Content area
Full Text
Introduction
Pancreatic cancer is a one of the most highly malignant tumors of the digestive tract and has an extremely poor prognosis, with a 5-year relative survival rate of 9%. In 2019, an estimated 56,770 individuals were newly diagnosed with pancreatic cancer, which may result in ~45,750 cancer-related deaths in the United States (1). In China, the incidence rate of pancreatic cancer has also increased from 2000 to 2011. Pancreatic cancer accounts for the second leading upward trend of age-standardized mortality rates (2). Metastasis is the leading cause of pancreatic cancer-related mortality, as ~80% of the patients are not deemed suitable for surgical resection due to early relapse or advanced metastasis at diagnosis (3). Therefore, it is crucial to elucidate the molecular mechanisms underlying the invasion and metastasis of pancreatic cancer, and novel comprehensive and effective therapeutic interventions are urgently needed to improve the treatment outcome.
Pancreatic cancer is characterized by an excessive desmoplastic reaction, which favors hypoxia, further inducing epithelial-to-mesenchymal transition (EMT) and tumor metastasis (4). It has become obvious that the tumor microenvironment, which includes several types of stromal cells, such as immune, inflammatory and endothelial cells, as well as pancreatic stellate cells (PSCs), plays a key role in tumor invasion and metastasis (5). PSCs generally exist in one of two statuses: Quiescent and activated. Under physiological conditions, non-activated PSCs contain abundant cytoplasmic vitamin A-containing lipid droplets, which produce very low levels of extracellular matrix (ECM). After activation, PSCs are characterized by a decrease in lipid droplets and increased expression of α-smooth muscle actin (α-SMA) and collagen-I, which are crucial for tumor development, evasion of immune surveillance, invasion and metastasis (6). In addition, activated PSCs can produce a number of soluble factors, such as interleukin (IL)-6, transforming growth factor (TGF)-β and stromal cell-derived factor (SDF)-1, which promote the malignant behavior of pancreatic cancer cells (7). IL-6 is a potent pro-inflammatory cytokine secreted by PSCs in the pancreatic cancer microenvironment. In addition to the inflammatory response, IL-6 is also associated with tumor progression, including proliferation, angiogenesis, chemoresistance, invasion, EMT and metastasis (7,8). Our previous study demonstrated that PSCs cultured under hypoxic conditions display higher levels of IL-6, vascular endothelial growth factor (VEGF)-A and SDF-1 transcription and secretion (9).
Low oxygen tension (hypoxia), which is...