Pancreatic cancer as a complication of chronic pancreatitis – diagnostic approach

Patients with underlying chronic pancreatitis (CP) are at increased risk of pancreatic cancer (PC) development. The pathogenesis of the neoplastic transformation remains unclear. However, chronic inflammation, pancreatic stellate cells over-proliferation and genetic alterations play a major role in carcinogenesis progression. Early diagnosis and differentiation between benign and malignant disease is of a great importance. Better understanding the connection of the two entities could provide new therapeutic options.

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Activated Pancreatic Stellate Cells Enhance the Warburg Effect to Cause the Malignant Development in Chronic Pancreatitis

10.21203/rs.3.rs-524181/v1 ◽

2021 ◽

Author(s):

Tao Ye ◽

Shao Feng ◽

Liu Zheng ◽

Cai Ming ◽

Meng Futao ◽

...

Keyword(s):

Pancreatic Cancer ◽

Chronic Pancreatitis ◽

Epithelial Cells ◽

Pancreatic Duct ◽

Cancer Cells ◽

Stellate Cells ◽

Glycolytic Enzymes ◽

Pancreatic Stellate Cells ◽

Migration And Invasion ◽

Pancreatic Cancer Cells

Abstract Background: 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. We aimed to find out whether PSCs play a key role in this " inflammationcancer transition ". Methods: 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-qPCR and western blotting were used to detect the mRNA and protein expressions of glycolytic enzymes 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 glycolytic enzymes and α-SMA, 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 glycolytic enzymes PKM2 and LDHA 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 glycolytic enzymes PKM2 and LDHA 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 PKM2/LDHA 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 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.

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Selective phytochemicals targeting pancreatic stellate cells as new anti-fibrotic agents for chronic pancreatitis and pancreatic cancer

Acta Pharmaceutica Sinica B ◽

10.1016/j.apsb.2019.11.008 ◽

2020 ◽

Vol 10 (3) ◽

pp. 399-413 ◽

Cited By ~ 4

Author(s):

Puvanesswaray Ramakrishnan ◽

Wei Mee Loh ◽

Subash C.B. Gopinath ◽

Srinivasa Reddy Bonam ◽

Ismail M. Fareez ◽

...

Keyword(s):

Pancreatic Cancer ◽

Chronic Pancreatitis ◽

Stellate Cells ◽

Pancreatic Stellate Cells

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Chronic Pancreatitis and the Development of Pancreatic Cancer

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200423095700 ◽

2020 ◽

Vol 20 (8) ◽

pp. 1182-1210

Author(s):

Hemanth K. Kandikattu ◽

Sathisha U. Venkateshaiah ◽

Anil Mishra

Keyword(s):

Pancreatic Cancer ◽

Chronic Pancreatitis ◽

Digestive Enzymes ◽

Inflammatory Cell ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Inflammatory Disorder ◽

Ductal Cells ◽

Pancreatic Cells

Pancreatitis is a fibro-inflammatory disorder of the pancreas that can occur acutely or chronically as a result of the activation of digestive enzymes that damage pancreatic cells, which promotes inflammation. Chronic pancreatitis with persistent fibro-inflammation of the pancreas progresses to pancreatic cancer, which is the fourth leading cause of cancer deaths across the globe. Pancreatic cancer involves cross-talk of inflammatory, proliferative, migratory, and fibrotic mechanisms. In this review, we discuss the role of cytokines in the inflammatory cell storm in pancreatitis and pancreatic cancer and their role in the activation of SDF1α/CXCR4, SOCS3, inflammasome, and NF-κB signaling. The aberrant immune reactions contribute to pathological damage of acinar and ductal cells, and the activation of pancreatic stellate cells to a myofibroblast-like phenotype. We summarize several aspects involved in the promotion of pancreatic cancer by inflammation and include a number of regulatory molecules that inhibit that process.

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Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer

Journal of Cancer ◽

10.7150/jca.38616 ◽

2020 ◽

Vol 11 (6) ◽

pp. 1505-1515 ◽

Cited By ~ 1

Author(s):

Guihua Jin ◽

Weilong Hong ◽

Yangyang Guo ◽

Yongheng Bai ◽

Bicheng Chen

Keyword(s):

Pancreatic Cancer ◽

Chronic Pancreatitis ◽

Molecular Mechanism ◽

Stellate Cells ◽

Pancreatic Stellate Cells

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Activated Pancreatic Stellate Cells Enhance the Warburg Effect to Cause the Malignant Development in Chronic Pancreatitis

10.21203/rs.3.rs-524181/v2 ◽

2021 ◽

Author(s):

Tao Ye ◽

Shao Feng ◽

Liu Zheng ◽

Cai Ming ◽

Meng Futao ◽

...

Keyword(s):

Pancreatic Cancer ◽

Chronic Pancreatitis ◽

Epithelial Cells ◽

Pancreatic Duct ◽

Cancer Cells ◽

Stellate Cells ◽

Monocarboxylate Transporter ◽

Pancreatic Stellate Cells ◽

Glucose Transporter 1 ◽

Pancreatic Cancer Cells

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.

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Activated Pancreatic Stellate Cells Enhance the Warburg Effect to Cause the Malignant Development in Chronic Pancreatitis

Frontiers in Oncology ◽

10.3389/fonc.2021.714598 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ye Tao ◽

Feng Shao ◽

Ming Cai ◽

Zhen Liu ◽

Yao Peng ◽

...

Keyword(s):

Pancreatic Cancer ◽

Chronic Pancreatitis ◽

Epithelial Cells ◽

Pancreatic Duct ◽

Cancer Cells ◽

Stellate Cells ◽

Monocarboxylate Transporter ◽

Pancreatic Stellate Cells ◽

Glucose Transporter 1 ◽

Pancreatic Cancer Cells

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.

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Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽

10.3390/biom11060901 ◽

2021 ◽

Vol 11 (6) ◽

pp. 901

Author(s):

Ramiz S. Ahmad ◽

Timothy D. Eubank ◽

Slawomir Lukomski ◽

Brian A. Boone

Keyword(s):

Pancreatic Cancer ◽

Extracellular Matrix ◽

Immune Cells ◽

Immune Cell ◽

Treatment Strategies ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Cellular Mechanisms ◽

Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

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