in late stage samples, suggesting that CREB could be involved in tumour initiation and could be an early molecular marker for lung cancer. Results from these studies show the importance of the IGF and CREB families in lung tumor development and these data also suggests that IGF-II, IGF-IR and CREB may be important biological markers for human lung adenocarcinoma and potential therapeutic targets for this disease.