The interactive role of inflammatory mediators and metabolic reprogramming in pancreatic cancer

Inflammation and metabolic reprogramming play critical roles in the development and progression of pancreatic cancer by inducing and/or regulating key tumorigenic events. KRAS mutation, inflammatory mediators, and autophagy induce metabolic reprogramming such as rewiring of glycolytic pathways, salvaging nutrients, and regulation of redox status for survival and growth of malignant cells under a harsh tumor microenvironment. An aggressive basal-like/squamous molecular subtype of pancreatic cancer uses glycolytic intermediates effectively, whereas the classical/progenitor subtype accelerates lipogenic pathways. Understanding the circuitry of the inter-regulatory role of inflammatory pathways and metabolic reprogramming in pancreatic cancer potentially provides opportunities to improve the effectiveness of existing treatment regimens as well as identifies novel targets in designing potentially effective strategies for clinical intervention. Pancreatic ductal adenocarcinoma (PDAC) is characterized by its highly reactive inflammatory desmoplastic stroma with evidence of an extensive tumor stromal interaction largely mediated by inflammatory factors. KRAS mutation and inflammatory signaling promote protumorigenic events, including metabolic reprogramming with several inter-regulatory crosstalks to fulfill the high demand of energy and regulate oxidative stress for tumor growth and progression. Notably, the more aggressive molecular subtype of PDAC enhances influx of glycolytic intermediates. This review focuses on the interactive role of inflammatory signaling and metabolic reprogramming with emerging evidence of crosstalk, which supports the development, progression, and therapeutic resistance of PDAC. Understanding the emerging crosstalk between inflammation and metabolic adaptations may identify potential targets and develop novel therapeutic approaches for PDAC. Pancreatic ductal adenocarcinoma (PDAC) is characterized by its highly reactive inflammatory desmoplastic stroma with evidence of an extensive tumor stromal interaction largely mediated by inflammatory factors. KRAS mutation and inflammatory signaling promote protumorigenic events, including metabolic reprogramming with several inter-regulatory crosstalks to fulfill the high demand of energy and regulate oxidative stress for tumor growth and progression. Notably, the more aggressive molecular subtype of PDAC enhances influx of glycolytic intermediates. This review focuses on the interactive role of inflammatory signaling and metabolic reprogramming with emerging evidence of crosstalk, which supports the development, progression, and therapeutic resistance of PDAC. Understanding the emerging crosstalk between inflammation and metabolic adaptations may identify potential targets and develop novel therapeutic approaches for PDAC. cell degradation process necessary for cellular turnover. Removes and replaces damaged cellular components, which are then used to prevent accumulation of abnormal protein or to recycle protein in nutrient-starved conditions for preserving cell homeostasis. originating from pancreatic stellate cells, CAFs are responsible for collagen deposits in desmoplasia and recruitment of inflammatory/immune cells into the tumor microenvironment, and they play multiple roles in the tumor microenvironment supporting tumor growth and progression. CAFs possess unique characteristics as compared with normal fibroblasts but maintain a myofibroblastic phenotype, such as the expression of α-smooth muscle actin, which plays a role in permanent tissue contraction. a highly reactive massive stroma, which is a well-established characteristic of pancreatic ductal adenocarcinoma. It is made up of collagens, fibronectin, and fibroblasts and is maintained by pancreatic stellate cells. Desmoplastic stroma may act as a barrier for chemotherapeutics and encourage tumor cell growth. However, it may also restrain tumor cells and inhibit migration to distant organs. a form of programmed cell death dependent on iron and characterized by the accumulation of lipid ROS, which is caused by the imbalance between the levels of oxidative damage and glutathione-dependent antioxidant defenses. metabolic pathway that breaks down glucose into pyruvate under aerobic conditions and lactate in anaerobic conditions. oxygen-deprived tumor microenvironment. signaling molecules released by cells of the immune system that contribute to inflammation. Some examples include cytokines, chemokines, complements, histamine, bradykinin, serotonin, prostaglandin, leukotriene, platelet-activating factor, and reactive oxygen species. a proinflammatory cytokine that regulates immunity and inflammation. MIF is secreted by several cell types, including immune cells, cancer cells, epithelial cells, and endothelial cells. MIF induces the expression of cytokines such as interleukin-1 and interleukin-6. considered one of the hallmarks of cancer, this process consists of key metabolic adaptations supporting tumor growth and progression. heterogeneous group of immune cells that are derived from myeloid lineage and play a role in inhibiting antitumor immunity. metabolic pathway for ATP synthesis that occurs in the inner mitochondrial membrane and requires oxygen. activated myofibroblasts that secrete and synthesize extracellular matrix components consisting of more than half of the tumor stroma. They can differentiate into different CAF populations and contribute to the aggressive nature of pancreatic ductal adenocarcinoma. pancreatic intraepithelial neoplasia is a noninvasive precursor lesion that may develop into pancreatic ductal adenocarcinoma. a pathway that metabolizes glucose-6-phosphate into glyceraldehyde 3-phosphate, which provides biomolecules, including deoxyribose, ribose, and pentose. PPP may involve oxidative and/or nonoxidative pathways. highly reactive molecules/irons/radicals that are derived from oxygen and are products of oxygen metabolism. Depending on the levels and cellular context, they may have either pro- or antitumorigenic functions. immediate surrounding of tumor tissue in which tumor cells are embedded. It consists of a variety of cells, including immune and inflammatory cells, inflammatory mediators, extracellular matrix, and blood vessels, which may have multiple effects on tumor progression.