Inflammation et oncogenèse pancréatique : physiologie et physiopathologie

Chronic pancreatitis is a well described risk factor of pancreatic adenocarcinoma. The link between chronic inflammation and oncogenesis is partially known. However, the role of pancreatic stellate cells (PSC) and hypoxia seems to be the key in the pathophysiological process. Their activation following pancreatic injury results in extracellular matrix remodeling and changes in cell/cell and epithelial cell/stroma relationship. It also regulates the expression of cytokines and growth factors and promotes fibrosis, cell proliferation and migration and tumor invasion. In patients with chronic pancreatitis, the detection of precancerous lesions (Pancreatic intraepithelial neoplasia (PanIN) and Intraductal pancreatic mucinous neoplasrns (IPMN)), is made difficult by the pancreatic architectural modifications. Despite advances in knowledge of the genome to proteome of these lesions, tools do not allow effective screening in patients at high risk of pancreatic cancer. We proposed three approaches in order to assess the relationship between pancreatic inflammation and oncogenesis. Firstly, we assessed the prevalence of precancerous lesions (PanIN) in long standing pancreatic inflammation (hereditary pancreatitis) and found frequent early and severe PanIN lesions in the course of hereditary pancreatitis. Secondly, we developed a model of culture of thick sections of human normal pancreas and assessed an early activation of pancreatic stellate cells in hypoxic conditions. Finally, we identified specific biomarkers of high grade of dysplasia in precancerous lesions (IPMN) by mass spectrometry imagery. Identifications (Ubiquitin and Thymosin-p4) were validated on IPMN EUS FNA samples.