Epidermal growth factor (EGF) chronic stimulation causes Smad4-dependent signaling bypass in PDAC

s / Pancreatology 14 (2014) S1eS129 S69 Background: Apelin, the endogenous ligand for a G Protein-Coupled Receptor named APJ, acts as a key regulator of tumour neovascularisation. Its gene is upregulated in one third of human tumours and more specifically in pancreatic ductal adenocarcinoma (PDAC). Aims: PDAC is an asymptomatic and multi-steps disease with late prognosis and no effective therapeutics. Thus, finding new biomarkers and therapeutic targets is crucial and apelin signalling could represent a promising candidate. Materials & methods: Apelin and APJ expression is studied by immunohistochemistry realised on human (40 patients) and K-ras mouse (Lox-Stop-Lox-KrasG12D/+/Pdx1-Cre) pancreatic cancer slides. Apelin signalling function was characterised in the human pancreatic cancer cell line MiaPaCa and the regulation of intracellular effectors after apelin stimulation was analysed by western blot. Furthermore, we characterised cellular effects induced by apelin on cancer cells, especially proliferation, migration and glucose uptake. Results: By immunohistochemistry on human tumours and the K-ras mouse model which recapitulates all the stages of the disease, we show that apelin and its receptor are expressed by tumour and endothelial cells since the first steps of carcinogenesis. Characterisation of apelin signalling function in human pancreatic tumour cells reveals that apelin induces activation of key effectors which regulate several cellular effects. Indeed, apelin induces proliferation, migration and glucose uptake, which are crucial properties involved in cancer progression. Conclusion: A better understanding of apelin signalling function in pancreatic carcinogenesis could lead to the identification of a new therapeutic target and could open new perspectives for the treatment of PDAC.