World Cancer, Oncology and Therapeutics Congress

Biography

Biography: Dr Julia Gerasimenko

Abstract

Acute pancreatitis (AP) is a dangerous and in up to 5% of cases deadly disease with no specific cure. AP often results in development of chronic pancreatitis (CP) and increased occurrence of pancreatic cancer (PC). The most common form of PC is pancreatic ductal adenocarcinoma and CP patients are at significant risk of developing PC. Activation of PSCs - during pancreatic injury - induces proliferation as well as secretion of extracellular matrix components, thereby playing an important role in the fibrosis that occurs in CP and PC. The leading causes of AP have been identified as gallstone biliary disease and high alcohol intake, while abnormality in calcium signalling in pancreatic acinar cells was found to be one of the first events in this process. We have shown previously that bile acids and non-oxidative alcohol metabolites induce Ca2+overload, premature activation of pancreatic pro-enzymes, digesting the pancreas and its surroundings. In this study, we explored Ca2+ signalling in the different cell types in the acinar environment of the pancreatic tissue using a pancreatic lobule preparation. We have, for the first time, recorded depolarization-evoked Ca2+ signals in pancreatic nerves and shown that whereas acinar cells receive a functional cholinergic innervation, there is no evidence for functional innervation of the pancreatic stellate cells. The principal agent evoking Ca2+ signals in the stellate cells is bradykinin, but in experimental alcohol-related acute pancreatitis, these cells become much less responsive to bradykinin and then acquire sensitivity to trypsin. Our new findings have implications for understanding of the development of acute pancreatitis and we propose a scheme in which Ca2+ signals in stellate cells provide an amplification loop promoting acinar cell death. Initial release of the proteases kallikrein and trypsin from dying acinar cells can, via bradykinin generation and protease-activated receptors, induce Ca2+ signals in stellate cells which can then, possibly via nitric oxide generation, damage more acinar cells and thereby cause additional release of proteases, generating a vicious circle. This results in AP and subsequently in CP, increasing chances of PC.

A number of approaches have been successfully tried to alleviate alcohol-induced AP in vitro and in vivo. Inhibitor of story-operated calcium entry CM4620 (currently in the 3rd phase of human trials by CalciMedica, US) have been shown recently in our lab to reduce pathology in much lower than previously reported concentrations. Galactose as an oral supplementation has also efficiently reduced AP effects. Both approaches are currently the most promising perspectives to develop an effective AP treatment and subsequently reduce probability of CP and PC. Our findings are beneficial for understanding of new mechanisms that could help combatting pancreatic disorders.