Activated Pancreatic Stellate Cells Enhance The Warburg Effect To Cause The Malignant Development In Chronic Pancreatitis

Background: Pancreatic stellate cells（PSCs）are pancreatic-specific mesenchymal cells that accumulate around blood vessels and ducts in pancreatic tissue and surround the base of acini.In normal pancreatic tissue,In normal pancreatic tissue,PSC mainly presents a resting phenotype and is involved in maintaining extracellular matrix（ECM）balance.PSCs are activated by various physicochemical factors and has a myofibroblast-like phenotype.Activated Pancreatic stellate cells play an important role in the progression of Pancreatic fibrosis in both Chronic pancreatitis（CP）and Pancreatic ductal adenocarcinoma（PDAC）,and their abnormal activity leads to ECM imbalance,thus promoting the occurrence and development of pancreatic diseases.Chronic pancreatitis（CP）is a precancerous condition associated with pancreatic ductal adenocarcinoma（PDAC）,but its evolutionary mechanism is unclear.In recent years,research on PSC have attracted much attention,and it has been confirmed that PSC is closely associated with the occurrence and development of chronic pancreatitis and pancreatic cancer.We aimed to find out whether PSC plays a key role in this "inflammation-cancer transition ".Objective: This study explored the role and mechanism of PSC in pancreatitiscarcinoma transition,and provided ideas for prevention of malignant transformation of chronic pancreatitis and early diagnosis and treatment of pancreatic cancer.Methods: In order to evaluate the effect of activated pancreatic stellate cells on normal pancreatic duct epithelial cells and pancreatic cancer cells,pancreatic stellate cells isolated from human tissues were co-cultured with these two cells,respectively.Functional assays assessed the proliferation,migration,and invasion of these two cells.RT-q PCR and western blotting were used to detect the m RNA and protein expressions of the glycolysis markers（pyruvate kinase M2,lactate dehydrogenase A,glucose transporter 1,hexokinase-II and monocarboxylate transporter 4;PKM2,LDHA,GLUT1,HK2 and MCT4）in these two cells.Lactate production and glucose utilization assays assessed the aerobic glycolysis level of these two cells.Immunohistochemistry was used to detect the expression of the glycolysis markers in pancreatic duct epithelial cells and α-SMA in pancreatic stellate cells,and the correlation between the two was analyzed in human tissues.Results: Our research found that co-culture with activated PSCs promoted the proliferation,migration and invasion of normal pancreatic duct epithelial cells and pancreatic cancer cells.At the same time,activated PSCs had a significant effect on the expression of the glycolysis markers in normal pancreatic duct epithelial cells and pancreatic cancer cells and increased lactic acid production and glucose consumption in these two cells.In vivo experiments showed that the expression of the glycolysis markers in pancreatic duct epithelial cells and the marker protein（α-SMA）of activated PSCs in the pancreatic duct peripancreatic interstitium were higher in pancreatic cancer tissues and chronic pancreatitis tissues than in normal pancreatic tissues in both animals and humans.In addition,analysis of human tissue specimens showed that there is a correlation between the expression of the glycolysis markers and α-SMA.Conclusion: These findings indicate that activated PSCs play an important role in the development and progression of chronic pancreatitis into pancreatic cancer by regulating and promoting the Warburg effect.Our research provides a new theoretical basis for further understanding the mechanism of CP malignancy and the selection of targets for reversing CP malignancy.