ABSTRACT
Pancreatic cancer is an aggressive malignant tumor with poor prognosis. On the one hand, it has a narrow therapeutic window due to the lack of specific markers and obvious clinical symptoms. Once diagnosed, it has often developed to an advanced stage. On the other hand, located in a vital region of the body, pancreatic operation is difficult and the postoperative recurrence rate is high. Therefore, surgical treatment is only sui-table for a small number of early patients. Pancreatic cancer has a tumor microenvironment with the characteristic of dense stroma, hypoxia, paucity of blood vessels and highly immunosuppression. It is often insensitive to traditional radiation and chemotherapy. Therefore, strategies targeting on tumor microenvironment have a potential prospect. This article reviews the research progress in tumor microenvironment of pancreatic cancer, in order to provide the references in the further research and treatment of pancreatic cancer.
ABSTRACT
Pancreatic cancer is an aggressive malignant tumor with poor prognosis.On the one hand,it has a narrow therapeutic window due to the lack of specific markers and obvious clinical symptoms.Once diagnosed,it has often developed to an advanced stage.On the other hand,located in a vital region of the body,pancreatic operation is difficult and the postoperative recurrence rate is high.Therefore,surgical treatment is only suitable for a small number of early patients.Pancreatic cancer has a tumor microenvironment with the characteristic of dense stroma,hypoxia,paucity of blood vessels and highly immunosuppression.It is often insensitive to traditional radiation and chemotherapy.Therefore,strategies targeting on tumor microenvironment have a potential prospect.This article reviews the research progress in tumor microenvironment of pancreatic cancer,in order to provide the references in the further research and treatment of oancreatic cancer.
ABSTRACT
Objective: To investigate the inhibitory effect of resveratrol on the activation of pancreatic stellate cells and to explore the role of the Hippo signaling pathway in it. Methods: Pancreatic stellate cells (PSCs) were isolated by trypsin digestion and then treated with resveratrol. Western blot and immunofluorescence staining were used to detect the activation of the cells. Transwell invasion assay and Western blot were used to detect the invasive ability of Panc-1 and the expressions of E-cadherin and Vimentin in pancreatic cancer cells (PCs)-PSCs indirect co-culture conditions. Results: Resveratrol could inhibit the activation of PSCs and inhibit YAP, CTGF and CYR61 expressions. After co-culture with PSCs condition medium pre-treated with resveratrol, the invasive ability of Panc-1 cells was significant reduced (P<0.05). E-cadherin expression was increased while Vimentin expression was decreased (P<0.05). Conclusion: Resveratrol can inhibit the activation of pancreatic stellate cells via inhibiting YAP expression and can also inhibit the invasion and EMT transformation of Panc-1 cells under co-culture conditions.
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Objective: To investigate the effects of hypoxia on the activation of pancreatic stellate cells (PSCs) and progression of pancreatic cancer. Methods :In the present study, PSCs were cultured under normoxic or hypoxic conditions or co-cultured with pancreatic cancer cell line Panc-1. Then, the shRNA of HIF-1α was stably transfected into PSC cells. Activation of PSCs was detected by immunofluorescence. Secretions of IL-6, SDF-1 and VEGF-A in PSCs were determined by ELISA assay. Invasion of Panc-1 was detected by the Transwell assay. The proteins of E-cadherin and Vimentin in Panc-1 cells were determined by Western blot. Results: Hypoxia activated PSCs and significantly increased IL-6, SDF-1 and VEGF-A secretion in PSCs. Moreover, hypoxia significantly upregulated the PSCs-induced invasion of Panc-1 cells, increased the protein expressions of HIF-1α and Vimentin, and decreased the protein expression of E-cadherin. Furthermore, knockdown of HIF-1α obviously abrogated hypoxia-induced PSC activation and IL-6, SDF-1 and VEGF-A secretion in PSCs, and abolished hypoxia-enhanced epithelial-mesenchymal transition and invasion of Panc-1 cells. Conclusion: Hypoxia enhances the epithelial-mesenchymal transition and invasion of PSCs and strengthens HIF-1α expression via activating PSCs.
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Objective To clarify whether oxymatrine ( OM) could suppress the activation of pancreatic stellate cells ( PSC) and explore the potential molecular mechanism .Methods The proliferation of PSC line LTC 14 being activated by TGF-β1 with OM treatment at different concentrations (OM group) was measured. SOD level was determined by ELISA and p 38-MAPK mRNA was determined by real-time PCR.Results The proliferation of PSC in the control group , 0.1, 0.5, 1, 2, 5 g/L OM group was (1.51 ±0.08), (1.50 ± 0.07), (1.15 ±0.04), (1.15 ±0.04), (1.08 ±0.06), and (1.08 ±0.10), respectively.The level of the control group was lower than the groups where the concentration of OM reached or exceeded 0.5mg/ml ( all P=0.000).SOD level of LTC 14 cells in the control group, TGF-β1 group, 0.5 and 1 g/L OM group was (0.087 ±0.005), (0.073 ± 0.004), (0.085 ± 0.010), and (0.086 ± 0.007), respectively. No statistically significant difference existed among the groups (P=0.095).The p38-MAPK mRNA expression of PSC in the control group, TGF-β1 group, 0.5, and 1 g/L OM group was (1.000 ±0.000), (1.979 ± 0.505), (0.606 ±0.111), and (0.303 ±0.159), respectively.The p38-MAPK mRNA level of TGF-β1 group was higher than that of the control group (P=0.002), and that of 0.5 mg/ml OM group and 1 mg/ml OM group was lower that of TGF-β1 group ( P=0.000 ) , while no statistical difference was found between 0.5 mg/ml OM group and 1 mg/ml OM group.Conclusions OM could suppress the activation of PSC in vitro and the suppression of p38-MAPK mRNA expression may be involved .
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Pancreatic stellate cell (PSC) activation in islet fibrosis of insulin-resistant rats induced by high-fat diet was investigated. After 20 weeks, the glucose infusion rate and glucose-stimulated insulin secretion in high-fat group were significantly decreased while fasting plasma glucose, fasting serum insulin, free fatty acid and the basal glucagon secretion were significantly increased compared with those parameters of the control rats (P< 0.05 or P<0.01). Activated PSC and collagen fiber ( type Ⅰ and Ⅲ) were found in islets of rats fed with high-fat. The result suggests that PSC activation, proliferation and migration to islet may contribute to islet fibrosis in insulin-resistant rats.
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AIM To investigate the effects and possible mechanism s of Glycyrrhizin on rat pancreatic fibrosis induced by TNBS (trinitrobenzenesulfonic acid, TNBS ). METHODS Chronic pancreatitis model was induced in male Sprague -Dawley rats by injection of 2% TNBS into bile duct. All the rats were randomly divided into two groups. The rats in Glycyrrhizin intervention group were treat ed with Glycyrrhizin 8 mg?kg -1 by injection into tail vein from day 3 to day 28, while the rats in control group were administrated with same volume of saline vehicle. Ten rats in the Glycyrrhizin intervention group and eight rats in the control group wer e sacrificed on day 29, the blood was collected to determine amylase and hyaluro nic acid by enzyme dynamic and RIA method. The histological change of pancreatic tissue was evaluated by H&E stain and modified Van-Gieson stain. Mast cell in pancreas was stained by thionine blue. Expression of TGF-? 1,Collagen Ⅰ and ?-SMA in pancreas were assessed by immunohistochemistry and western blot. RESULTS In the Glycyrrhizin intervention group, the mast cell number and the percentage of degranulation decreased significantly, and the expression of ?-SMA protein also decreased compared to the control group, but there was no difference in amylase or hyaluronic acid between the treatment group and the control group. In the Glycyrrhizin intervention group, inflammation and fibrosis were ameliorated and expression of collageⅠ and TGF-? 1 was also decreased significantly compared to the control group. CONCLUSION Glycyrrhizin inhibits pancreatic fibrosis in chronic pancreatitis rats induced by TNBS. This action might be related to protecting pancreatic acinus cells from being destructed by mast cell activation and inhibiting extracellular matrix synthesis stimulated by pancreatic stellate cell.
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Objective To observe the activation of pancreatic stellate cells (PSC) during the formation of pancreatic fibrosis induced by the pancreatic injection of trinitrobenzene sulfonic acid (TNBS). Meanwhile, the effects of PSC-related factors, such as transforming growth factor ? 1 (TGF-? 1), collagen Ⅰ and MMP-2 on the pathogenesis of pancreatic fibrosis in rats were also evaluated. Methods Pancreatic fibrosis model in rats was induced by the injection of 2% TNBS in ethanolate-phosphate buffer solution into the pancreatic duct. The rats were sacrificed and the pancreata were removed at the 72nd hour, 3rd week, 4th week, 5th week, 6th week and 7th week after the operation respectively. Expressions of ?-smooth muscle actin (?-SMA), transforming growth factor ? 1 (TGF-? 1), collagen Ⅰ and MMP-2 were determined by either immunohistochemistry or RT-PCR, or Western blot respectively. The ultrastructure of pancreas was studied by electron microscope at different time points. Results The inflammation, swelling and necrosis were the major pathological changes of the pancreas at the early stage after the injection of 2% TNBS. Subsequently, the fibrotic manifestations such as proliferation of the fibrosis, atrophy of vesicles, deposition of collagen because prominent at the 3rd week after the operation, which peaked at 4th week. The expression of TGF-? 1 was increased significantly at the 3rd week after the operation and reached maximum at the 4th week. The expression of ?-SMA, which indicated the activation of PSC, could be detected at the 3rd week and also reached the peak value at the 4th week. After wards, it was decreased gradually. During the first 72 hours, the expression of MMP-2 mRNA was increased significantly and then was fluctuated but still higher than that in normal rats. The deposition of type Ⅰ collagen was increased in the areas of fibrotic tissues. Conclusions PSC might involve in the courses of the development and progression of TNBS induced pancreatic fibrosis in rats. This action was achieved via the activation of PSC by TGF-? 1, the production of those extracellular matrix metabolic associated enzymes such as the synthesis of collagen Ⅰ and the secretion of MMP-2.
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Objectives To analyze the role and mechanisms of mast cells in the inflammation and fibrosis of 2 ,4, 6-trinitrobenzene sulfonic acid (TNBS)-induced rat pancreatic fibrosis. Methods Rats were received the aseptic instillation of TNBS in ethanol via bilo-pancreatic duct, and then injected with nedocromil sodium, a mast cell stabilizer, and compound 18/80, a mast cell activator, or saline. Rats were sacrificed respectively on 3, 7, 14, 21 or 28 days. Pancreatic inflammation and fibrosis were assessed by gross and histopathological evaluation. Pancreatic fibrosis were observed by Van Gieson. Pancreatic mast cells distribution, number and their state of activation (toluidine blue) were evaluated. The activation of pancreatic stellate cells (PSCs) were assessed by the expression of a-smooth muscle actin (?-SMA) through immunohistochemistry. The expression of angiotensin Ⅱ AT1 and AT2 receptors and transforming growth factor (TGF) ? 1 raRNA, which were the factors of fibrogenesis, were also assessed. Results Typical pancreatic fibrosis changes occurred in the model of rats received TNBS at 4th week by morphological evaluation. The positive expression of ?-SMA and TGF?1 in the pancreatic tissues were detected at day 3, especially at 4th week. The expression of angiotensin Ⅱ AT1 and AT2 receptors mRNA increased gradually in all the three groups, also especially at 4th week. Compared to the control group, there were more higher expression of ?-SMA, TGF?1, angiotensin Ⅱ AT1 and AT2 receptor in the compound 48/80 group, while there were lower expression of these proteins in the nedocromil group. Conclusions Mast cells are involved in TNBS-induced pancreatic inflammation and fibrosis in rats. After being activated, mast cells will promote the activation and proliferation of PSCs and upregulate the expression of angiotensin Ⅱ AT1 receptor and AT2 receptor, and then lead to pancreatic fibrosis gradually.