Abstract
Background: The progression and response to systemic treatment of cancer is substantially dependent on the balance between cancer cell death (apoptosis and necroptosis) and cancer cell survival (autophagy). Although well characterized in experimental systems, the status of cancer cell survival and cell death in human pancreatic ductal adenocarcinoma (PDAC), especially in response to chemotherapy and different types of chemotherapy is poorly described. Results: The median (95% confidence interval) survival was 31.6 (24.5–44.5) months after FOLFIRINOX versus 15.8 (2.0–20.5) months after gemcitabine-based therapy (p = 0.039). PDAC tissue autophagy was reduced compared to normal pancreata based on reduced BECLIN-1 expression and LC3-Lamp-2 colocalization, whilst necroptosis (RIP-1) was increased. Neoadjuvant therapy was associated with further reduced autophagy based on p62/SQSTM-1 accumulation, and increased necroptosis (RIP3 and pMLKL) and apoptosis (BAX, cleaved CASPASE-9 and CASPASE-3) markers, increased nuclear p65 (NF-κB) and extracellular HMGB1 expression, with greater CD8+ lymphocyte infiltration. Survival was associated with reduced autophagy and increased apoptosis. Necroptosis (RIP-3, pMLKL) and apoptosis (BAX and cleaved CASPASE-9) markers were higher after FOLFIRINOX than gemcitabine-based treatment. Patients and methods: Cancer cell autophagy, apoptosis, and necroptosis marker expression was compared in pancreatic tissue samples from 51 subjects, comprising four groups: (1) surgical resection for PDAC after FOLFIRINOX (n = 11), or (2) after gemcitabine-based (n = 14) neoadjuvant therapy, (3) patients undergoing PDAC resection without prior chemotherapy (n = 13), and (4) normal pancreata from 13 organ donors. Marker expression was undertaken using semi-automated immunofluorescence-FACS-like analysis, defining PDAC cells by CK-7+ expression.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) has a rising incidence with poor survival and is set to become the second commonest cause of cancer death [1, 2]
Cytotoxicity will lead to the activation of receptor interacting kinases (RIP)-1 and RIP-3 leading to necrosome assembly, which in turn recruits mixed lineage kinase domain-like protein (MLKL) and its phosphorylation, leading to necroptosis and the release of damage associated molecular patterns (DAMPs) [15]
In this study we found that pancreatic cancer epithelial cells had reduced autophagy compared to normal epithelial cells and was further reduced by chemotherapy
Summary
Pancreatic ductal adenocarcinoma (PDAC) has a rising incidence with poor survival and is set to become the second commonest cause of cancer death [1, 2]. Different mechanisms of cell death are involved in the pathogenesis of PDAC and responses and resistance mechanisms to cytotoxicity. The contribution of these mechanisms including autophagy, necroptosis and apoptosis are complex with evolving concepts but with relatively few clinical studies. The progression and response to systemic treatment of cancer is substantially dependent on the balance between cancer cell death (apoptosis and necroptosis) and cancer cell survival (autophagy). Well characterized in experimental systems, the status of cancer cell survival and cell death in human pancreatic ductal adenocarcinoma (PDAC), especially in response to chemotherapy and different types of chemotherapy is poorly described
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