EMT and Treatment Resistance in Pancreatic Cancer

Abstract

Pancreatic cancer (PC) is the third leading cause of adult cancer mortality in the United States. The poor prognosis for patients with PC is mainly due to its aggressive course, the limited efficacy of active systemic treatments, and a metastatic behavior, demonstrated throughout the evolution of the disease. On average, 80% of patients with PC are diagnosed with metastatic disease, and the half of those who undergo surgery and adjuvant therapy develop liver metastasis within two years. Metastatic dissemination is an early event in PC and is mainly attributed to an evolutionary biological process called epithelial-to-mesenchymal transition (EMT). This innate mechanism could have a dual role during embryonic growth and organ differentiation, and in cancer progression, cancer stem cell intravasation, and metastasis settlement. Many of the molecular pathways decisive in EMT progression have been already unraveled, but little is known about the causes behind the induction of this mechanism. EMT is one of the most distinctive and critical features of PC, occurring even in the very first stages of tumor development. This is known as pancreatic intraepithelial neoplasia (PanIN) and leads to early dissemination, drug resistance, and unfavorable prognosis and survival. The intention of this review is to shed new light on the critical role assumed by EMT during PC progression, with a particular focus on its role in PC resistance.

Keywords: EMT; pancreatic cancer; resistance.

Figure 1

Molecular hallmarks/fluctuations/switching regulating the epithelial-to-mesenchymal transition (EMT) process in pancreatic cancer. The EMT process involves loss of cell polarization, a gain in migratory abilities and progressive acquisition of a mesenchymal phenotype. The EMT mechanism is characterized by the ‘cadherin switch’, where E-cadherin expression is progressively downregulated and replaced by the expression of N-cadherin. The transition process is associated to a decrease of miR-200 levels and an increase of classical E-cadherin transcriptional suppressors—such as ZEB1, Snail, and Slug—activated upstream by TGF-β. Cells undergoing EMT commonly quit the expression of extracellular matrix (ECM) elements mediating structural rigidity and cell adhesion in favor of proteases, cytokines, growth factors, and ECM components which improve cell migration and intravasation in bloodstream. Pancreatic cancer cell cytokines accelerate transformation of fibroblasts into quiescent pancreatic stellate cells (PSCs) and then into activated pancreatic stellate cells (aPSCs). Furthermore, inflammatory cytokines recruit myeloid progenitor cells and mediate their subsequent differentiation into myeloid-derived suppressive cells (MDSCs), which suppress the immune surveillance function. IL: interleukin; TGF: transforming growth factor; TNF: tumor necrosis factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; HGF: hepatocyte growth factor; CTGF: connective tissue growth factor; EGF: epidermal growth factor; IFN: interferon; PDGF: platelet-derived growth factor; MCP-1: macrophage inflammatory protein 1; RANTES: regulated upon activation normally T-expressed and presumably secreted; VEGF: vascular endothelial growth factor; ANG-2: angiopoietin-2; ANGPTL: angiopoietin-like.