Notch signaling pathway in pancreatic tumorigenesis

Abstract

The Notch signaling pathway is an evolutionary conserved signal transduction cascade that is critical to embryonic and postnatal development, but aberrant Notch signaling is also implicated in tumorigenesis of many organs including the pancreas. Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy in the pancreas, with a dismally low survival rate due to the late-stage diagnosis and peculiar therapeutic resistance. Upregulation of the Notch signaling pathway has been found in preneoplastic lesions as well as PDACs in genetically engineered mouse models and human patients, and inhibition of the Notch signaling suppresses tumor development and progression in mice as well as patient-derived xenograft tumor growth, suggesting a critical role for Notch in PDAC. However, the role of Notch signaling pathway remains contentious, exemplified by differential functions of Notch receptors and contrasting outcomes of abolishing Notch signaling in murine PDAC models with distinct cell-of-origin or at different stages. Glycosylation of Notch receptors represents a powerful regulatory mechanism of Notch signaling, and its functional significance in PDAC has begun to emerge. Beyond its impact on tumor cells, Notch signaling is an important regulator of the components of pancreatic tumor microenvironment, including blood vasculature, stellate cells, fibroblasts, and immune cells. Finally, Notch may act as a tumor suppressor in pancreatic neuroendocrine tumor, the second most common pancreatic neoplasm with the incidence on rise. This review summarizes the research on the complex roles of Notch signaling in pancreatic tumorigenesis and the development of potential Notch-targeting therapies for pancreatic cancer.

Keywords: Acinar-to-ductal metaplasia (ADM); Cancer cell-of-origin; Cancer stem cell; Epithelial-mesenchymal transition (EMT); Intraductal papillary mucinous neoplasm (IPMN); Notch signaling pathway; Pancreatic ductal adenocarcinoma (PDAC); Pancreatic intraepithelial neoplasia (PanIN); Pancreatic neuroendocrine tumor (PNET); Tumor microenvironment.