Primary cultures of pancreatic stellate cells(PSCs) remain an important basis for in vitro study.However,effective methods for isolating abundant PSCs are currently lacking.We report on a novel approach to isolating...Primary cultures of pancreatic stellate cells(PSCs) remain an important basis for in vitro study.However,effective methods for isolating abundant PSCs are currently lacking.We report on a novel approach to isolating PSCs from normal rat pancreases and human pancreatic ductal adenocarcinoma(PDAC) tissue.After anaesthesia and laparotomy of the rat,a blunt cannula was inserted into the pancreatic duct through the anti-mesentery side of the duodenum,and the pancreas was slowly infused with an enzyme solution until all lobules were fully dispersed.The pancreas was then pre-incubated,finely minced and incubated to procure a cell suspension.PSCs were obtained after the cell suspension was filtered,washed and subject to gradient centrifugation with Nycodenz solution.Fresh human PDAC tissue was finely minced into 1×1×l mm^3 cubes with sharp blades.Tissue blocks were placed at the bottom of a culture plate with fresh plasma(EDTA-anti-coagulated plasma from the same patient,mixed with CaCL) sprinkled around the sample.After culture for 5-10 days under appropriate conditions,activated PSCs were harvested.An intraductal perfusion of an enzyme solution simplified the procedure of isolation of rat PSCs,as compared with the multiple injections technique,and a modified outgrowth method significantly shortened the outgrowth time of the activated cells.Our modification in PSC isolation methods significantly increased the isolation efficiency and shortened the culture period,thus facilitating future PSC-related research.展开更多
Background:Pancreatic stellate cells(PSCs)foster the progression of pancreatic adenocarcinoma and chronic pancreatitis(CP)by producing a dense fibrotic stroma.However,the incomplete knowledge of PSCs biology hampers t...Background:Pancreatic stellate cells(PSCs)foster the progression of pancreatic adenocarcinoma and chronic pancreatitis(CP)by producing a dense fibrotic stroma.However,the incomplete knowledge of PSCs biology hampers the exploration of antifibrotic therapies.Here,we explored the role of the Hippo pathway in the context of PSCs activation and experimental CP.Methods:CP model was created in rats with the tail vein injection of dibutyltin dichloride(DBTC).The expression of Yes-associated protein(YAP)in CP tissue was assessed.Primary and immortalized rats PSCs were treated with the YAP-inhibitor verteporfin.Furthermore,YAP siRNA was employed.Subsequently,DNA synthesis,cell survival,levels ofα-smooth muscle actin(α-SMA)protein,presence of lipid droplets and PSCs gene expression were evaluated.Upstream regulators of YAP signaling were studied by reporter gene assays.Results:In DBTC-induced CP,pronounced expression of YAP in areas of tubular structures and periduc-tal fibrosis was observed.Verteporfin diminished DNA replication in PSCs in a dose-dependent fash-ion.Knockdown of YAP reduced cell proliferation.Primary cultures of PSCs were characterized by a de-crease of lipid droplets and increased synthesis ofα-SMA protein.Both processes were not affected by verteporfin.At the non-cytotoxic concentration of 100 nmol/L,verteporfin significantly reduced mRNA levels of transforming growth factor-β1(Tgf-β1)and Ccn family member 1(Ccn1).YAP signaling was acti-vated by TGF-β1,but repressed by interferon-γ.Conclusions:Activated YAP enhanced PSCs proliferation.The antifibrotic potential of Hippo pathway in-hibitors warrants further investigation.展开更多
BACKGROUND: Pancreatic stellate cells (PSCs) play a major role in promoting pancreatic fibrosis. Transforming growth factor beta 1 (TGF-beta 1) is a critical mediator of this process. This study aimed to determine the...BACKGROUND: Pancreatic stellate cells (PSCs) play a major role in promoting pancreatic fibrosis. Transforming growth factor beta 1 (TGF-beta 1) is a critical mediator of this process. This study aimed to determine the expression of the Smad3 and Smad7 genes in the process of PSC activation, and explore the mechanisms of chronic pancreatitis. METHODS: The expressions of Smad3 and Smad7 in PSCs before and after TGF-beta 1 treatment were detected by reverse transcription-polymerase chain reaction and Western blotting analysis. Smad3 expression was detected in PSCs after treatment with 5 ng/ml of TGF-beta 1 for 24 hours. RESULTS: Smad7 expression was decreased in TGF-beta 1 -activated PSCs (P<0.05) in a dose-dependent manner. When TGF-beta 1 concentration reached 10 ng/ml, the expression of p-Smad3, Smad3, and Smad7 was inhibited (P<0.05). CONCLUSIONS: TGF-beta 1 promotes the expression of Smad3 and inhibits the expression of Smad7 during the activation of PSCs. In contrast, high-dose TGF-beta 1 downregulates the expression of Smad3 in completely activated PSCs.展开更多
Background:Pancreatic stellate cells(PSCs)activation plays a critical role in the development of chronic pancreatitis.Previous studies confirmed that thromboxane A2 receptor(TxA2r)was overexpressed in activated PSCs i...Background:Pancreatic stellate cells(PSCs)activation plays a critical role in the development of chronic pancreatitis.Previous studies confirmed that thromboxane A2 receptor(TxA2r)was overexpressed in activated PSCs in rats.The purpose of this study was to investigate the role of TxA2r in the activation of PSCs induced by 8-epi-prostaglandin F2α(8-epi-PGF2α).Methods:TxA2r expression in both quiescent and activated PSCs was detected by immunocytochemistry and immunoblot assay.Isolated PSCs were treated with 8-epi-PGF2α(10^-6,10^-7,10^-8 mol/L)for 48 h,and SQ29548(10^-4,10^-6,and 10^-7 mol/L),a TxA2r-specific antagonist,for 48 h,respectively,to identify the drug concentration with the best biological effect and the least cytotoxicity.Then isolated PSCs were treated with SQ29548(10^-4 mol/L)for 2 h,followed by 10^-7 mol/L 8-epi-PGF2α for 48 h.Real-time polymerase chain reaction was performed to detect the messenger RNA(mRNA)levels of a-smooth muscle actin(a-SMA)and collagen I.Comparisons between the groups were performed using Student’s t test.Results:TxA2r was up-regulated in activated PSCs in vitro compared with quiescent PSCs(all P<0.001).Compared with the control group,different concentrations of 8-epi-PGF2α significantly increased mRNA levels of a-SMA(10^-6 mol/L:2.23±0.18 vs.1.00±0.07,t=10.70,P<0.001;10^-7 mol/L:2.91±0.29 vs.1.01±0.08,t=10.83,P<0.001;10^-8 mol/L,1.67±0.07 vs.1.00±0.08,t=11.40,P<0.001)and collagen I(10^-6 mol/L:2.68±0.09 vs.1.00±0.07,t=24.94,P<0.001;10^-7 mol/L:2.12±0.29 vs.1.01±0.12,t=6.08,P<0.001;10^-8 mol/L:1.46±0.15 vs.1.00±0.05,t=4.93,P=0.008).However,different concentrations of SQ29548 all significantly reduced the expression of collagen I(10^-4 mol/L:0.55±0.07 vs.1.00±0.07,t=10.47,P<0.001;10^-6 mol/L:0.56±0.10 vs.1.00±0.07,t=6.185,P<0.001;10^-7 mol/L:0.27±0.04 vs.1.00±0.07,t=15.41,P<0.001)and a-SMA(10^-4 mol/L:0.06±0.01 vs.1.00±0.11,t=15.17,P<0.001;10^-6 mol/L:0.28±0.03 vs.1.00±0.11,t=11.29,P<0.001;10^-7 mol/L:0.14±0.04 vs.1.00±0.11,t=12.86,P<0.001).After being treated with SQ29548(10^-4 mol/L)and then 8-epi-PGF2α(10^-7 mol/L),the mRNA levels of a-SMA(0.20±0.08 vs.1.00±0.00,t=17.46,P<0.001)and collagen I(0.69±0.13 vs.1.00±0.00,t=4.20,P=0.014)in PSCs were significantly lower than those of the control group.Conclusions:The results show that 8-epi-PGF2α promoted PSCs activation,while SQ29548 inhibited PSCs activation induced by 8-epi-PGF2α.The result indicated that TxA2r plays an important role during PSC activation and collagen synthesis induced by 8-epi-PGF2α in vitro.This receptor may provide a potential target for more effective antioxidant therapy for pancreatic fibrosis.展开更多
BACKGROUND:Pancreatic stellate cells(PSCs)play a critical role in the development of pancreatic fibrosis.In this study we used a novel method to isolate and culture rat PSCs and then investigated the inhibitory eff...BACKGROUND:Pancreatic stellate cells(PSCs)play a critical role in the development of pancreatic fibrosis.In this study we used a novel method to isolate and culture rat PSCs and then investigated the inhibitory effects of adipose-derived stem cells(ADSCs)on activation and proliferation of PSCs.METHODS:Pancreatic tissue was obtained from SpragueDawley rats for PSCs isolation.Transwell cell cultures were adopted for co-culture of ADSCs and PSCs. PSCs prolifera- tion and apoptosis were determined using CCK-8 and flow cytometry, respectively, a-SMA expressions were analyzed using Western blotting. The levels of cytokines [nerve growth factor (NGF), interleukin-10 (IL-10) and transforming growth factor-ill (TGF-[31)] in conditioned medium were detected by ELISA. Gene expression (MMP-2, MMP-9 and TIMP-1) was analyzed using qRT-PCR. RESULTS: This method produced 17.6_+6.5 ~ 103 ceils per gram of the body weight with a purity of 90%-95% and a viability of 92%-97%. Co-culture of PSCs with ADSCs significantly inhib- ited PSCs proliferation and induced PSCs apoptosis. Moreover, a-SMA expression was significantly reduced in PSCs+ADSCs compared with that in PSC-only cultures, while expression of fibrinolytic proteins (e.g., MMP-2 and MMP-9) was upregulated and anti-fibrinolytic protein (TIMP-1) was downregulated. In addition, NGF expression was up-regulated, but IL-10 and TGF-β1 expressions were down-regulated in the coculture conditioned medium compared with those in the PSC- only culture medium. CONCLUSIONS: This study provided an easy and reliable technique to isolate PSCs. The data demonstrated the inhibitory effects of ADSCs on the activation and proliferation of PSCs in vitro.展开更多
Pancreatic cancer(PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of ...Pancreatic cancer(PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells. Cancer-associated fibroblasts(CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim of this review is to describe the complex interplay between PC cells and the cellular and noncellular components of the tumour stroma. Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells. However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers. Hence, the precise role of the tumour stroma in PC remains to be elucidated. However, it is likely that a contextdependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients.展开更多
BACKGROUND: Pancreatic stellate cells (PSCs) play a critical role in the pathogenesis of pancreatic fibrosis and have emerging functions as progenitor cells, immune cells or intermediaries in pancreatic exocrine se...BACKGROUND: Pancreatic stellate cells (PSCs) play a critical role in the pathogenesis of pancreatic fibrosis and have emerging functions as progenitor cells, immune cells or intermediaries in pancreatic exocrine secretion. Increasing evidence has shown that desmin as an exclusive cytoskeleton marker of PSC is only expressed in part of these cells. This study was to establish a desmin-positive PSC cell line and evaluate its actions on pancreatic fibrosis, inflammation and immunity.展开更多
Background Galectin-1 is aβ-galactoside-binding protein overexpressed in the pancreatic stellate cells(PSCs)of pancreatic ductal adenocarcinoma(PDAC),while its expression is typically low in pancreatic cancer cells(P...Background Galectin-1 is aβ-galactoside-binding protein overexpressed in the pancreatic stellate cells(PSCs)of pancreatic ductal adenocarcinoma(PDAC),while its expression is typically low in pancreatic cancer cells(PCCs).The point at which galectin-1 expression in PCCs increases,and its association with PDAC progression,have been unclear.Methods Galectin-1 expression in PDAC and metastatic lymph nodes was investigated using an immunohistochemical assay.PANC-1 PCC cells were co-cultured with PSCs expressing different levels of galectin-1.Subsequently,galectin-1 was overexpressed in PANC-1 cells using recombinant lentiviruses,and their proliferation,invasion,anchorage-independent growth,and in vivo tumorigenicity were evaluated.Results There was intermediate galectin-1 expression in PCCs,and it was positively associated with galectin-1 expression in PSCs in the PDAC tissues.Galectin-1 was strongly expressed in the metastatic lymph nodes.In the co-culture,high galectin-1 expression in the PSCs increased the galectin-1 expression in the PANC-1 cells.The galectin-1 overexpression in the PANC-1 cells enhanced their clone formation ability,proliferation,and invasion,increased the expression of proliferating cell nuclear antigen(PCNA)and BCL-2,and decreased Bax expression,promoting the establishment and growth of tumors.Conclusion High galectin-1 expression in PSCs induces galectin-1 expression in PCCs and subsequently promotes the malignant biological behavior of PDAC.展开更多
Objective This review focuses on the state-of-the-art of CXCL12/CXCR4 signaling axis in pancreatic cancer and its role in tumor progression. Data sources Relevant articles published in English were identified by searc...Objective This review focuses on the state-of-the-art of CXCL12/CXCR4 signaling axis in pancreatic cancer and its role in tumor progression. Data sources Relevant articles published in English were identified by searching in Pubmed from 1997 to 2013, with keywords "CXCL12", "CXCR4" and "pancreatic cancer". Important references from selected articles were also retrieved. Study selection Articles about CXCL12/CXCR4 signaling axis in pancreatic cancer and relevant mechanisms were selected. Results Pancreatic cancer has been one of the most lethal human malignancies, with median survival less than one year and overall 5-year survival only 6%. Tumor cells from pancreatic cancer express high level of CXCR4. CXCL12, the ligand for CXCR4, is extensively secreted by neighboring stromal cells and other distant organs. CXCL12 primarily binds to CXCR4, induces intracellular signaling through several divergent pathways, which are involved in progression and metastasis of pancreatic cancer. Conclusions CXCL12/CXCR4 signaling axis may play an important role in the communication between pancreatic cancer cells and their microenvironment, which may have effect on tumor proliferation, invasion, angiogenesis, metastasis and chemoresistance. CXCL12/CXCR4 signaling axis may serves as a novel therapeutic target for pancreatic cancer.展开更多
基金partially supported by the National Natural Science Foundation of China(81300351, 81272239,81170336)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD,JX10231801)
文摘Primary cultures of pancreatic stellate cells(PSCs) remain an important basis for in vitro study.However,effective methods for isolating abundant PSCs are currently lacking.We report on a novel approach to isolating PSCs from normal rat pancreases and human pancreatic ductal adenocarcinoma(PDAC) tissue.After anaesthesia and laparotomy of the rat,a blunt cannula was inserted into the pancreatic duct through the anti-mesentery side of the duodenum,and the pancreas was slowly infused with an enzyme solution until all lobules were fully dispersed.The pancreas was then pre-incubated,finely minced and incubated to procure a cell suspension.PSCs were obtained after the cell suspension was filtered,washed and subject to gradient centrifugation with Nycodenz solution.Fresh human PDAC tissue was finely minced into 1×1×l mm^3 cubes with sharp blades.Tissue blocks were placed at the bottom of a culture plate with fresh plasma(EDTA-anti-coagulated plasma from the same patient,mixed with CaCL) sprinkled around the sample.After culture for 5-10 days under appropriate conditions,activated PSCs were harvested.An intraductal perfusion of an enzyme solution simplified the procedure of isolation of rat PSCs,as compared with the multiple injections technique,and a modified outgrowth method significantly shortened the outgrowth time of the activated cells.Our modification in PSC isolation methods significantly increased the isolation efficiency and shortened the culture period,thus facilitating future PSC-related research.
文摘Background:Pancreatic stellate cells(PSCs)foster the progression of pancreatic adenocarcinoma and chronic pancreatitis(CP)by producing a dense fibrotic stroma.However,the incomplete knowledge of PSCs biology hampers the exploration of antifibrotic therapies.Here,we explored the role of the Hippo pathway in the context of PSCs activation and experimental CP.Methods:CP model was created in rats with the tail vein injection of dibutyltin dichloride(DBTC).The expression of Yes-associated protein(YAP)in CP tissue was assessed.Primary and immortalized rats PSCs were treated with the YAP-inhibitor verteporfin.Furthermore,YAP siRNA was employed.Subsequently,DNA synthesis,cell survival,levels ofα-smooth muscle actin(α-SMA)protein,presence of lipid droplets and PSCs gene expression were evaluated.Upstream regulators of YAP signaling were studied by reporter gene assays.Results:In DBTC-induced CP,pronounced expression of YAP in areas of tubular structures and periduc-tal fibrosis was observed.Verteporfin diminished DNA replication in PSCs in a dose-dependent fash-ion.Knockdown of YAP reduced cell proliferation.Primary cultures of PSCs were characterized by a de-crease of lipid droplets and increased synthesis ofα-SMA protein.Both processes were not affected by verteporfin.At the non-cytotoxic concentration of 100 nmol/L,verteporfin significantly reduced mRNA levels of transforming growth factor-β1(Tgf-β1)and Ccn family member 1(Ccn1).YAP signaling was acti-vated by TGF-β1,but repressed by interferon-γ.Conclusions:Activated YAP enhanced PSCs proliferation.The antifibrotic potential of Hippo pathway in-hibitors warrants further investigation.
基金supported by grants from the Natural Science Foundation of Jiangsu Province,China (No. BK2006241)the Foundation for Talents in Six Fields of Jiangsu Province (No. 07-B-038)
文摘BACKGROUND: Pancreatic stellate cells (PSCs) play a major role in promoting pancreatic fibrosis. Transforming growth factor beta 1 (TGF-beta 1) is a critical mediator of this process. This study aimed to determine the expression of the Smad3 and Smad7 genes in the process of PSC activation, and explore the mechanisms of chronic pancreatitis. METHODS: The expressions of Smad3 and Smad7 in PSCs before and after TGF-beta 1 treatment were detected by reverse transcription-polymerase chain reaction and Western blotting analysis. Smad3 expression was detected in PSCs after treatment with 5 ng/ml of TGF-beta 1 for 24 hours. RESULTS: Smad7 expression was decreased in TGF-beta 1 -activated PSCs (P<0.05) in a dose-dependent manner. When TGF-beta 1 concentration reached 10 ng/ml, the expression of p-Smad3, Smad3, and Smad7 was inhibited (P<0.05). CONCLUSIONS: TGF-beta 1 promotes the expression of Smad3 and inhibits the expression of Smad7 during the activation of PSCs. In contrast, high-dose TGF-beta 1 downregulates the expression of Smad3 in completely activated PSCs.
基金This study was supported by the grant from the National Natural Science Foundation Youth Fund(No.81200325).
文摘Background:Pancreatic stellate cells(PSCs)activation plays a critical role in the development of chronic pancreatitis.Previous studies confirmed that thromboxane A2 receptor(TxA2r)was overexpressed in activated PSCs in rats.The purpose of this study was to investigate the role of TxA2r in the activation of PSCs induced by 8-epi-prostaglandin F2α(8-epi-PGF2α).Methods:TxA2r expression in both quiescent and activated PSCs was detected by immunocytochemistry and immunoblot assay.Isolated PSCs were treated with 8-epi-PGF2α(10^-6,10^-7,10^-8 mol/L)for 48 h,and SQ29548(10^-4,10^-6,and 10^-7 mol/L),a TxA2r-specific antagonist,for 48 h,respectively,to identify the drug concentration with the best biological effect and the least cytotoxicity.Then isolated PSCs were treated with SQ29548(10^-4 mol/L)for 2 h,followed by 10^-7 mol/L 8-epi-PGF2α for 48 h.Real-time polymerase chain reaction was performed to detect the messenger RNA(mRNA)levels of a-smooth muscle actin(a-SMA)and collagen I.Comparisons between the groups were performed using Student’s t test.Results:TxA2r was up-regulated in activated PSCs in vitro compared with quiescent PSCs(all P<0.001).Compared with the control group,different concentrations of 8-epi-PGF2α significantly increased mRNA levels of a-SMA(10^-6 mol/L:2.23±0.18 vs.1.00±0.07,t=10.70,P<0.001;10^-7 mol/L:2.91±0.29 vs.1.01±0.08,t=10.83,P<0.001;10^-8 mol/L,1.67±0.07 vs.1.00±0.08,t=11.40,P<0.001)and collagen I(10^-6 mol/L:2.68±0.09 vs.1.00±0.07,t=24.94,P<0.001;10^-7 mol/L:2.12±0.29 vs.1.01±0.12,t=6.08,P<0.001;10^-8 mol/L:1.46±0.15 vs.1.00±0.05,t=4.93,P=0.008).However,different concentrations of SQ29548 all significantly reduced the expression of collagen I(10^-4 mol/L:0.55±0.07 vs.1.00±0.07,t=10.47,P<0.001;10^-6 mol/L:0.56±0.10 vs.1.00±0.07,t=6.185,P<0.001;10^-7 mol/L:0.27±0.04 vs.1.00±0.07,t=15.41,P<0.001)and a-SMA(10^-4 mol/L:0.06±0.01 vs.1.00±0.11,t=15.17,P<0.001;10^-6 mol/L:0.28±0.03 vs.1.00±0.11,t=11.29,P<0.001;10^-7 mol/L:0.14±0.04 vs.1.00±0.11,t=12.86,P<0.001).After being treated with SQ29548(10^-4 mol/L)and then 8-epi-PGF2α(10^-7 mol/L),the mRNA levels of a-SMA(0.20±0.08 vs.1.00±0.00,t=17.46,P<0.001)and collagen I(0.69±0.13 vs.1.00±0.00,t=4.20,P=0.014)in PSCs were significantly lower than those of the control group.Conclusions:The results show that 8-epi-PGF2α promoted PSCs activation,while SQ29548 inhibited PSCs activation induced by 8-epi-PGF2α.The result indicated that TxA2r plays an important role during PSC activation and collagen synthesis induced by 8-epi-PGF2α in vitro.This receptor may provide a potential target for more effective antioxidant therapy for pancreatic fibrosis.
基金supported in part by a grant from Zhejiang Province Key Surgery Projects(Zhejiang High-Tech 2008-255)
文摘BACKGROUND:Pancreatic stellate cells(PSCs)play a critical role in the development of pancreatic fibrosis.In this study we used a novel method to isolate and culture rat PSCs and then investigated the inhibitory effects of adipose-derived stem cells(ADSCs)on activation and proliferation of PSCs.METHODS:Pancreatic tissue was obtained from SpragueDawley rats for PSCs isolation.Transwell cell cultures were adopted for co-culture of ADSCs and PSCs. PSCs prolifera- tion and apoptosis were determined using CCK-8 and flow cytometry, respectively, a-SMA expressions were analyzed using Western blotting. The levels of cytokines [nerve growth factor (NGF), interleukin-10 (IL-10) and transforming growth factor-ill (TGF-[31)] in conditioned medium were detected by ELISA. Gene expression (MMP-2, MMP-9 and TIMP-1) was analyzed using qRT-PCR. RESULTS: This method produced 17.6_+6.5 ~ 103 ceils per gram of the body weight with a purity of 90%-95% and a viability of 92%-97%. Co-culture of PSCs with ADSCs significantly inhib- ited PSCs proliferation and induced PSCs apoptosis. Moreover, a-SMA expression was significantly reduced in PSCs+ADSCs compared with that in PSC-only cultures, while expression of fibrinolytic proteins (e.g., MMP-2 and MMP-9) was upregulated and anti-fibrinolytic protein (TIMP-1) was downregulated. In addition, NGF expression was up-regulated, but IL-10 and TGF-β1 expressions were down-regulated in the coculture conditioned medium compared with those in the PSC- only culture medium. CONCLUSIONS: This study provided an easy and reliable technique to isolate PSCs. The data demonstrated the inhibitory effects of ADSCs on the activation and proliferation of PSCs in vitro.
基金Supported by University of Southern DenmarkOdense University Hospital Research Fund
文摘Pancreatic cancer(PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells. Cancer-associated fibroblasts(CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim of this review is to describe the complex interplay between PC cells and the cellular and noncellular components of the tumour stroma. Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells. However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers. Hence, the precise role of the tumour stroma in PC remains to be elucidated. However, it is likely that a contextdependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients.
基金support by grants from the National Natural Science Foundation of China(81070370 and 81270544)
文摘BACKGROUND: Pancreatic stellate cells (PSCs) play a critical role in the pathogenesis of pancreatic fibrosis and have emerging functions as progenitor cells, immune cells or intermediaries in pancreatic exocrine secretion. Increasing evidence has shown that desmin as an exclusive cytoskeleton marker of PSC is only expressed in part of these cells. This study was to establish a desmin-positive PSC cell line and evaluate its actions on pancreatic fibrosis, inflammation and immunity.
文摘Background Galectin-1 is aβ-galactoside-binding protein overexpressed in the pancreatic stellate cells(PSCs)of pancreatic ductal adenocarcinoma(PDAC),while its expression is typically low in pancreatic cancer cells(PCCs).The point at which galectin-1 expression in PCCs increases,and its association with PDAC progression,have been unclear.Methods Galectin-1 expression in PDAC and metastatic lymph nodes was investigated using an immunohistochemical assay.PANC-1 PCC cells were co-cultured with PSCs expressing different levels of galectin-1.Subsequently,galectin-1 was overexpressed in PANC-1 cells using recombinant lentiviruses,and their proliferation,invasion,anchorage-independent growth,and in vivo tumorigenicity were evaluated.Results There was intermediate galectin-1 expression in PCCs,and it was positively associated with galectin-1 expression in PSCs in the PDAC tissues.Galectin-1 was strongly expressed in the metastatic lymph nodes.In the co-culture,high galectin-1 expression in the PSCs increased the galectin-1 expression in the PANC-1 cells.The galectin-1 overexpression in the PANC-1 cells enhanced their clone formation ability,proliferation,and invasion,increased the expression of proliferating cell nuclear antigen(PCNA)and BCL-2,and decreased Bax expression,promoting the establishment and growth of tumors.Conclusion High galectin-1 expression in PSCs induces galectin-1 expression in PCCs and subsequently promotes the malignant biological behavior of PDAC.
基金This study was supported by grants from Natural Science Foundation of Jiangsu province (BK201288), the Key Projects of the Jiangsu Provincial Health Department (H201115) and Qing Lan Project of Jiangsu province (JX2161015019).
文摘Objective This review focuses on the state-of-the-art of CXCL12/CXCR4 signaling axis in pancreatic cancer and its role in tumor progression. Data sources Relevant articles published in English were identified by searching in Pubmed from 1997 to 2013, with keywords "CXCL12", "CXCR4" and "pancreatic cancer". Important references from selected articles were also retrieved. Study selection Articles about CXCL12/CXCR4 signaling axis in pancreatic cancer and relevant mechanisms were selected. Results Pancreatic cancer has been one of the most lethal human malignancies, with median survival less than one year and overall 5-year survival only 6%. Tumor cells from pancreatic cancer express high level of CXCR4. CXCL12, the ligand for CXCR4, is extensively secreted by neighboring stromal cells and other distant organs. CXCL12 primarily binds to CXCR4, induces intracellular signaling through several divergent pathways, which are involved in progression and metastasis of pancreatic cancer. Conclusions CXCL12/CXCR4 signaling axis may play an important role in the communication between pancreatic cancer cells and their microenvironment, which may have effect on tumor proliferation, invasion, angiogenesis, metastasis and chemoresistance. CXCL12/CXCR4 signaling axis may serves as a novel therapeutic target for pancreatic cancer.