TGF-β1 secreted by pancreatic stellate cells promotes stemness and tumourigenicity in pancreatic cancer cells through L1CAM downregulation

ABSTRACTPancreatic cancer is refractory and characterized by extensively surrounding- and intra-tumor fibrotic reactions that are contributed by activated pancreatic stellate cells (PSCs). Activation of PSCs plays a pivotal role for developing fibrotic reactions to affect themselves or pancreatic cancer cells (PCCs). In the current study, we demonstrated that hepatoma-derived growth factor (HDGF) was secreted from transforming growth factor-β1 (TGF-β1)-treated PSCs. We found that HDGF contributed to anti-apoptosis of PSCs and led to synthesis and depositions of extracellular matrix proteins for stabilizing PSCs/PCCs tumor foci. CCAAT/enhancer binding protein δ (CEBPD) responds to TGF-β1 through a reciprocal loop regulation and further activated hypoxia inducible factor-1α (HIF-1α) contributed to up-regulation ofHDGFgene. It agrees with the observation that severe stromal growth positively correlated with stromal HDGF and CEBPD in pancreatic cancer specimens. Collectively, the identification of TGF-β1-activated CEBPD/HIF-1α/HDGF axis provides new insights for the novel discoveries of HDGF in anti-apoptosis and pro-fibrosis of PSCs and outgrowth of pancreatic cancer cells.

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The Ratio of Pancreatic Stellate Cells to Pancreatic Cancer Cells Plays a Critical Role in Modulating Carcinoma Cell Behaviour

Gastroenterology ◽

10.1016/s0016-5085(11)62960-0 ◽

2011 ◽

Vol 140 (5) ◽

pp. S-713

Author(s):

Raghu Kadaba ◽

Fieke Froeling ◽

Erdinc Soylu ◽

Satyajit Bhattacharya ◽

Ian Hart ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Carcinoma Cell ◽

Critical Role ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Cell Behaviour ◽

Pancreatic Cancer Cells

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Differential Gemcitabine Sensitivity in Primary Human Pancreatic Cancer Cells and Paired Stellate Cells Is Driven by Heterogenous Drug Uptake and Processing

Cancers ◽

10.3390/cancers12123628 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3628

Author(s):

Manoj Amrutkar ◽

Nils Tore Vethe ◽

Caroline S. Verbeke ◽

Monica Aasrum ◽

Anette Vefferstad Finstadsveen ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Stellate Cells ◽

Drug Uptake ◽

Pancreatic Stellate Cells ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells ◽

The Impact

Gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) is attributed to cancer cell-intrinsic drug processing and the impact of the tumor microenvironment, especially pancreatic stellate cells (PSCs). This study uses human PDAC-derived paired primary cancer cells (PCCs) and PSCs from four different tumors, and the PDAC cell lines BxPC-3, Mia PaCa-2, and Panc-1, to assess the fate of gemcitabine by measuring its cellular uptake, cytotoxicity, and LC-MS/MS-based metabolite analysis. Expression analysis and siRNA-mediated knockdown of key regulators of gemcitabine (hENT1, CDA, DCK, NT5C1A) was performed. Compared to PSCs, both the paired primary PCCs and cancer cell lines showed gemcitabine-induced dose-dependent cytotoxicity, high uptake, as well as high and variable intracellular levels of gemcitabine metabolites. PSCs were gemcitabine-resistant and demonstrated significantly lower drug uptake, which was not influenced by co-culturing with their paired PCCs. Expression of key gemcitabine regulators was variable, but overall strong in the cancer cells and significantly lower or undetectable in PSCs. In cancer cells, hENT1 inhibition significantly downregulated gemcitabine uptake and cytotoxicity, whereas DCK knockdown reduced cytotoxicity. In conclusion, heterogeneity in gemcitabine processing among different pancreatic cancer cells and stellate cells results from the differential expression of molecular regulators which determines the effect of gemcitabine.

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Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2017.10.141 ◽

2018 ◽

Vol 495 (1) ◽

pp. 71-77 ◽

Cited By ~ 29

Author(s):

Atsushi Masamune ◽

Naoki Yoshida ◽

Shin Hamada ◽

Tetsuya Takikawa ◽

Tatsuhide Nabeshima ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Pancreatic Cancer 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/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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