The Role of Adrenomedullin Signalling in Pancreatic Cancer

Abstract

Pancreatic cancer (PaCa) is the 4th most common cause of cancer related death and incidence rates are increasing. Understanding how PaCa develops is important for earlier detection and better treatment outcomes. ADM is a peptide hormone associated with many cancers. It has physiological and pathological roles regulated through receptor complexes composed of CLR and RAMPs. RAMPs alter the selectivity of receptor, the AM1 receptor (CLR and RAMP-2) is associated with physiological roles (regulating blood pressure), the AM2 receptor (CLR and RAMP-3) is associated with pathological roles. The AM2 receptor has been shown to regulate tumour growth and survival, angiogenesis, immunosuppression and epithelial-to-mesenchymal transition. The aim of this study was the elucidate the role of ADM in PaCa. The results showed that in a panel of seven PaCa cell lines, ADM, CLR and RAMPs were expressed at both mRNA and protein level. Therefore, inducible CFPAC-1 ADM KDs, CFPAC-1 RAMP-3 KDs and scrshRNA controls were developed and used for in vitro and in vivo experiments. In vitro, viability and apoptosis assays showed that both KD and control cells responded to gemcitabine treatment but not to 5-fluorouracil. In vivo, both orthotopic and subcutaneous models showed no significant difference in tumour weight or volume between different groups (CFPAC-1 ADM KD, scrshRNA and wild-type cells). There were no significant differences between the percentage of immune cells in different groups. Furthermore, immunohistochemistry showed no significant differences in the number of Ki67 positive cells. Analysis of α-SMA and endomucin needed further work. Overall, the results demonstrate that ADM and its receptor components are expressed in PaCa cell lines. However, further elucidation of the exact role of ADM in tumour development is needed with more focus on the tumour stroma. Focus on pancreatic stellate cells (α-SMA) shows promise in the field of PaCa