Abstract
Chronic pancreatitis (CP) is a precancerous condition associated with pancreatic ductal adenocarcinoma (PDAC), but its evolutionary mechanism is unclear. Pancreatic stellate cells (PSCs) are closely related to the occurrence and development of CP and PDAC, but it is not clear whether PSCs play a key role in this “inflammation-cancer transition”. 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 (pyruvate kinase M2, lactate dehydrogenase A, glucose transporter 1, hexokinase-II and monocarboxylate transporter 4; PKM2, LDHA, GLUT1, HK2 and MCT4) 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 glycolysis markers and α-SMA. 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 aerobic glycolysis. Our research provides a new theoretical basis for further understanding the mechanism of CP malignancy and the selection of targets for reversing CP malignancy.
Highlights
Pancreatic cancer is a highly malignant tumor with a poor prognosis
Pancreatic stellate cells (PSCs) are activated during pancreatic tissue injury and stress and acquire a myofibroblast phenotype
Phenotypic identification of CaPSCs was performed by immunofluorescence labelling of a-smooth muscle actin (a-SMA), a marker protein of activated pancreatic stellate cells
Summary
Pancreatic cancer is a highly malignant tumor with a poor prognosis. Its mortality ranked seventh among all malignant tumors in 2020, and its incidence is increasing annually [1].Early pancreatic cancer lacks specific clinical symptoms. 85% of patients have lost the chance for radical surgical resection by the time they consult a doctor, and their 5-year survival rate is less than 6%. The 5-year survival rate of patients is less than 25% [2]. Clinical studies have shown that patients with chronic pancreatitis have a much higher risk of pancreatic cancer than normal people [5, 6]. Exploring the mechanism of pancreatic cancer transformation from chronic pancreatitis and reversing the progression of chronic pancreatitis are important issues that urgently need to be solved
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