|
1
|
Zhang M, Yu T, Liu Y, Lu X, Chen W, Zhou L, Xu Y, Yang M, Miller AD, Lin H. SMAD2 S-palmitoylation promotes its linker region phosphorylation and T H17 cell differentiation in a mouse model of multiple sclerosis. Sci Signal 2025; 18:eadr2008. [PMID: 40424363 DOI: 10.1126/scisignal.adr2008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 05/07/2025] [Indexed: 05/29/2025]
Abstract
The transcriptional regulators SMAD2 and SMAD3 share the same primary signaling pathway in response to the cytokine TGFβ. However, whereas SMAD2 stimulates the differentiation of naive CD4+ T cells into proinflammatory T helper 17 cells (TH17 cells), SMAD3 stimulates the differentiation of anti-inflammatory regulatory T cells (Treg cells). Here, we report a dynamic SMAD2-specific posttranslational modification important for TH17 cell differentiation. SMAD2, but not SMAD3, was reversibly S-palmitoylated at cysteine-41 and cysteine-81 by the palmitoyltransferase DHHC7 and depalmitoylated by the acyl protein thioesterase APT2. As a result, SMAD2 was recruited to intracellular membranes where its linker region was phosphorylated, leading to its interaction with the transcriptional regulator STAT3. Nuclear translocation of the SMAD2-STAT3 complex induced the expression of their target genes that promoted TH17 cell differentiation. Perturbation of SMAD2-STAT3 binding by inhibiting the palmitoylation-depalmitoylation cycle suppressed TH17 cell differentiation and reduced disease severity in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis (MS). Thus, the S-palmitoylation-depalmitoylation cycle mediated by DHHC7 and APT2 specifically regulates SMAD2, providing insights into the functional differences between SMAD2 and SMAD3 and the distinct role of SMAD2 in TH17 cell differentiation. The findings further highlight DHHC7 and APT2 as potential therapeutic targets for the treatment of TH17 cell-mediated inflammatory diseases, including MS.
Collapse
MESH Headings
- Animals
- Cell Differentiation/immunology
- Smad2 Protein/metabolism
- Smad2 Protein/genetics
- Smad2 Protein/immunology
- Th17 Cells/immunology
- Th17 Cells/metabolism
- Th17 Cells/pathology
- Th17 Cells/cytology
- Mice
- Lipoylation
- Phosphorylation
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Encephalomyelitis, Autoimmune, Experimental/genetics
- STAT3 Transcription Factor/metabolism
- STAT3 Transcription Factor/genetics
- STAT3 Transcription Factor/immunology
- Disease Models, Animal
- Multiple Sclerosis/immunology
- Multiple Sclerosis/metabolism
- Multiple Sclerosis/pathology
- Multiple Sclerosis/genetics
- Humans
- Mice, Inbred C57BL
- Acyltransferases/metabolism
- Acyltransferases/genetics
- Signal Transduction
Collapse
Affiliation(s)
- Mingming Zhang
- Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Tao Yu
- Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Yinong Liu
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Xuan Lu
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Wenzhe Chen
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Lixing Zhou
- Center of Gerontology and Geriatrics/National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuejie Xu
- Department of Gastroenterology, Drum Tower Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China
| | - Min Yang
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Andrew D Miller
- Section of Anatomic Pathology, Department of Population Medicine and Diagnostic Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA
| | - Hening Lin
- Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
| |
Collapse
|
|
2
|
Huang BW, Wang PY, Hu LH. Transcriptional regulation of pancreatic stellate cell activation in chronic pancreatitis. Shijie Huaren Xiaohua Zazhi 2023; 31:877-881. [DOI: 10.11569/wcjd.v31.i21.877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/21/2023] [Accepted: 11/01/2023] [Indexed: 11/08/2023] Open
Abstract
Pancreatic fibrosis is an important feature in the occurrence and development of chronic pancreatitis (CP), and activated pancreatic stellate cells (PSC) play an important role in the progression of pancreatic fibrosis. In recent years, more and more signaling pathways related to pancreatic fibrosis have been found. These signaling pathways regulate the activation of pancreatic stellate cells through transcription factors, thereby affecting pancreatic fibrosis and the progression of CP. This article reviews the progress in the research of the signaling pathways and related transcription factors involved in PSC activation in pancreatic fibrosis, hoping to provide ideas for further understanding the mechanism and therapeutic targets of pancreatic fibrosis in CP.
Collapse
Affiliation(s)
- Bang-Wei Huang
- Department of Gastroenterology, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Peng-Yuan Wang
- Department of Gastroenterology, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
- Department of Gastroenterology, The 981st Hospital, Chengde 067000, Hebei Province, China
| | - Liang-Hao Hu
- Department of Gastroenterology, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| |
Collapse
|
|
3
|
Zheng M, Li H, Gao Y, Brigstock DR, Gao R. Vitamin D 3 analogue calcipotriol inhibits the profibrotic effects of transforming growth factor- β1 on pancreatic stellate cells. Eur J Pharmacol 2023; 957:176000. [PMID: 37604222 DOI: 10.1016/j.ejphar.2023.176000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 08/04/2023] [Accepted: 08/17/2023] [Indexed: 08/23/2023]
Abstract
OBJECTIVE To evaluate the inhibitory effect of vitamin D3 analogue calcipotriol (Cal) on the fibrosis of pancreatic stellate cells (PSCs) induced by TGF-β1 and the rationality of Cal use in alcoholic chronic pancreatitis (ACP). MATERIAL AND METHODS Double-labeling immunofluorescence was used for the identification of VDR+PSCs in the pancreas of healthy controls (HC) and ACP patients. Van Gieson staining for examination of collagen fibers. RT-qPCR and Western Blot for determining the mRNAs and proteins of VDR, TGF-β1 and COL1A1 in the pancreas of ACP or in vitro PSCs. ELISA or LC-MS/MS for detection of serum TGF-β1 and COL1A1 or 25(OH)D3. The PSC line (RP-2 cell) was used for the determination of proteomic alterations in Cal plus TGF-β1 versus TGF-β1 and to examine the effect of VDR gene knockdown. RESULTS Enhanced expression of VDR was detected in RP-2 cells stimulated with alcohol (ALC) plus Cal versus Cal alone and in PSCs in the pancreas of ACP versus HC. The increased VDR+PSCs were positively correlated with the levels of COL1A1 mRNAs or areas of collagen deposition in the pancreas of ACP. TGF-β1 was overexpressed in the pancreas of ACP and ALC-treated RP-2 cells while 25(OH)D3 level in serum was significantly decreased in ACP versus HC. Through a VDR-dependent mechanism, Cal antagonized 16 profibrotic proteins in TGF-β1-induced RP-2 cells that included 7 extracellular matrix components, 2 cytoskeletal proteins, 2 fibrosis-associated factors (RUNX1 and TRAF2), TIMP-1, CCN1, integrin α11, an adhesion scaffold protein (TGFB1i1) and an enzyme mediating TGF-β1-induced fibrogenesis (ENPP1). CONCLUSION This study suggests that Cal administration may be a potential antifibrotic strategy via inhibiting TGF-β1-mediated PSC action during the development of ACP.
Collapse
Affiliation(s)
- Meifang Zheng
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China
| | - Hongyan Li
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China
| | - Yanhang Gao
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China
| | - David R Brigstock
- The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
| | - Runping Gao
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China.
| |
Collapse
|
|
4
|
Ni YH, Wang R, Wang W, Li DZ, Liu G, Jiang CS, Wang Y, Lin X, Zeng XP. Tcf21 Alleviates Pancreatic Fibrosis by Regulating the Epithelial-Mesenchymal Transformation of Pancreatic Stellate Cells. Dig Dis Sci 2023:10.1007/s10620-023-07849-w. [PMID: 36943591 DOI: 10.1007/s10620-023-07849-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 01/25/2023] [Indexed: 03/23/2023]
Abstract
BACKGROUND AND AIMS The activation of pancreatic stellate cells (PSCs) plays a key role in the occurrence and development of chronic pancreatitis (CP) and pancreatic fibrosis, which is related to the process of epithelial-mesenchymal transition (EMT). This study was designed to investigate the effect and mechanism of Tcf21 (one of tumor suppressor genes) on pancreatic inflammation and fibrosis in vivo and in vitro. METHODS C57BL/6 male mice were intraperitoneally injected with caerulein for 6 weeks to establish CP animal model. Fixed pancreatic tissue paraffin-embedded sections were used for immunohistochemistry staining of Tcf21, fibrosis-related markers (α-SMA), interstitial markers (Vimentin) and epithelial markers (E-cadherin). Western blotting and qRT-PCR assay were performed to analyze the change of expression of the above markers after stimulation of TGF-β1 or overexpressed Tcf21 lentivirus transfection in human pancreatic stellate cells (HPSCs). RESULTS The pancreatic expression of α-SMA and Vimentin of CP mice significantly increased, while the expression of Tcf21 and E-cadherin significantly decreased. TGF-β1 could promote activation and EMT process of HPSCs, and inhibited the expression of Tcf21. Overexpression of Tcf21 could significantly down-regulate the expression of α-SMA, Fibronectin and Vimentin, and up-regulated the expression of ZO-1 of HPSCs. Cell Counting Kit-8 assay and scratch wound-healing assay results showed that overexpression of Tcf21 could significantly inhibit the cell migration and proliferation of HPSCs. CONCLUSIONS Overexpression of Tcf21 could significantly alleviate the activation, proliferation, migration of PSCs by regulating the EMT process. Tcf21 had a potential prospect of a new target for CP therapy.
Collapse
Affiliation(s)
- Yan-Hong Ni
- Department of Digestive Diseases, 900TH Hospital of Joint Logistics Support Force, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Rong Wang
- Department of Digestive Diseases, 900TH Hospital of Joint Logistics Support Force, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Department of Digestive Diseases, Fuzong Clinical Medical College, Fujian Medical University, 156 North Road of West No.2 Ring, Fuzhou, 350025, China
- Department of Digestive Diseases, Dongfang Hospital, Xiamen University, Fuzhou, China
| | - Wen Wang
- Department of Digestive Diseases, 900TH Hospital of Joint Logistics Support Force, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Department of Digestive Diseases, Fuzong Clinical Medical College, Fujian Medical University, 156 North Road of West No.2 Ring, Fuzhou, 350025, China
- Department of Digestive Diseases, Dongfang Hospital, Xiamen University, Fuzhou, China
| | - Da-Zhou Li
- Department of Digestive Diseases, 900TH Hospital of Joint Logistics Support Force, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Department of Digestive Diseases, Fuzong Clinical Medical College, Fujian Medical University, 156 North Road of West No.2 Ring, Fuzhou, 350025, China
- Department of Digestive Diseases, Dongfang Hospital, Xiamen University, Fuzhou, China
| | - Gang Liu
- Department of Digestive Diseases, 900TH Hospital of Joint Logistics Support Force, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Department of Digestive Diseases, Fuzong Clinical Medical College, Fujian Medical University, 156 North Road of West No.2 Ring, Fuzhou, 350025, China
- Department of Digestive Diseases, Dongfang Hospital, Xiamen University, Fuzhou, China
| | - Chuan-Shen Jiang
- Department of Digestive Diseases, 900TH Hospital of Joint Logistics Support Force, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- Department of Digestive Diseases, Fuzong Clinical Medical College, Fujian Medical University, 156 North Road of West No.2 Ring, Fuzhou, 350025, China
- Department of Digestive Diseases, Dongfang Hospital, Xiamen University, Fuzhou, China
| | - Yi Wang
- Department of Digestive Diseases, 900TH Hospital of Joint Logistics Support Force, Fujian University of Traditional Chinese Medicine, Fuzhou, China
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Xia Lin
- Department of Digestive Diseases, Fuzong Clinical Medical College, Fujian Medical University, 156 North Road of West No.2 Ring, Fuzhou, 350025, China
| | - Xiang-Peng Zeng
- Department of Digestive Diseases, 900TH Hospital of Joint Logistics Support Force, Fujian University of Traditional Chinese Medicine, Fuzhou, China.
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.
- Department of Digestive Diseases, Fuzong Clinical Medical College, Fujian Medical University, 156 North Road of West No.2 Ring, Fuzhou, 350025, China.
- Department of Digestive Diseases, Dongfang Hospital, Xiamen University, Fuzhou, China.
| |
Collapse
|
|
5
|
Kweon B, Kim DU, Oh JY, Oh H, Kim YC, Mun YJ, Bae GS, Park SJ. Arecae pericarpium water extract alleviates chronic pancreatitis by deactivating pancreatic stellate cells. Front Pharmacol 2022; 13:941955. [PMID: 36105227 PMCID: PMC9465814 DOI: 10.3389/fphar.2022.941955] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 08/02/2022] [Indexed: 01/30/2023] Open
Abstract
Chronic pancreatitis (CP) is a chronic inflammatory disease of the pancreas with irreversible morphological changes. Arecae pericarpium (ARP), known to improve gastrointestinal disorders, has not yet been reported to inhibit fibrosis in CP. Therefore, we investigated the beneficial effects of ARP on cerulein-induced CP. Cerulein (50 μg/kg) was administered intraperitoneally to mice every hour, six times a day, four times a week for a total of 3 weeks to induce CP. To ascertain the prophylactic effects of ARP, ARP water extract (50, 100, or 200 mg/kg) or saline was administered intraperitoneally 1 h before the onset of CP. To determine the therapeutic effects of ARP, ARP water extract (200 mg/kg) or saline was administered for a total of 1 week or 2 weeks, starting 2 weeks or 1 week after the onset of CP. The pancreas was collected immediately for histological analysis. Additionally, to determine the effectiveness and mechanism of ARP in alleviating pancreatic fibrosis, pancreatic stellate cells (PSCs) were isolated. ARP treatment considerably improved glandular atrophy and inflammation and repressed collagen deposition in the pancreas. Furthermore, ARP water extract inhibited extracellular matrix (ECM) constituents such as alpha-smooth muscle actin (α-SMA), collagen I, and fibronectin 1 (FN1) in pancreatic tissue and PSCs. ARP also suppressed transforming growth factor-β (TGF-β) signaling by inhibiting Smad2 phosphorylation. Our study suggests that ARP exhibits anti-fibrotic effects in cerulein-induced CP by inhibiting TGF-β/Smad signaling.
Collapse
Affiliation(s)
- Bitna Kweon
- Department of Pharmacology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, South Korea
| | - Dong-Uk Kim
- Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, South Korea
| | - Jin-Young Oh
- Department of Pharmacology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, South Korea
| | - Hyuncheol Oh
- Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, South Korea
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeollabuk-do, South Korea
| | - Youn-Chul Kim
- Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeollabuk-do, South Korea
| | - Yeun-Ja Mun
- Department of Anatomy, College of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, South Korea
- Research Center of Traditional Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, South Korea
| | - Gi-Sang Bae
- Department of Pharmacology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, South Korea
- Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, South Korea
- Research Center of Traditional Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, South Korea
- *Correspondence: Gi-Sang Bae, ; Sung-Joo Park,
| | - Sung-Joo Park
- Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, South Korea
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, South Korea
- *Correspondence: Gi-Sang Bae, ; Sung-Joo Park,
| |
Collapse
|
|
6
|
Radoslavova S, Fels B, Pethö Z, Gruner M, Ruck T, Meuth SG, Folcher A, Prevarskaya N, Schwab A, Ouadid-Ahidouch H. TRPC1 channels regulate the activation of pancreatic stellate cells through ERK1/2 and SMAD2 pathways and perpetuate their pressure-mediated activation. Cell Calcium 2022; 106:102621. [PMID: 35905654 DOI: 10.1016/j.ceca.2022.102621] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 11/02/2022]
Abstract
Pancreatic stellate cell (PSC) activation is a major event occurring during pancreatic ductal adenocarcinoma (PDAC) development. Up to now mechanisms underlying their activation by mechanical cues such as the elevated tissue pressure in PDAC remain poorly understood. Here we investigate the role of one potential mechano-transducer, TRPC1 ion channel, in PSC activation. Using pre-activated human siTRPC1 and murine TRPC1-KO PSCs, we show that TRPC1 promotes αSMA (α-smooth muscle actin) expression, the main activation marker, in cooperation with the phosphorylated SMAD2, under normal and elevated pressure. Functional studies following TRPC1 silencing demonstrate the dual role of TRPC1 in the modulation of PSC proliferation and IL-6 secretion through the activation of ERK1/2 and SMAD2 pathways. Moreover, pressurization changes the mechanical behavior of PSCs by increasing their cellular stiffness and emitted traction forces in a TRPC1-dependent manner. In summary, these results point to a role of TRPC1 channels in sensing and transducing the characteristic mechanical properties of the PDAC microenvironment in PSCs.
Collapse
Affiliation(s)
- Silviya Radoslavova
- Laboratory of Cellular and Molecular Physiology, UR-UPJV 4667, University of Picardie Jules Verne, 80039 Amiens, France; University of Lille, Inserm U1003 - PHYCEL - Cellular Physiology, F-59000 Lille, France
| | - Benedikt Fels
- Institute of Physiology, University Lübeck, Lübeck, Germany; DZHK (German Research Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany
| | - Zoltan Pethö
- Institute of Physiology II, University Münster, Münster, Germany
| | - Matthias Gruner
- Institute of Physiology II, University Münster, Münster, Germany
| | - Tobias Ruck
- Klinik für Neurologie, Medical Faculty, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
| | - Sven G Meuth
- Klinik für Neurologie, Medical Faculty, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
| | - Antoine Folcher
- University of Lille, Inserm U1003 - PHYCEL - Cellular Physiology, F-59000 Lille, France
| | - Natalia Prevarskaya
- University of Lille, Inserm U1003 - PHYCEL - Cellular Physiology, F-59000 Lille, France.
| | - Albrecht Schwab
- Institute of Physiology II, University Münster, Münster, Germany.
| | - Halima Ouadid-Ahidouch
- Laboratory of Cellular and Molecular Physiology, UR-UPJV 4667, University of Picardie Jules Verne, 80039 Amiens, France.
| |
Collapse
|
|
7
|
Ng B, Viswanathan S, Widjaja AA, Lim WW, Shekeran SG, Goh JWT, Tan J, Kuthubudeen F, Lim SY, Xie C, Schafer S, Adami E, Cook SA. IL11 Activates Pancreatic Stellate Cells and Causes Pancreatic Inflammation, Fibrosis and Atrophy in a Mouse Model of Pancreatitis. Int J Mol Sci 2022; 23:ijms23073549. [PMID: 35408908 PMCID: PMC8999048 DOI: 10.3390/ijms23073549] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/14/2022] [Accepted: 03/22/2022] [Indexed: 02/06/2023] Open
Abstract
Interleukin-11 (IL11) is important for fibrosis and inflammation, but its role in the pancreas is unclear. In pancreatitis, fibrosis, inflammation and organ dysfunction are associated with pancreatic stellate cell (PSC)-to-myofibroblast transformation. Here, we show that IL11 stimulation of PSCs, which specifically express IL11RA in the pancreas, results in transient STAT3 phosphorylation, sustained ERK activation and PSC activation. In contrast, IL6 stimulation of PSCs caused sustained STAT3 phosphorylation but did not result in ERK activation or PSC transformation. Pancreatitis factors, including TGFβ, CTGF and PDGF, induced IL11 secretion from PSCs and a neutralising IL11RA antibody prevented PSC activation by these stimuli. This revealed an important ERK-dependent role for autocrine IL11 activity in PSCs. In mice, IL11 was increased in the pancreas after pancreatic duct ligation, and in humans, IL11 and IL11RA levels were elevated in chronic pancreatitis. Following pancreatic duct ligation, administration of anti-IL11RA to mice reduced pathologic (ERK, STAT, NF-κB) signalling, pancreatic atrophy, fibrosis and pro-inflammatory cytokine (TNFα, IL6 and IL1β) levels. This is the first description of IL11-mediated activation of PSCs, and the data suggest IL11 as a stromal therapeutic target in pancreatitis.
Collapse
Affiliation(s)
- Benjamin Ng
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore; (W.-W.L.); (J.T.); (C.X.); (S.A.C.)
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (S.V.); (A.A.W.); (S.G.S.); (J.W.T.G.); (F.K.); (S.Y.L.); (S.S.)
- Correspondence: (B.N.); (E.A.)
| | - Sivakumar Viswanathan
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (S.V.); (A.A.W.); (S.G.S.); (J.W.T.G.); (F.K.); (S.Y.L.); (S.S.)
| | - Anissa A. Widjaja
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (S.V.); (A.A.W.); (S.G.S.); (J.W.T.G.); (F.K.); (S.Y.L.); (S.S.)
| | - Wei-Wen Lim
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore; (W.-W.L.); (J.T.); (C.X.); (S.A.C.)
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (S.V.); (A.A.W.); (S.G.S.); (J.W.T.G.); (F.K.); (S.Y.L.); (S.S.)
| | - Shamini G. Shekeran
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (S.V.); (A.A.W.); (S.G.S.); (J.W.T.G.); (F.K.); (S.Y.L.); (S.S.)
| | - Joyce Wei Ting Goh
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (S.V.); (A.A.W.); (S.G.S.); (J.W.T.G.); (F.K.); (S.Y.L.); (S.S.)
| | - Jessie Tan
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore; (W.-W.L.); (J.T.); (C.X.); (S.A.C.)
| | - Fathima Kuthubudeen
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (S.V.); (A.A.W.); (S.G.S.); (J.W.T.G.); (F.K.); (S.Y.L.); (S.S.)
| | - Sze Yun Lim
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (S.V.); (A.A.W.); (S.G.S.); (J.W.T.G.); (F.K.); (S.Y.L.); (S.S.)
| | - Chen Xie
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore; (W.-W.L.); (J.T.); (C.X.); (S.A.C.)
| | - Sebastian Schafer
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (S.V.); (A.A.W.); (S.G.S.); (J.W.T.G.); (F.K.); (S.Y.L.); (S.S.)
| | - Eleonora Adami
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (S.V.); (A.A.W.); (S.G.S.); (J.W.T.G.); (F.K.); (S.Y.L.); (S.S.)
- Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
- Correspondence: (B.N.); (E.A.)
| | - Stuart A. Cook
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore; (W.-W.L.); (J.T.); (C.X.); (S.A.C.)
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169857, Singapore; (S.V.); (A.A.W.); (S.G.S.); (J.W.T.G.); (F.K.); (S.Y.L.); (S.S.)
- MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London W12 0NN, UK
| |
Collapse
|
|
8
|
Choi JW, Shin JY, Zhou Z, Kim DU, Kweon B, Oh H, Kim YC, Song HJ, Bae GS, Park SJ. Stem bark of Fraxinus rhynchophylla ameliorates the severity of pancreatic fibrosis by regulating the TGF-β/Smad signaling pathway. J Investig Med 2022; 70:1285-1292. [PMID: 35078865 DOI: 10.1136/jim-2021-002169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2022] [Indexed: 11/04/2022]
Abstract
Chronic pancreatitis (CP) is a pathological fibroinflammatory syndrome of the pancreas. Currently, there are no therapeutic agents available for treating CP-associated pancreatic fibrosis. Fraxinus rhynchophylla (FR) reportedly exhibits anti-inflammatory, antioxidative and antitumor activities. Although FR possesses numerous properties associated with the regulation of diverse diseases, the effects of FR on CP remain unknown. Herein, we examined the effects of FR on CP. For CP induction, mice were intraperitoneally administered cerulein (50 μg/kg) 6 times a day, 4 days per week for 3 weeks. FR extract (100 or 400 mg/kg) or saline (control group) was intraperitoneally injected 1 hour before the first cerulein injection. After 3 weeks, the pancreas was harvested for histological analysis. In addition, pancreatic stellate cells (PSCs) were isolated to examine the antifibrogenic effects and regulatory mechanisms of FR. Administration of FR significantly inhibited histological damage in the pancreas, increased pancreatic acinar cell survival, decreased PSC activation and collagen deposition, and decreased pro-inflammatory cytokines. Moreover, FR treatment inhibited the expression of fibrotic mediators, such as α-smooth muscle actin (α-SMA), collagen, fibronectin 1, and decreased pro-inflammatory cytokines in isolated PSCs stimulated with transforming growth factor (TGF)-β. Furthermore, FR treatment suppressed the phosphorylation of Smad 2/3 but not of Smad 1/5 in TGF-β-stimulated PSCs. Collectively, these results suggest that FR ameliorates pancreatic fibrosis by inhibiting PSC activation during CP.
Collapse
Affiliation(s)
- Ji-Won Choi
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea.,Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| | - Joon Yeon Shin
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| | - Ziqi Zhou
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| | - Dong-Uk Kim
- Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| | - Bitna Kweon
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| | - Hyuncheol Oh
- Institute of Pharmaceutical Research and Development, College of Pharmacy, WonkwangUniversity, Iksan, Jeollabuk-do, Republic of Korea
| | - Youn-Chul Kim
- Institute of Pharmaceutical Research and Development, College of Pharmacy, WonkwangUniversity, Iksan, Jeollabuk-do, Republic of Korea
| | - Ho-Joon Song
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| | - Gi-Sang Bae
- Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea .,Department of Pharmacology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea.,Research Center of Traditional Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| | - Sung-Joo Park
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea .,Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan, Jeollabuk-do, Republic of Korea
| |
Collapse
|
|
9
|
Mitra S, Anand U, Jha NK, Shekhawat MS, Saha SC, Nongdam P, Rengasamy KRR, Proćków J, Dey A. Anticancer Applications and Pharmacological Properties of Piperidine and Piperine: A Comprehensive Review on Molecular Mechanisms and Therapeutic Perspectives. Front Pharmacol 2022; 12:772418. [PMID: 35069196 PMCID: PMC8776707 DOI: 10.3389/fphar.2021.772418] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/18/2021] [Indexed: 12/26/2022] Open
Abstract
Piperine and piperidine are the two major alkaloids extracted from black pepper (Piper nigrum); piperidine is a heterocyclic moiety that has the molecular formula (CH2)5NH. Over the years, many therapeutic properties including anticancer potential of these two compounds have been observed. Piperine has therapeutic potential against cancers such as breast cancer, ovarian cancer, gastric cancer, gliomal cancer, lung cancer, oral squamous, chronic pancreatitis, prostate cancer, rectal cancer, cervical cancer, and leukemia. Whereas, piperidine acts as a potential clinical agent against cancers, such as breast cancer, prostate cancer, colon cancer, lung cancer, and ovarian cancer, when treated alone or in combination with some novel drugs. Several crucial signalling pathways essential for the establishment of cancers such as STAT-3, NF-κB, PI3k/Aκt, JNK/p38-MAPK, TGF-ß/SMAD, Smac/DIABLO, p-IκB etc., are regulated by these two phytochemicals. Both of these phytochemicals lead to inhibition of cell migration and help in cell cycle arrest to inhibit survivability of cancer cells. The current review highlights the pharmaceutical relevance of both piperine and piperidine against different types of cancers.
Collapse
Affiliation(s)
- Sicon Mitra
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
| | - Uttpal Anand
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, India
| | - Mahipal S Shekhawat
- Department of Plant Biology and Biotechnology, Kanchi Mamunivar Government Institute for Postgraduate Studies and Research, Lawspet, India
| | - Suchismita Chatterjee Saha
- Department of Zoology, Nabadwip Vidyasagar College (Affiliated to the University of Kalyani), Nabadwip, India
| | | | - Kannan R R Rengasamy
- Green Biotechnologies Research Centre of Excellence, University of Limpopo, Sovenga, South Africa
| | - Jarosław Proćków
- Department of Plant Biology, Institute of Environmental Biology, Wrocław University of Environmental and Life Sciences, Wrocław, Poland
| | - Abhijit Dey
- Ethnopharmacology and Natural Product Research Laboratory, Department of Life Sciences, Presidency University, Kolkata, India
| |
Collapse
|
|
10
|
Li X, Nania S, Kleiter I, Löhr JM, Heuchel RL. Targeting of Smad7 in Mesenchymal Cells Does Not Exacerbate Fibrosis During Experimental Chronic Pancreatitis. Pancreas 2021; 50:1427-1434. [PMID: 35041343 DOI: 10.1097/mpa.0000000000001951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Transforming growth factor-β (TGF-β)-mediated accumulation of extracellular matrix proteins such as collagen I is a common feature of fibrosis. Pancreatic stellate cells play an integral role in the pathogenesis of pancreatitis, and their profibrotic ability is mainly mediated by TGF-β signaling. To specifically address the role of fibrogenic cells in experimental pancreatic fibrosis, we deleted Smad7, the main feedback inhibitor of TGF-β signaling in this cell type in mice. METHODS A mouse strain harboring a conditional knockout allele of Smad7 (Smad7fl/fl) with the tamoxifen-inducible inducible Col1a2-CreERT allele was generated and compared with wild-type mice challenged with the cerulein-based model of chronic pancreatitis. RESULTS Pancreatic stellate cells lacking Smad7 had significantly increased collagen I and fibronectin production and showed a higher activation level in vitro. Surprisingly, the fibrotic index in the pancreata of treated conditional knockout mice was only slightly increased, without statistical significance. Except for fibronectin, the expression of different extracellular matrix proteins and the numbers of fibroblasts and inflammatory cells were similar between Smad7-mutant and control mice. CONCLUSIONS There was no clear evidence that the lack of Smad7 in pancreatic stellate cells plays a major role in experimental pancreatitis, at least in the mouse model investigated here.
Collapse
Affiliation(s)
- Xuan Li
- From the Pancreas Cancer Research (PaCaRes) Lab, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
| | - Salvatore Nania
- From the Pancreas Cancer Research (PaCaRes) Lab, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
| | - Ingo Kleiter
- Department of Neurology, Ruhr-Universität Bochum, Bochum, Germany
| | - J-Matthias Löhr
- From the Pancreas Cancer Research (PaCaRes) Lab, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
| | - Rainer L Heuchel
- From the Pancreas Cancer Research (PaCaRes) Lab, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
11
|
Zhao X, Yang X, Wang X, Zhao X, Zhang Y, Liu S, Anderson GJ, Kim SJ, Li Y, Nie G. Penetration Cascade of Size Switchable Nanosystem in Desmoplastic Stroma for Improved Pancreatic Cancer Therapy. ACS NANO 2021; 15:14149-14161. [PMID: 34478262 DOI: 10.1021/acsnano.0c08860] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) cells are surrounded by a dense extracellular matrix (ECM), which greatly restricts the access of therapeutic agents, resulting in poor clinical response to chemotherapy. Transforming growth factor-β1 (TGF-β1) signaling plays a crucial role in construction of the desmoplastic stroma and provides potential targets for PDAC therapy. To surmount the pathological obstacle, we developed a size switchable nanosystem based on PEG-PLGA nanospheres encapsulated within liposomes for the combined delivery of vactosertib (VAC), a TGF-β1 receptor kinase inhibitor, and the cytotoxic drug paclitaxel (TAX). By surface modification of the liposomes with a peptide, APTEDB, the nanosystem can be anchored to abundant tumor-associated fibronectin in PDAC stroma and decreases its size by releasing encapsulated TAX-loaded nanospheres, as well as VAC after collapse of the liposomes. The inhibition of ECM hyperplasia by VAC allows TAX more ready access to the cancer cells in addition to its small size, thereby shrinking pancreatic tumor xenografts more effectively than a combination of the free drugs. This size switchable nanosystem enables sequential delivery of drugs at a fixed dose combination with simplified administration and provides an encouraging cascade approach of drug penetration for enhanced chemotherapy in cancers with a dense desmoplastic stroma.
Collapse
Affiliation(s)
- Xiaozheng Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, P. R. China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Xiao Yang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, P. R. China
| | - Xudong Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, P. R. China
| | - Xiao Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, P. R. China
| | - Yinlong Zhang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, P. R. China
| | - Shaoli Liu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, P. R. China
| | - Gregory J Anderson
- QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia
| | - Seong-Jin Kim
- GILO Institute, GILO Foundation, Seoul 06668, Republic of Korea
- Medpacto Inc., 92 Myeongdal-ro, Seocho-gu, Seoul 06668, Republic of Korea
| | - Yiye Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, P. R. China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Guangjun Nie
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, P. R. China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, P. R. China
- GBA Research Innovation Institute for Nanotechnology, Guangdong 510700, China
| |
Collapse
|
|
12
|
Cannon A, Thompson CM, Bhatia R, Armstrong KA, Solheim JC, Kumar S, Batra SK. Molecular mechanisms of pancreatic myofibroblast activation in chronic pancreatitis and pancreatic ductal adenocarcinoma. J Gastroenterol 2021; 56:689-703. [PMID: 34279724 PMCID: PMC9052363 DOI: 10.1007/s00535-021-01800-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/15/2021] [Indexed: 02/04/2023]
Abstract
Pancreatic fibrosis (PF) is an essential component of the pathobiology of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Activated pancreatic myofibroblasts (PMFs) are crucial for the deposition of the extracellular matrix, and fibrotic reaction in response to sustained signaling. Consequently, understanding of the molecular mechanisms of PMF activation is not only critical for understanding CP and PDAC biology but is also a fertile area of research for the development of novel therapeutic strategies for pancreatic pathologies. This review analyzes the key signaling events that drive PMF activation including, initiating signals from transforming growth factor-β1, platelet derived growth factor, as well as other microenvironmental cues, like hypoxia and extracellular matrix rigidity. Further, we discussed the intracellular signal events contributing to PMF activation, and crosstalk with different components of tumor microenvironment. Additionally, association of epidemiologically established risk factors for CP and PDAC, like alcohol intake, tobacco exposure, and metabolic factors with PMF activation, is discussed to comprehend the role of lifestyle factors on pancreatic pathologies. Overall, this analysis provides insight into the biology of PMF activation and highlights salient features of this process, which offer promising therapeutic targets.
Collapse
Affiliation(s)
- Andrew Cannon
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Christopher Michael Thompson
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Rakesh Bhatia
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | | | - Joyce Christopher Solheim
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder Kumar Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| |
Collapse
|
|
13
|
Li CX, Cui LH, Zhang LQ, Yang L, Zhuo YZ, Cui NQ, Zhang SK. Role of NLR family pyrin domain-containing 3 inflammasome in the activation of pancreatic stellate cells. Exp Cell Res 2021; 404:112634. [PMID: 34004193 DOI: 10.1016/j.yexcr.2021.112634] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 12/21/2022]
Abstract
NLRP3 inflammasome activation plays an important role in the development of pancreatic fibrosis. However, it is unclear whether the activation of the NLRP3 inflammasome is directly involved in the activation of Pancreatic stellate cells (PSCs). The aim of this study was to investigate the role and mechanism of the NLRP3 inflammasome in the activation of PSCs. In vivo, a rat model of chronic pancreatitis (CP) was induced by intravenous injection of dibutyltin dichloride (DBTC). In vitro, rat primary PSCs were isolated from pancreatic tissues and incubated with the NLRP3 inflammasome activator LPS, the NLRP3 inhibitor MCC950, or NLRP3 siRNA. The results showed that the expression of NLRP3, pro-Caspase-1, Caspase-1 and IL-18 was increased in the rat model of CP and during PSCs activation. LPS increased the protein levels of NLRP3, ASC, Caspase-1, IL-1β and IL-18 accompanied by the upregulation of α-SMA, Col I and FN expression. Moreover, MCC950 or NLPR3 siRNA decreased the expression of α-SMA, Col I, FN, TGF-β1 and p-Smad3. Furthermore, MCC950 reversed the LPS-induced upregulation of α-SMA, FN and Col Ⅰ expression in PSCs. This study revealed that the NLRP3 inflammasome is directly involved in the activation of PSCs in vivo and in vitro. Inhibiting NLRP3 suppresses the activation of PSCs through the TGF-β1/Smad3 pathway.
Collapse
Affiliation(s)
- Cai-Xia Li
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, 300100, China
| | - Li-Hua Cui
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, 300100, China
| | - Lan-Qiu Zhang
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, 300100, China
| | - Lei Yang
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, 300100, China
| | - Yu-Zhen Zhuo
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, 300100, China
| | - Nai-Qiang Cui
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, 300100, China; Hepatobiliary and Pancreatic Surgery, Tianjin Nankai Hospital, Tianjin, 300100, China
| | - Shu-Kun Zhang
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, 300100, China.
| |
Collapse
|
|
14
|
Orai1 Channel Regulates Human-Activated Pancreatic Stellate Cell Proliferation and TGF β1 Secretion through the AKT Signaling Pathway. Cancers (Basel) 2021; 13:cancers13102395. [PMID: 34063470 PMCID: PMC8156432 DOI: 10.3390/cancers13102395] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/04/2021] [Accepted: 05/12/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Activated pancreatic stellate cells (aPSCs), the main source of cancer-associated fibroblasts in pancreatic ductal adenocarcinoma (PDAC), are well known as the key actor of the abundant fibrotic stroma development surrounding the tumor cells. In permanent communication with the tumor cells, they enhance PDAC early spreading and limit the drug delivery. However, the understanding of PSC activation mechanisms and the associated signaling pathways is still incomplete. In this study, we aimed to evaluate the role of Ca2+, and Orai1 Ca2+ channels, in two main PSC activation processes: cell proliferation and cytokine secretion. Indeed, Ca2+ is a versatile second messenger implicated in the regulation of numerous biological processes. We believe that a better comprehension of PSC Ca2+ -dependent activation mechanisms will bring up new crucial PDAC early prognostic markers or new targeting approaches in PDAC treatment. Abstract Activated pancreatic stellate cells (aPSCs), the crucial mediator of pancreatic desmoplasia, are characterized, among others, by high proliferative potential and abundant transforming growth factor β1 (TGFβ1) secretion. Over the past years, the involvement of Ca2+ channels in PSC pathophysiology has attracted great interest in pancreatic cancer research. We, thus, aimed to investigate the role of the Orai1 Ca2+ channel in these two PSC activation processes. Using the siRNA approach, we invalided Orai1 expression and assessed the channel functionality by Ca2+ imaging, the effect on aPSC proliferation, and TGFβ1 secretion. We demonstrated the functional expression of the Orai1 channel in human aPSCs and its implication in the store-operated Ca2+ entry (SOCE). Orai1 silencing led to a decrease in aPSC proliferation, TGFβ1 secretion, and AKT activation. Interestingly, TGFβ1 induced a higher SOCE response by increasing Orai1 mRNAs and proteins and promoted both AKT phosphorylation and cell proliferation, abolished by Orai1 silencing. Together, our results highlight the role of Orai1-mediated Ca2+ entry in human aPSC pathophysiology by controlling cell proliferation and TGFβ1 secretion through the AKT signaling pathway. Moreover, we showed a TGFβ1-induced autocrine positive feedback loop by promoting the Orai1/AKT-dependent proliferation via the stimulation of Orai1 expression and function.
Collapse
|
|
15
|
Zheng M, Li H, Sun L, Brigstock DR, Gao R. Interleukin-6 participates in human pancreatic stellate cell activation and collagen I production via TGF-β1/Smad pathway. Cytokine 2021; 143:155536. [PMID: 33893003 DOI: 10.1016/j.cyto.2021.155536] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/24/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic stellate cells (PSCs) play a key role in fibrogenesis during alcoholic chronic pancreatitis (ACP). Transforming growth factor-β1 (TGF-β1) is a major regulator of PSC activation and extracellular matrix production. Interleukin-6 (IL-6) has shown to participate in TGF-β1 production and rat PSC activation. This study aimed to investigate whether IL-6 promotes human PSC activation and collagen 1(Col1) production through the TGF-β1/Smad pathway. Our results showed that the expression of IL-6 and IL-6R in activated PSCs and macrophages (Mφs) were enhanced in the pancreas of ACP compared to healthy controls and that the mRNA expression of IL-6, IL-6R, TGF-β1, α-SMA or Col1a1 were significantly increased in the pancreas of ACP, showing positive correlations between elevated IL-6 levels and either TGF-β1 or α-SMA or Col1a1 levels and between elevated TGF-β1 levels and α-SMA or Col1a1 levels. In in vitro studies, we identified that IL-6R expression or IL-6 and TGF-β1 secretions were significantly increased in, respectively, Mφs and PSCs by ethanol (EtOH) or lipopolysaccharide (LPS) stimulation while EtOH- or LPS-induced α-SMA or Col1a1 mRNA and protein production in PSCs were partially blocked by IL-6 antibody. IL-6-induced TGF-β1 production in PSCs was antagonized by si-IL-6R RNA or by an inhibitor of STAT3. Additionally, IL-6-promoted α-SMA or Col1a1 protein production was blocked by TGF-β1 antibody and IL-6-induced phosphorylation of Smad2/3 and transcription of α-SMA and Col1a1 mRNA were antagonized by si-TGF-β1 RNA. Our findings indicate that IL-6 contributes to PSC activation and Col1 production through up-regulation of TGF-β1/Smad2/3 pathway.
Collapse
Affiliation(s)
- Meifang Zheng
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China
| | - Hongyan Li
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China
| | - Li Sun
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China
| | - David R Brigstock
- The Research Institute at Nationwide Children's Hospital, Columbus, OH United States
| | - Runping Gao
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China.
| |
Collapse
|
|
16
|
Hic-5 is required for activation of pancreatic stellate cells and development of pancreatic fibrosis in chronic pancreatitis. Sci Rep 2020; 10:19105. [PMID: 33154390 PMCID: PMC7645689 DOI: 10.1038/s41598-020-76095-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 10/22/2020] [Indexed: 12/18/2022] Open
Abstract
Accumulated evidence suggests that activated pancreatic stellate cells (PSCs) serve as the main source of the extracellular matrix proteins accumulated under the pathological conditions leading to pancreatic fibrosis in chronic pancreatitis (CP). However, little is known about the mechanisms of PSC activation. PSCs have morphologic and functional similarities to hepatic stellate cells, which are activated by hydrogen peroxide-inducible clone-5 (Hic-5), a TGF-β1-induced protein. In this study, we investigated whether Hic-5 activates PSCs, which promote pancreatic fibrosis development in CP. Hic-5-knockout and wild type mice were subjected to caerulein injection to induce CP. Hic-5 expression was strongly upregulated in activated PSCs from human CP tissue and from mouse pancreatic fibrosis in caerulein-induced CP. Hic-5 deficiency significantly attenuated mouse pancreatic fibrosis and PSC activation in the experimental murine CP model. Mechanistically, Hic-5 knock down significantly inhibited the TGF-β/Smad2 signaling pathway, resulting in reduced collagen production and α-smooth muscle actin expression in the activated PSCs. Taken together, we propose Hic-5 as a potential marker of activated PSCs and a novel therapeutic target in CP treatment.
Collapse
|
|
17
|
Kusiak AA, Szopa MD, Jakubowska MA, Ferdek PE. Signaling in the Physiology and Pathophysiology of Pancreatic Stellate Cells - a Brief Review of Recent Advances. Front Physiol 2020; 11:78. [PMID: 32116785 PMCID: PMC7033654 DOI: 10.3389/fphys.2020.00078] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 01/23/2020] [Indexed: 12/12/2022] Open
Abstract
The interest in pancreatic stellate cells (PSCs) has been steadily growing over the past two decades due mainly to the central role these cells have in the desmoplastic reaction associated with diseases of the pancreas, such as pancreatitis or pancreatic cancer. In recent years, the scientific community has devoted substantial efforts to understanding the signaling pathways that govern PSC activation and interactions with neoplastic cells. This mini review aims to summarize some very recent findings on signaling in PSCs and highlight their impact to the field.
Collapse
Affiliation(s)
- Agnieszka A Kusiak
- Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Mateusz D Szopa
- Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | | | - Pawel E Ferdek
- Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| |
Collapse
|
|
18
|
Jin G, Hong W, Guo Y, Bai Y, Chen B. Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer. J Cancer 2020; 11:1505-1515. [PMID: 32047557 PMCID: PMC6995390 DOI: 10.7150/jca.38616] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 12/08/2019] [Indexed: 12/14/2022] Open
Abstract
Activated pancreatic stellate cells (PSCs) are the main effector cells in the process of fibrosis, a major pathological feature in pancreatic diseases that including chronic pancreatitis and pancreatic cancer. During tumorigenesis, quiescent PSCs change into an active myofibroblast-like phenotype which could create a favorable tumor microenvironment and facilitate cancer progression by increasing proliferation, invasiveness and inducing treatment resistance of pancreatic cancer cells. Many cellular signals are revealed contributing to the activation of PSCs, such as transforming growth factor-β, platelet derived growth factor, mitogen-activated protein kinase (MAPK), Smads, nuclear factor-κB (NF-κB) pathways and so on. Therefore, investigating the role of these factors and signaling pathways in PSCs activation will promote the development of PSCs-specific therapeutic strategies that may provide novel options for pancreatic cancer therapy. In this review, we systematically summarize the current knowledge about PSCs activation-associated stimulating factors and signaling pathways and hope to provide new strategies for the treatment of pancreatic diseases.
Collapse
Affiliation(s)
- Guihua Jin
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Weilong Hong
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Yangyang Guo
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Yongheng Bai
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Bicheng Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| |
Collapse
|
|
19
|
Sun L, Qu L, Brigstock DR, Li H, Li Y, Gao R. Biological and Proteomic Characteristics of an Immortalized Human Pancreatic Stellate Cell Line. Int J Med Sci 2020; 17:137-144. [PMID: 31929747 PMCID: PMC6945563 DOI: 10.7150/ijms.36337] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 12/12/2019] [Indexed: 02/07/2023] Open
Abstract
Human pancreatic stellate cells (PSCs) play a critical role in fibrogenesis during chronic pancreatitis (CP). However, primary PSCs have a short lifespan in vitro, which seriously affects their use in various applications. We have established a stable immortalized human PSC line (HP-1) by RSV promoter/enhancer-driven SV40 T antigen expression in primary activated human PSCs. HP-1 cells express cytoskeleton proteins including glial fibrillary acidic protein (GFAP), α-smooth muscle actin (α-SMA), vimentin and desmin, and are typical of PSCs, which are high transfeciability and viable in 0.5% serum. The cells express receptors such as TGFβR2, PDGFR, TGF-β pseudoreceptor Bambi and PPRPγ that are commonly found in PSCs. HP-1 cells are similar to activated human PSCs in that they have enhanced expression of α-SMA, CTGF, Col1 and TIMP-2 mRNAs or proteins, as well as decreased expression of MMP-1/2 mRNAs or proteins in response to TGF-β1 stimulation. Comparative proteomics revealed 4,537 shared proteins between HP-1 cells and PSCs and no single protein in HP-1 cells versus PSCs. Statistical analysis reveals no significantly difference between HP-1 cells and PSCs in their expression of proteins associated with matrix and matrix remodeling. The similarity between HP-1 cell and PSC is further shown by the finding that only 9 proteins are differentially up-regulated > ± 2-fold in HP-1 cells and 13 proteins are up-regulated > ± 2-fold in PSCs and none of these proteins include ECM proteins, cytokines, growth factors or matrix remodeling regulatory proteins. Therefore, HP-1 cells can be used as an effective tool for the study of PSC-mediated pancreatic fibrosis.
Collapse
Affiliation(s)
- Li Sun
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, 130021, China
| | - Limei Qu
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, 130021, China
| | - David R Brigstock
- Research Institute at Nationwide Children's Hospital, Columbus, 43205, United States
| | - Hongyan Li
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, 130021, China
| | - Yanyan Li
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, 130021, China
| | - Runping Gao
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, 130021, China
| |
Collapse
|
|
20
|
Bynigeri RR, Mitnala S, Talukdar R, Singh SS, Duvvuru NR. Pancreatic stellate cell-potentiated insulin secretion from Min6 cells is independent of interleukin 6-mediated pathway. J Cell Biochem 2020; 121:840-855. [PMID: 31452250 DOI: 10.1002/jcb.29329] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 07/15/2019] [Indexed: 02/07/2025]
Abstract
Pancreatic stellate cells (PSCs) secrete various factors, which can influence the β-cell function. The identification of stellate cell infiltration into the islets in pancreatic diseases suggests possible existence of cross-talk between these cells. To elucidate the influence of PSCs on β-cell function, mouse PSCs were cocultured with Min6 cells using the Transwell inserts. Glucose-stimulated insulin secretion from Min6 cells in response to PSCs was quantified by enzyme-linked immunosorbent assay and insulin gene expression was measured by quantitative polymerase chain reaction. Upon cytometric identification of IL6 in PSC culture supernatants, Min6 cells were cultured with IL6 to assess its influence on the insulin secretion and gene expression. PLC-IP3 pathway inhibitors were added in the cocultures, to determine the influence of PSC-secreted IL6 on Glucose-stimulated insulin secretion from Min6 cells. Increased insulin secretion with a concomitant decrease in total insulin content was noticed in PSC-cocultured Min6 cells. Although increased GSIS was noted from IL6-treated Min6 cells, no change in the total insulin content was noted. Coculture of Min6 cells with PSCs or their exposure to IL6 did not alter either the expression of β-cell-specific genes or that of miRNA-375. PSC-cocultured Min6 cells, in the presence of PLC-IP3 pathway inhibitors (U73122, Neomycin, and Xestospongin C), did not revoke the observed increase in GSIS. In conclusion, the obtained results indicate that augmented insulin secretion from Min6 cells in response to PSC secretions is independent of IL6-mediated PLC-IP3 pathway.
Collapse
Affiliation(s)
| | - Sasikala Mitnala
- Department of Basic Sciences, Asian Healthcare Foundation, Hyderabad, India
| | - Rupjyoti Talukdar
- Department of Basic Sciences, Asian Healthcare Foundation, Hyderabad, India
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Surya S Singh
- Department of Biochemistry, Osmania University, Hyderabad, India
| | | |
Collapse
|
|
21
|
Choi JW, Lee SK, Kim MJ, Kim DG, Shin JY, Zhou Z, Jo IJ, Song HJ, Bae GS, Park SJ. Piperine ameliorates the severity of fibrosis via inhibition of TGF‑β/SMAD signaling in a mouse model of chronic pancreatitis. Mol Med Rep 2019; 20:3709-3718. [PMID: 31485676 PMCID: PMC6755249 DOI: 10.3892/mmr.2019.10635] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 08/12/2019] [Indexed: 12/26/2022] Open
Abstract
Chronic pancreatitis (CP) is characterized by recurrent pancreatic injury, resulting in inflammation and fibrosis. Currently, there are no drugs for the treatment of pancreatic fibrosis associated with CP. Piperine, a natural alkaloid found in black pepper, has been reported to show anti-inflammatory, anti-oxidative, and antitumor activities. Although piperine exhibits numerous properties in regards to the regulation of diverse diseases, the effects of piperine on CP have not been established. To investigate the effects of piperine on CP in vivo, we induced CP in mice through the repetitive administration of cerulein (50 µg/kg) six times at 1-h intervals, 5 times per week, for a total of 3 weeks. In the pre-treatment groups, piperine (1, 5, or 10 mg/kg) or corn oil were administrated orally at 1 h before the first cerulein injection, once a day, 5 times a week, for a total of 3 weeks. In the post-treatment groups, piperine (10 mg/kg) or corn oil was administered orally at 1 or 2 week after the first cerulein injection. Pancreases were collected for histological analysis. In addition, pancreatic stellate cells (PSCs) were isolated to examine the anti-fibrogenic effects and regulatory mechanisms of piperine. Piperine treatment significantly inhibited histological damage in the pancreas, increased the pancreatic acinar cell survival, reduced collagen deposition and reduced pro-inflammatory cytokines and chemokines. In addition, piperine treatment reduced the expression of fibrotic mediators, such as α-smooth muscle actin (α-SMA), collagen, and fibronectin 1 in the pancreas and PSCs. Moreover, piperine treatment reduced the production of transforming growth factor (TGF)-β in the pancreas and PSCs. Furthermore, piperine treatment inhibited TGF-β-induced pSMAD2/3 activation but not pSMAD1/5 in the PSCs. These findings suggest that piperine treatment ameliorates pancreatic fibrosis by inhibiting TGF-β/SMAD2/3 signaling during CP.
Collapse
Affiliation(s)
- Ji-Won Choi
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Sung-Kon Lee
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Myoung-Jin Kim
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Dong-Gu Kim
- Hanbang Cardio‑Renal Syndrome Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Joon-Yeon Shin
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Ziqi Zhou
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Il-Joo Jo
- Division of Beauty Sciences, School of Natural Sciences, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Ho-Joon Song
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Gi-Sang Bae
- Hanbang Cardio‑Renal Syndrome Research Center, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Sung-Joo Park
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| |
Collapse
|
|
22
|
Abstract
PURPOSE OF REVIEW The goal of this manuscript is to review the current literature related to fibrogenesis in the pancreatobiliary system and how this process contributes to pancreatic and biliary diseases. In particular, we seek to define the current state of knowledge regarding the epigenetic mechanisms that govern and regulate tissue fibrosis in these organs. A better understanding of these underlying molecular events will set the stage for future epigenetic therapeutics. RECENT FINDINGS We highlight the significant advances that have been made in defining the pathogenesis of pancreatobiliary fibrosis as it relates to chronic pancreatitis, pancreatic cancer, and the fibro-obliterative cholangiopathies. We also review the cell types involved as well as concepts related to epithelial-mesenchymal crosstalk. Furthermore, we outline important signaling pathways (e.g., TGFβ) and diverse epigenetic processes (i.e., DNA methylation, non-coding RNAs, histone modifications, and 3D chromatin remodeling) that regulate fibrogenic gene networks in these conditions. We review a growing body of scientific evidence linking epigenetic regulatory events to fibrotic disease states in the pancreas and biliary system. Advances in this understudied area will be critical toward developing epigenetic pharmacological approaches that may lead to more effective treatments for these devastating and difficult to treat disorders.
Collapse
Affiliation(s)
- Sayed Obaidullah Aseem
- Division of Gastroenterology and Hepatology, Rochester, FL, USA
- Gastroenterology Research Unit, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Robert C Huebert
- Division of Gastroenterology and Hepatology, Rochester, FL, USA.
- Gastroenterology Research Unit, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
- Mayo Clinic Foundation, Rochester, MN, USA.
| |
Collapse
|
|
23
|
Liu C, Li S, Zhang Q, Guo F, Tong M, Martinez MFYM, Wang HH, Zhao Y, Shang D. Emerging Role of Chinese Herbal Medicines in the Treatment of Pancreatic Fibrosis. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:709-726. [PMID: 31091974 DOI: 10.1142/s0192415x1950037x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic fibrosis is the main pathologic characteristic in chronic pancreatitis (CP), a common disease that arises from surgery. Pancreatitis is caused by various etiologies, but the mechanism of fibrosis is not completely understood. Existing clinical approaches mainly focus on mitigating the symptoms and therefore do not cure the phenomena. In recent years, there has been a heightened interest in the use of Chinese herbal medicine (CHMs) in the prevention and cure of CP as expressed by increasing numbers of clinical and experimental research. Despite early cell culture and animal models, CHMs are able to interact with plenty of molecular targets involved in the pathogenesis of pancreatic fibrosis mostly via the TGF- β /Smads pathway; however, integrated and up-to-date communication in this domain is unavailable. This review focuses on the research progress of CHMs against pancreatic fibrosis due to CP in vitro and in vivo and summarizes the potential mechanisms. We also outlined the toxicology of some CHMs for fibrosis treatment in order to provide a fuller understanding of drug safety. This review may provide reference for further innovative drug research and the future development of treatments for CP with pancreatic fibrosis.
Collapse
Affiliation(s)
- Chang Liu
- * Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P. R. China.,† Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P. R. China
| | - Shuang Li
- * Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P. R. China.,† Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P. R. China
| | - Qingkai Zhang
- * Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P. R. China.,† Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P. R. China
| | - Fangyue Guo
- * Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P. R. China.,† Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P. R. China
| | - Mengying Tong
- ‡ Department of Ultrasound, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P. R. China
| | | | - Heather H Wang
- ¶ Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Yutong Zhao
- ¶ Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Dong Shang
- * Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P. R. China.,† Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P. R. China
| |
Collapse
|
|
24
|
Huang H, Chen J, Peng L, Yao Y, Deng D, Zhang Y, Liu Y, Wang H, Li Z, Bi Y, Haddock AN, Zhan X, Lu W, Logsdon CD, Ji B. Transgenic expression of cyclooxygenase-2 in pancreatic acinar cells induces chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 2019; 316:G179-G186. [PMID: 30431318 PMCID: PMC6383372 DOI: 10.1152/ajpgi.00096.2018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 11/06/2018] [Accepted: 11/06/2018] [Indexed: 01/31/2023]
Abstract
Replacement of the exocrine parenchyma by fibrous tissue is a main characteristic of chronic pancreatitis. Understanding the mechanisms of pancreatic fibrogenesis is critical for the development of preventive and therapeutic interventions. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin synthesis, is expressed in patients with chronic pancreatitis. However, it is unknown whether COX-2 can cause chronic pancreatitis. To investigate the roles of pancreatic acinar COX-2 in fibrogenesis and the development of chronic pancreatitis, COX-2 was ectopically expressed specifically in pancreatic acinar cells in transgenic mice. Histopathological changes and expression levels of several profibrogenic factors related to chronic pancreatitis were evaluated. COX-2 was expressed in the pancreas of the transgenic mice, as detected by Western blot analysis. Immunohistochemical staining showed COX-2 was specifically expressed in pancreatic acinar cells. COX-2 expression led to progressive changes in the pancreas, including pancreas megaly, persistent inflammation, collagen deposition, and acinar-to-ductal metaplasia. Quantitative RT-PCR and immunostaining showed that profibrogenic factors were upregulated and pancreatic stellate cells were activated in the COX-2 transgenic mice. Expression of COX-2 in pancreatic acinar cells is sufficient to induce chronic pancreatitis. Targeting this pathway may be valuable in the prevention of chronic pancreatitis. NEW & NOTEWORTHY COX-2 expression is observed in pancreatic tissues of human chronic pancreatitis. In this study, we showed that COX-2 expression caused the development of chronic pancreatitis in transgenic mice, supporting the idea that COX-2 inhibition may be an effective preventive and therapeutic strategy.
Collapse
Affiliation(s)
- Haojie Huang
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University , Shanghai , China
- Department of Cancer Biology, University of Texas, MD Anderson Cancer Center , Houston, Texas
| | - Jiaxiang Chen
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Lisi Peng
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University , Shanghai , China
| | - Yao Yao
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University , Shanghai , China
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Defeng Deng
- Department of Cancer Biology, University of Texas, MD Anderson Cancer Center , Houston, Texas
| | - Yang Zhang
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University , Shanghai , China
- Department of Cancer Biology, University of Texas, MD Anderson Cancer Center , Houston, Texas
| | - Yan Liu
- Department of Cancer Biology, University of Texas, MD Anderson Cancer Center , Houston, Texas
| | - Huamin Wang
- Departments of Anatomic Pathology and Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center , Houston, Texas
| | - Zhaoshen Li
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University , Shanghai , China
| | - Yan Bi
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
- Department of Gastroenterology, Mayo Clinic , Jacksonville, Florida
| | - Ashley N Haddock
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Xianbao Zhan
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
- Department of Oncology, Changhai Hospital, Second Military Medical University , Shanghai , China
| | - Weiqin Lu
- Department of Medicine, Stony Brook University , Stony Brook, New York
| | - Craig D Logsdon
- Department of Cancer Biology, University of Texas, MD Anderson Cancer Center , Houston, Texas
- Department of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center , Houston, Texas
| | - Baoan Ji
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| |
Collapse
|
|
25
|
Liu SL, Cao SG, Li Y, Sun B, Chen D, Wang DS, Zhou YB. Pancreatic stellate cells facilitate pancreatic cancer cell viability and invasion. Oncol Lett 2018; 17:2057-2062. [PMID: 30675272 PMCID: PMC6341873 DOI: 10.3892/ol.2018.9816] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 04/12/2018] [Indexed: 12/26/2022] Open
Abstract
The biological features of pancreatic cancer and the associated hypoxic environment around the cancer cells often lead to resistance to radiotherapy and chemotherapy. The present study was performed in order to explore the effect pancreatic stellate cells (PSCs) have on the proliferation of pancreatic cancer cells. In the present study, PSCs from human pancreatic cancer tissues were isolated, and the PSCs markers α-smooth muscle actin and desmin were overexpressed in the cytoplasm of PSCs. An MTT assay revealed that PSCs promoted the viability of pancreatic cancer cells. However, the viability of pancreatic cancer cells promoted by PSCs was partially blocked by SB525334. Cellular invasion analysis demonstrated that PSCs promoted the invasion ability of pancreatic cancer cells. An apoptosis assay indicated that PSCs decreased the level of apoptosis induced by gemcitabine. In vivo experiments consisting of mice bearing MIA-PaCa-2 and PSCs demonstrated an increase in the rate of tumor growth compared with MIA-PaCA-2 alone, whereas SB525334 may delay the tumor progression induced by PSCs. The present findings indicated that PSCs promoted the viability and invasion of pancreatic cancer cells, and decreased the apoptosis of pancreatic cancer cells induced by gemcitabine.
Collapse
Affiliation(s)
- Shang-Long Liu
- Department of General Surgery, Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Shou-Gen Cao
- Department of General Surgery, Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Ying Li
- Department of Blood Transfusion, Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Bo Sun
- Department of Blood Transfusion, Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Dong Chen
- Department of General Surgery, Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Dong-Sheng Wang
- Department of General Surgery, Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Yan-Bing Zhou
- Department of General Surgery, Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong 266003, P.R. China
| |
Collapse
|
|
26
|
Li L, Wang G, Hu JS, Zhang GQ, Chen HZ, Yuan Y, Li YL, Lv XJ, Tian FY, Pan SH, Bai XW, Sun B. RB1CC1-enhanced autophagy facilitates PSCs activation and pancreatic fibrogenesis in chronic pancreatitis. Cell Death Dis 2018; 9:952. [PMID: 30237496 PMCID: PMC6147947 DOI: 10.1038/s41419-018-0980-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 08/21/2018] [Accepted: 08/23/2018] [Indexed: 12/13/2022]
Abstract
Chronic pancreatitis (CP) is described as a progressive fibro-inflammatory disorder of the exocrine disease, which eventually leads to damage of the gland. Excessive activation of pancreatic stellate cells (PSCs) is a critical participant in the initiation of CP. Autophagy is involved in multiple degeneration and inflammation in acute pancreatitis and CP. In our study, we report that retinoblastoma coiled coil protein 1 (RB1CC1) expression and the autophagic level are elevated in activated PSCs. RB1CC1 is positively correlated with pancreatic fibrogenesis in tissues and plasma of CP patients. Knockdown of RB1CC1 restrains alpha smooth muscle actin (α-SMA) and collagen expressions, and autophagy in activated PSCs in vitro. Furthermore, we show that RB1CC1 induces PSC activation via binding to ULK1 promoter and the direct interaction with ULK1 protein. These suppress ULK1 expression and its kinase activity. In mice, knockdown of RB1CC1 blocks autophagy and then inhibits the pancreatic duct ligation-induced pancreatic fibrosis. Consequently, our study highlights that RB1CC1-mediated autophagy is a key event for the activation of PSCs. Inhibition of RB1CC1 alleviates autophagy, which plays a critical role in anti-fibrotic activation in PSCs and CP progression. RB1CC1 could be a novel strategy for the treatment of pancreatic fibrosis.
Collapse
Affiliation(s)
- Le Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Gang Wang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ji-Sheng Hu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Guang-Quan Zhang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Hong-Ze Chen
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yue Yuan
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yi-Long Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Xin-Jian Lv
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Feng-Yu Tian
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Shang-Ha Pan
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.,Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Xue-Wei Bai
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
| |
Collapse
|
|
27
|
Abstract
Stellate cells are resident lipid-storing cells of the pancreas and liver that transdifferentiate to a myofibroblastic state in the context of tissue injury. Beyond having roles in tissue homeostasis, stellate cells are increasingly implicated in pathological fibrogenic and inflammatory programs that contribute to tissue fibrosis and that constitute a growth-permissive tumor microenvironment. Although the capacity of stellate cells for extracellular matrix production and remodeling has long been appreciated, recent research efforts have demonstrated diverse roles for stellate cells in regulation of epithelial cell fate, immune modulation, and tissue health. Our present understanding of stellate cell biology in health and disease is discussed here, as are emerging means to target these multifaceted cells for therapeutic benefit.
Collapse
Affiliation(s)
- Mara H Sherman
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon 97201, USA;
| |
Collapse
|
|
28
|
Abstract
OBJECTIVES The purpose of this study is to assess the effect and possible mechanism of luteolin on chronic pancreatitis (CP). METHODS Trinitrobenzenesulfonic acid-induced CP was used as CP models in vivo. After the intervention of luteolin for 28 days, chronic pancreatic injury was assessed by serum hydroxyproline and pancreatic histology. α-Smooth muscle actin (α-SMA) expression was performed to detect the activation of pancreatic stellate cells (PSCs). Pancreatic stellate cells were also isolated and cultured in vitro, and the effect of luteolin on PSCs was evaluated. Transforming growth factor β (TGF-β1) signaling and its regulated mRNA expression was tested by Western blot and quantitative real-time polymerase chain reaction, respectively. RESULTS The protective role of luteolin on CP was confirmed by increased pancreas/body weight ratio, decreased pancreas hydroxyproline level, and reduced fibrosis. α-SMA expressions in PSCs were significantly decreased both in vitro and in vivo after the management of luteolin. Pancreas TGF-β1 expression was significantly decreased by luteolin. Luteolin inhibited the proliferation and activation of PSCs in a dose-dependent manner. CONCLUSIONS Luteolin played a protective role in CP in many aspects, partly by regulating release of inflammatory cytokines through TGF-β1 signaling pathway.
Collapse
|
|
29
|
Sun L, Xiu M, Wang S, Brigstock DR, Li H, Qu L, Gao R. Lipopolysaccharide enhances TGF-β1 signalling pathway and rat pancreatic fibrosis. J Cell Mol Med 2018; 22:2346-2356. [PMID: 29424488 PMCID: PMC5867168 DOI: 10.1111/jcmm.13526] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 12/08/2017] [Indexed: 12/20/2022] Open
Abstract
Pancreatic stellate cells (PSCs) play a critical role in fibrogenesis during alcoholic chronic pancreatitis (ACP). Transforming growth factor-beta1 (TGF-β1) is a key regulator of extracellular matrix production and PSC activation. Endotoxin lipopolysaccharide (LPS) has been recognized as a trigger factor in the pathogenesis of ACP. This study aimed to investigate the mechanisms by which LPS modulates TGF-β1 signalling and pancreatic fibrosis. Sprague-Dawley rats fed with a Lieber-DeCarli alcohol (ALC) liquid diet for 10 weeks with or without LPS challenge during the last 3 weeks. In vitro studies were performed using rat macrophages (Mφs) and PSCs (RP-2 cell line). The results showed that repeated LPS challenge resulted in significantly more collagen production and PSC activation compared to rats fed with ALC alone. LPS administration caused overexpression of pancreatic TLR4 or TGF-β1 which was paralleled by an increased number of TLR4-positive or TGF-β1-positive Mφs or PSCs in ALC-fed rats. In vitro, TLR4 or TGF-β1 production in Mφs or RP-2 cells was up-regulated by LPS. LPS alone or in combination with TGF-β1 significantly increased type I collagen and α-SMA production and Smad2 and 3 phosphorylation in serum-starved RP-2 cells. TGF-β pseudoreceptor BAMBI production was repressed by LPS, which was antagonized by Si-TLR4 RNA or by inhibitors of MyD88/NF-kB. Additionally, knockdown of Bambi with Si-Bambi RNA significantly increased TGF-β1 signalling in RP-2 cells. These findings indicate that LPS increases TGF-β1 production through paracrine and autocrine mechanisms and that LPS enhances TGF-β1 signalling in PSCs by repressing BAMBI via TLR4/MyD88/NF-kB activation.
Collapse
Affiliation(s)
- Li Sun
- Department of Hepatic Biliary Pancreatic MedicineFirst Hospital of Jilin UniversityChangchunChina
| | - Ming Xiu
- Department of Hepatic Biliary Pancreatic MedicineFirst Hospital of Jilin UniversityChangchunChina
| | - Shuhua Wang
- Department of Surgical GastroenterologyFirst Hospital of Jilin UniversityChangchunChina
| | | | - Hongyan Li
- Department of Hepatic Biliary Pancreatic MedicineFirst Hospital of Jilin UniversityChangchunChina
| | - Limei Qu
- Department of Hepatic Biliary Pancreatic MedicineFirst Hospital of Jilin UniversityChangchunChina
| | - Runping Gao
- Department of Hepatic Biliary Pancreatic MedicineFirst Hospital of Jilin UniversityChangchunChina
| |
Collapse
|
|
30
|
Manohar M, Verma AK, Venkateshaiah SU, Sanders NL, Mishra A. Pathogenic mechanisms of pancreatitis. World J Gastrointest Pharmacol Ther 2017; 8:10-25. [PMID: 28217371 PMCID: PMC5292603 DOI: 10.4292/wjgpt.v8.i1.10] [Citation(s) in RCA: 168] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 07/23/2016] [Accepted: 08/16/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatitis is inflammation of pancreas and caused by a number of factors including pancreatic duct obstruction, alcoholism, and mutation in the cationic trypsinogen gene. Pancreatitis is represented as acute pancreatitis with acute inflammatory responses and; chronic pancreatitis characterized by marked stroma formation with a high number of infiltrating granulocytes (such as neutrophils, eosinophils), monocytes, macrophages and pancreatic stellate cells (PSCs). These inflammatory cells are known to play a central role in initiating and promoting inflammation including pancreatic fibrosis, i.e., a major risk factor for pancreatic cancer. A number of inflammatory cytokines are known to involve in promoting pancreatic pathogenesis that lead pancreatic fibrosis. Pancreatic fibrosis is a dynamic phenomenon that requires an intricate network of several autocrine and paracrine signaling pathways. In this review, we have provided the details of various cytokines and molecular mechanistic pathways (i.e., Transforming growth factor-β/SMAD, mitogen-activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) that have a critical role in the activation of PSCs to promote chronic pancreatitis and trigger the phenomenon of pancreatic fibrogenesis. In this review of literature, we discuss the involvement of several pro-inflammatory and anti-inflammatory cytokines, such as in interleukin (IL)-1, IL-1β, IL-6, IL-8 IL-10, IL-18, IL-33 and tumor necrosis factor-α, in the pathogenesis of disease. Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. Additionally, we provided several intermediary molecules that are involved in major signaling pathways that might provide target molecules for future therapeutic treatment strategies for pancreatic pathogenesis.
Collapse
|
|
31
|
The common dietary flavonoid myricetin attenuates liver fibrosis in carbon tetrachloride treated mice. Mol Nutr Food Res 2017; 61. [DOI: 10.1002/mnfr.201600392] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 12/09/2016] [Accepted: 12/12/2016] [Indexed: 01/18/2023]
|
|
32
|
Bynigeri RR, Jakkampudi A, Jangala R, Subramanyam C, Sasikala M, Rao GV, Reddy DN, Talukdar R. Pancreatic stellate cell: Pandora's box for pancreatic disease biology. World J Gastroenterol 2017; 23:382-405. [PMID: 28210075 PMCID: PMC5291844 DOI: 10.3748/wjg.v23.i3.382] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 11/09/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic stellate cells (PSCs) were identified in the early 1980s, but received much attention after 1998 when the methods to isolate and culture them from murine and human sources were developed. PSCs contribute to a small proportion of all pancreatic cells under physiological condition, but are essential for maintaining the normal pancreatic architecture. Quiescent PSCs are characterized by the presence of vitamin A laden lipid droplets. Upon PSC activation, these perinuclear lipid droplets disappear from the cytosol, attain a myofibroblast like phenotype and expresses the activation marker, alpha smooth muscle actin. PSCs maintain their activated phenotype via an autocrine loop involving different cytokines and contribute to progressive fibrosis in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Several pathways (e.g., JAK-STAT, Smad, Wnt signaling, Hedgehog etc.), transcription factors and miRNAs have been implicated in the inflammatory and profibrogenic function of PSCs. The role of PSCs goes much beyond fibrosis/desmoplasia in PDAC. It is now shown that PSCs are involved in significant crosstalk between the pancreatic cancer cells and the cancer stroma. These interactions result in tumour progression, metastasis, tumour hypoxia, immune evasion and drug resistance. This is the rationale for therapeutic preclinical and clinical trials that have targeted PSCs and the cancer stroma.
Collapse
|
|
33
|
Pothula SP, Xu Z, Goldstein D, Pirola RC, Wilson JS, Apte MV. Key role of pancreatic stellate cells in pancreatic cancer. Cancer Lett 2016; 381:194-200. [PMID: 26571462 DOI: 10.1016/j.canlet.2015.10.035] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 10/29/2015] [Accepted: 10/29/2015] [Indexed: 02/07/2023]
Abstract
Pancreatic stellate cells (PSCs) are responsible for producing the collagenous stroma in pancreatic cancer. Findings from the majority of in vitro and in vivo studies to date indicate that PSCs interact with cancer cells as well as with other cellular elements in the stroma including immune cells, endothelial cells and neuronal cells to set up a growth permissive microenvironment for pancreatic tumours. However, two recent studies reporting a protective effect of myofibroblasts in pancreatic cancer have served to remind researchers of the possibility that the role of PSCs in this disease may be context and time-dependent, such that any possible early protective role of PSCs is subverted in later stages by the ability of cancer cells to turn PSCs into cancer-promoting aides. This concept is supported by the development in recent years of several novel therapeutic approaches targeting the stroma that have been successfully applied in pre-clinical settings to inhibit disease progression. A multi-pronged approach aimed at tumour cells as well as stromal elements may be the key to achieving better clinical outcomes in patients with pancreatic cancer.
Collapse
Affiliation(s)
- Srinivasa P Pothula
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
| | - Zhihong Xu
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
| | - David Goldstein
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia
| | - Romano C Pirola
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
| | - Jeremy S Wilson
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
| | - Minoti V Apte
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, Australia; Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia.
| |
Collapse
|
|
34
|
Xu W, Li W, Wang Y, Zha M, Yao H, Jones PM, Sun Z. Regenerating islet-derived protein 1 inhibits the activation of islet stellate cells isolated from diabetic mice. Oncotarget 2015; 6:37054-65. [PMID: 26496027 PMCID: PMC4741915 DOI: 10.18632/oncotarget.6163] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 10/04/2015] [Indexed: 01/11/2023] Open
Abstract
Emerging evidence indicates that the islet fibrosis is attributable to activation of islet stellate cells (ISCs). In the present study, we compared the differences in biological activity of ISCs isolated from diabetic db/db and non-diabetic db/m mice, and the effects of the regenerating islet-derived protein 1 (Reg1) on ISC function. We showed that ISCs isolated from db/db mice were activated more rapidly than those from db/m mice during culture. Both Reg1 and its putative receptor exostosin-like glycosyltransferase 3 (EXTL3) were highly expressed by diabetic ISCs. Treatment with Reg1 inhibited migration, viability, and synthesis and secretion of Type I Collagen(Col-I), Type III Collagen(Col-III) and Fibronectin(FN) by diabetic ISCs, and this was associated with deactivation of the PI3K/Akt, MAPK/Erk1/2 signaling pathway in an EXTL3-dependent manner. In conclusion, our observations (i) confirmed the presence of fibrogenic stellate cells within pancreatic islets, which are prone to be activated in Type 2 diabetes, and (ii) revealed a potential role for Reg1 in preventing ISC activation.
Collapse
Affiliation(s)
- Wei Xu
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, China
| | - Wei Li
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, China
| | - Ying Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, China
| | - Min Zha
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, China
| | - Honghong Yao
- Department of Pharmacology, Medical School of Southeast University, Nanjing, China
| | - Peter M. Jones
- Diabetes Research Group, Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Zilin Sun
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing, China
| |
Collapse
|
|
35
|
Chen K, Rong YM, Cao WL, Zong LF, Ji RL. Effect of oxymatrine on expression of molecules of Smad signal pathway in pancreatic stellate cells stimulated with TGF-β1. Shijie Huaren Xiaohua Zazhi 2015; 23:1883-1889. [DOI: 10.11569/wcjd.v23.i12.1883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of oxymatrine (OM) on the expression of molecules of the Smad signal pathway in pancreatic stellate cell line (LTC-14 cells) stimulated with transforming growth factor-β1 (TGF-β1).
METHODS: LTC-14 cells were divided into a normal control group, a TGF-β1 stimulated group and a TGF-β1 + OM (1 mg/mL) group. The mRNA and protein were extracted from LTC-14 cells 12 h after treatment. The mRNA and protein expression of Smad2/3/4/7 was detected by real-time PCR and Western blot, respectively.
RESULTS: Compared with the TGF-β1 stimulated group, the mRNA and protein expression of Smad2/3/4 was dramatically reduced in the OM treated group (P < 0.05). Compared with the TGF-β1 stimulated group, the mRNA expression of Smad7 was significantly decreased in the OM treated group (P < 0.05), whereas the Smad7 protein expression was increased.
CONCLUSION: OM might exert a therapeutic effect against pancreatic fibrosis in pancreatic stellate cells stimulated with TGF-β1 by interfering with the mRNA and protein expression of molecules of the TGF-β1/Smad pathway.
Collapse
|
|
36
|
Apte MV, Pirola RC, Wilson JS. Pancreatic Stellate Cells. STELLATE CELLS IN HEALTH AND DISEASE 2015:271-306. [DOI: 10.1016/b978-0-12-800134-9.00016-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
37
|
Neuzillet C, de Gramont A, Tijeras-Raballand A, de Mestier L, Cros J, Faivre S, Raymond E. Perspectives of TGF-β inhibition in pancreatic and hepatocellular carcinomas. Oncotarget 2014; 5:78-94. [PMID: 24393789 PMCID: PMC3960190 DOI: 10.18632/oncotarget.1569] [Citation(s) in RCA: 117] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Advanced pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are non-curable diseases with a particularly poor prognosis. Over the last decade, research has increasingly focused on the microenvironment surrounding cancer cells, and its role in tumour development and progression. PDAC and HCC differ markedly regarding their pathological features: PDAC are typically stromal-predominant, desmoplastic, poorly vascularized tumours, whereas HCC are cellular and highly vascularized. Despite these very different settings, PDAC and HCC share transforming growth factor-β (TGF-β) as a common key-signalling mediator, involved in epithelial-to-mesenchymal transition, invasion, and stroma-tumour dialogue. Recently, novel drugs blocking the TGF-β pathway have entered clinical evaluation demonstrating activity in patients with advanced PDAC and HCC. TGF-β signalling is complex and mediates both pro- and anti-tumoural activities in cancer cells depending on their context, in space and time, and their microenvironment. In this review we provide a comprehensive overview of the role of the TGF-β pathway and its deregulation in PDAC and HCC development and progression at the cellular and microenvironment levels. We also summarize key preclinical and clinical data on the role of TGF-β as a target for therapeutic intervention in PDAC and HCC, and explore perspectives to optimize TGF-β inhibition therapy.
Collapse
Affiliation(s)
- Cindy Neuzillet
- INSERM U728 and U773 and Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, Clichy, France
| | | | | | | | | | | | | |
Collapse
|
|
38
|
Masamune A, Nakano E, Hamada S, Takikawa T, Yoshida N, Shimosegawa T. Alteration of the microRNA expression profile during the activation of pancreatic stellate cells. Scand J Gastroenterol 2014; 49:323-31. [PMID: 24404812 DOI: 10.3109/00365521.2013.876447] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE. Pancreatic stellate cells (PSCs) play a pivotal role in the pancreatic fibrosis associated with chronic pancreatitis and pancreatic cancer. In response to pancreatic injury or inflammation, PSCs are activated to myofibroblast-like cells. MicroRNA (miRNA) is a small RNA, consisting of 17-25 nucleotides, which targets 3'-untranslated region sequences of mRNA. miRNAs regulate a variety of cell functions such as cell proliferation, differentiation, and carcinogenesis. We examined here whether the miRNA expression profiles are altered during the activation of PSCs. MATERIALS AND METHODS. Rat PSCs were isolated from the pancreas tissue of male Wistar rats. PSCs were activated in vitro by culture in serum-containing medium. miRNAs were prepared from quiescent (day 1) PSCs and culture-activated (day 14) PSCs. Agilent's miRNA microarray containing probes for 680 miRNAs was used to identify differentially expressed miRNAs. Ingenuity Pathway Analysis (IPA) was used for the integrated analysis of altered miRNAs. RESULTS. Upon activation, 42 miRNAs were upregulated (>2.0-fold) and 42 miRNAs were downregulated (<0.5-fold). Upregulated miRNAs included miR-31, miR-143, and miR-221. Downregulated miRNAs included miR-126, miR-146a, and miR-150. IPA revealed the most impacted biological processes including cellular development, cellular growth, and cell movement. Interestingly, IPA identified 22 miRNAs affected both in pancreatic cancer and PSC activation. The top network generated by IPA revealed the interactions of altered miRNAs with signaling pathways such as p38 mitogen-activated protein kinase, extracellular-signal-regulated kinase, and Smad2/3. CONCLUSIONS. Our results suggest a novel role of miRNAs in the activation of PSCs.
Collapse
Affiliation(s)
- Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine , Sendai , Japan
| | | | | | | | | | | |
Collapse
|
|
39
|
Gao X, Cao Y, Staloch DA, Gonzales MA, Aronson JF, Chao C, Hellmich MR, Ko TC. Bone morphogenetic protein signaling protects against cerulein-induced pancreatic fibrosis. PLoS One 2014; 9:e89114. [PMID: 24586530 PMCID: PMC3931685 DOI: 10.1371/journal.pone.0089114] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Accepted: 01/15/2014] [Indexed: 01/27/2023] Open
Abstract
Bone morphogenetic proteins (BMPs) have an anti-fibrogenic function in the kidney, lung, and liver. However, their role in chronic pancreatitis (CP) is unknown. The aim of this study was to define the anti-fibrogenic role of BMP signaling in the pancreas in vivo under CP induction. Mice with a deletion of BMP type II receptor (BMPR2+/−) were used in this study in comparison with wild-type mice. CP was induced by repetitive cerulein injection intraperitoneally for 4 weeks, and the severity of CP was evaluated. Pancreatic stellate cells (PSCs) were isolated from the mice and treated with BMP2 and TGF-β in vitro, and extracellular matrix protein (ECM) production was measured. Smad and mitogen-activated protein kinase (MAPK) signaling was also evaluated. BMPR2+/− mice revealed a greater pancreatic fibrosis, PSC activation and leukocyte infiltration after CP induction compared to wild-type mice (P<0.05). Under CP induction, phospho (p)Smad1/5/8 was elevated in wild-type mice and this effect was abolished in BMPR2+/− mice; pSmad2 and pp38MAPK were further enhanced in BMPR2+/− mice compared to wild-type mice (P<0.05). In vitro, BMP2 inhibited TGF-β-induced ECM protein fibronectin production in wild-type PSCs; this effect was abolished in BMPR2+/− PSCs (P<0.05). In BMPR2+/− PSCs, pSmad1/5/8 level was barely detectable upon BMP2 stimulation, while pSmad2 level was further enhanced by TGF-β stimulation, compared to wild-type PSCs (P<0.05). BMPR2/Smad1/5/8 signaling plays a protective role against cerulein-induced pancreatic fibrosis by inhibiting Smad2 and p38MAPK signaling pathways.
Collapse
Affiliation(s)
- Xuxia Gao
- Department of Surgery, The University of Texas Health Science Center-Houston, Houston, Texas, United States of America
| | - Yanna Cao
- Department of Surgery, The University of Texas Health Science Center-Houston, Houston, Texas, United States of America
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Dustin A. Staloch
- Department of Surgery, The University of Texas Health Science Center-Houston, Houston, Texas, United States of America
| | - Michael A. Gonzales
- Department of Surgery, The University of Texas Health Science Center-Houston, Houston, Texas, United States of America
| | - Judith F. Aronson
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Celia Chao
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Mark R. Hellmich
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Tien C. Ko
- Department of Surgery, The University of Texas Health Science Center-Houston, Houston, Texas, United States of America
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America
- * E-mail:
| |
Collapse
|
|
40
|
Yamada Y, Mashima H, Sakai T, Matsuhashi T, Jin M, Ohnishi H. Functional roles of TGF-β1 in intestinal epithelial cells through Smad-dependent and non-Smad pathways. Dig Dis Sci 2013; 58:1207-17. [PMID: 23306843 DOI: 10.1007/s10620-012-2515-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 12/03/2012] [Indexed: 01/21/2023]
Abstract
BACKGROUND AND AIMS Transforming growth factor-β1 (TGF-β1) is one of the growth factors expressed in the gut, and has been shown to play an important role in intestinal mucosal healing. We investigated the effects of TGF-β1 on the cellular functions of intestinal epithelial cells, and also evaluated its signaling pathways in these cells. METHODS We used the rat IEC-6 intestinal epithelial cell line for these studies. The expression of TGF-β1/Smad signaling molecules was examined. We evaluated the effect of TGF-β1 on the proliferation and differentiation by the BrdU incorporation assay and real-time PCR. We manipulated the expression levels of Smad2 and Smad3 using an adenovirus system and small interfering RNA to examine the signaling pathways. The expression of Smad2 and Smad3 along the crypt-villus axis was also examined in the murine intestine. RESULTS IEC-6 cells produced TGF-β1 and expressed functional TGF-β/Smad signaling molecules. The addition of TGF-β1 in the culture medium suppressed the proliferation and increased the expression of a differentiation marker of enterocytes, in a dose-dependent manner. The adenovirus-mediated and small interfering RNA-mediated studies clearly showed that the growth inhibitory effect and the promotion of differentiation were exerted through a Smad3-dependent and a Smad2-dependent pathway, respectively. IEC-6 cells exhibited upregulated expression of an inhibitory Smad (Smad7) as a form of negative feedback via a non-Smad pathway. Smad2 was predominantly expressed in villi, and Smad3 in crypts. CONCLUSIONS TGF-β1 regulates the cellular functions of intestinal epithelial cells through both Smad-dependent and non-Smad pathways.
Collapse
Affiliation(s)
- Yumi Yamada
- Department of Gastroenterology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | | | | | | | | | | |
Collapse
|
|
41
|
Understanding the functions of tumor stroma in resistance to ionizing radiation: Emerging targets for pharmacological modulation. Drug Resist Updat 2013; 16:10-21. [DOI: 10.1016/j.drup.2013.01.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Accepted: 01/14/2013] [Indexed: 02/08/2023]
|
|
42
|
Hindriksen S, Bijlsma MF. Cancer Stem Cells, EMT, and Developmental Pathway Activation in Pancreatic Tumors. Cancers (Basel) 2012; 4:989-1035. [PMID: 24213498 PMCID: PMC3712732 DOI: 10.3390/cancers4040989] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Revised: 10/02/2012] [Accepted: 10/09/2012] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer is a disease with remarkably poor patient survival rates. The frequent presence of metastases and profound chemoresistance pose a severe problem for the treatment of these tumors. Moreover, cross-talk between the tumor and the local micro-environment contributes to tumorigenicity, metastasis and chemoresistance. Compared to bulk tumor cells, cancer stem cells (CSC) have reduced sensitivity to chemotherapy. CSC are tumor cells with stem-like features that possess the ability to self-renew, but can also give rise to more differentiated progeny. CSC can be identified based on increased in vitro spheroid- or colony formation, enhanced in vivo tumor initiating potential, or expression of cell surface markers. Since CSC are thought to be required for the maintenance of a tumor cell population, these cells could possibly serve as a therapeutic target. There appears to be a causal relationship between CSC and epithelial-to-mesenchymal transition (EMT) in pancreatic tumors. The occurrence of EMT in pancreatic cancer cells is often accompanied by re-activation of developmental pathways, such as the Hedgehog, WNT, NOTCH, and Nodal/Activin pathways. Therapeutics based on CSC markers, EMT, developmental pathways, or tumor micro-environment could potentially be used to target pancreatic CSC. This may lead to a reduction of tumor growth, metastatic events, and chemoresistance in pancreatic cancer.
Collapse
Affiliation(s)
- Sanne Hindriksen
- Laboratory for Experimental Oncology and Radiobiology, Academic Medical Centre, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | | |
Collapse
|
|
43
|
Apte MV, Pirola RC, Wilson JS. Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol 2012; 3:344. [PMID: 22973234 PMCID: PMC3428781 DOI: 10.3389/fphys.2012.00344] [Citation(s) in RCA: 243] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Accepted: 08/09/2012] [Indexed: 12/12/2022] Open
Abstract
While the morphology and function of cells of the exocrine and endocrine pancreas have been studied over several centuries, one important cell type in the gland, the pancreatic stellate cell (PSC), had remained undiscovered until as recently as 20 years ago. Even after its first description in 1982, it was to be another 16 years before its biology could begin to be studied, because it was only in 1998 that methods were developed to isolate and culture PSCs from rodent and human pancreas. PSCs are now known to play a critical role in pancreatic fibrosis, a consistent histological feature of two major diseases of the pancreas-chronic pancreatitis and pancreatic cancer. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM) proteins. Recent studies have also implied other functions for PSCs as progenitor cells, immune cells or intermediaries in exocrine pancreatic secretion in humans. During pancreatic injury, PSCs transform from their quiescent phase into an activated, myofibroblast-like phenotype that secretes excessive amounts of ECM proteins leading to the fibrosis of chronic pancreatitis and pancreatic cancer. An ever increasing number of factors that stimulate and/or inhibit PSC activation via paracrine and autocrine pathways are being identified and characterized. It is also now established that PSCs interact closely with pancreatic cancer cells to facilitate cancer progression. Based on these findings, several therapeutic strategies have been examined in experimental models of chronic pancreatitis as well as pancreatic cancer, in a bid to inhibit/retard PSC activation and thereby alleviate chronic pancreatitis or reduce tumor growth in pancreatic cancer. The challenge that remains is to translate these pre-clinical developments into clinically applicable treatments for patients with chronic pancreatitis and pancreatic cancer.
Collapse
Affiliation(s)
- Minoti V. Apte
- Pancreatic Research Group, Faculty of Medicine, South Western Sydney Clinical School, University of New South WalesSydney, NSW, Australia
| | | | | |
Collapse
|
|
44
|
Liu H, Ma Q, Xu Q, Lei J, Li X, Wang Z, Wu E. Therapeutic potential of perineural invasion, hypoxia and desmoplasia in pancreatic cancer. Curr Pharm Des 2012; 18:2395-403. [PMID: 22372500 DOI: 10.2174/13816128112092395] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 01/18/2012] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer is one of the most fatal human malignancies. Though a relatively rare malignancy, it remains one of the deadliest tumors, with an extremely high mortality rate. The prognosis of patients with pancreatic cancer remains poor; only patients with small tumors and complete resection have a chance of a complete cure. Pancreatic cancer responds poorly to conventional therapies, including chemotherapy and irradiation. Tumor-specific targeted therapy is a relatively recent addition to the arsenal of anti-cancer therapies. It is important to find novel targets to distinguish tumor cells from their normal counterparts in therapeutic approaches. In the past few decades, studies have revealed the molecular mechanisms of pancreatic tumorigenesis, growth, invasion and metastasis. The proteins that participate in the pathophysiological processes of pancreatic cancer might be potential targets for therapy. This review describes the main players in perineural invasion, hypoxia and desmoplasia and the molecular mechanisms of these pathophysiological processes.
Collapse
Affiliation(s)
- Han Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | | | | | | | | | | | | |
Collapse
|
|
45
|
Bilezikjian LM, Justice NJ, Blackler AN, Wiater E, Vale WW. Cell-type specific modulation of pituitary cells by activin, inhibin and follistatin. Mol Cell Endocrinol 2012; 359:43-52. [PMID: 22330643 PMCID: PMC3367026 DOI: 10.1016/j.mce.2012.01.025] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2011] [Revised: 01/26/2012] [Accepted: 01/30/2012] [Indexed: 01/01/2023]
Abstract
Activins are multifunctional proteins and members of the TGF-β superfamily. Activins are expressed locally in most tissues and, analogous to the actions of other members of this large family of pleiotropic factors, play prominent roles in the regulation of diverse biological processes in both differentiated and embryonic stem cells. They have an essential role in maintaining tissue homeostasis in the adult and are known to contribute to the developmental programs in the embryo. Activins are further implicated in the growth and metastasis of tumor cells. Through distinct modes of action, inhibins and follistatins function as antagonists of activin and several other TGF-β family members, including a subset of BMPs/GDFs, and modulate cellular responses and the signaling cascades downstream of these ligands. In the pituitary, the activin pathway is known to regulate key aspects of gonadotrope functions and also exert effects on other pituitary cell types. As in other tissues, activin is produced locally by pituitary cells and acts locally by exerting cell-type specific actions on gonadotropes. These local actions of activin on gonadotropes are modulated by the autocrine/paracrine actions of locally secreted follistatin and by the feedback actions of gonadal inhibin. Knowledge about the mechanism of activin, inhibin and follistatin actions is providing information about their importance for pituitary function as well as their contribution to the pathophysiology of pituitary adenomas. The aim of this review is to highlight recent findings and summarize the evidence that supports the important functions of activin, inhibin and follistatin in the pituitary.
Collapse
Affiliation(s)
- Louise M Bilezikjian
- Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
| | | | | | | | | |
Collapse
|
|
46
|
Lee BJ, Lee HS, Kim CD, Jung SW, Seo YS, Kim YS, Jeen YT, Chun HJ, Um SH, Lee SW, Choi JH, Ryu HS. The Effects of Combined Treatment with an HMG-CoA Reductase Inhibitor and PPARγ Agonist on the Activation of Rat Pancreatic Stellate Cells. Gut Liver 2012; 6:262-9. [PMID: 22570758 PMCID: PMC3343167 DOI: 10.5009/gnl.2012.6.2.262] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Revised: 09/15/2011] [Accepted: 10/13/2011] [Indexed: 12/13/2022] Open
Abstract
Background/Aims Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) and peroxisome proliferator-activated receptor gamma (PPARγ) ligands can modulate cellular differentiation, proliferation, and apoptosis through various pathways. It has been shown that HMG-CoA reductase inhibitors and PPARγ agonists separately inhibit pancreatic stellate cell (PaSC) activation. We studied the effects of a combination of both types of drugs on activated PaSCs via platelet-derived growth factor (PDGF), which has not previously been reported. The present study was performed to elucidate the underlying mechanisms of these effects by focusing on the impact of the signaling associated with cell-cycle progression. Methods Primary cultures of rat PaSCs were exposed to simvastatin and troglitazone. Proliferation was quantified using the BrdU method, and cell-cycle analysis was performed using a fluorescent activated cell sorter. The protein expression levels of smooth muscle actin (SMA), extracellular signal-regulated kinase (ERK), and a cell cycle machinery protein (p27Kip1) were investigated using Western blot analysis. Results Simvastatin reversed the effects of PDGF on cell proliferation in a dose-dependent manner. The combination of a low concentration of simvastatin (1 mM) and troglitazone (10 mM) synergistically reversed the effects of PDGF on cell proliferation but had no effect on cell viability. The expression of a-SMA was markedly attenuated by combining the two drugs, which blocked the cell cycle beyond the G0/G1 phase by reducing the levels of phosphorylated ERK and reversed the expression of p27Kip1 interrupted by PDGF. Conclusions Simvastatin and troglitazone synergistically inhibited cell proliferation in activated PaSCs by blocking the cell cycle beyond the G0/G1 phase. This inhibition was due to the synergistic modulation of the ERK pathway and the cell cycle machinery protein p27Kip1.
Collapse
Affiliation(s)
- Beom Jae Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Stroma and pancreatic ductal adenocarcinoma: an interaction loop. Biochim Biophys Acta Rev Cancer 2012; 1826:170-8. [PMID: 22521638 DOI: 10.1016/j.bbcan.2012.04.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Revised: 04/06/2012] [Accepted: 04/08/2012] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDA) has two exceptional features. First, it is a highly lethal disease, with a median survival of less than 6 months and a 5-year survival rate less than 5%. Second, PDA tumor cells are surrounded by an extensive stroma, which accounts for up to 90% of the tumor volume. It is well recognized that stromal microenvironment can accelerate malignant transformation, tumor growth and progression. More importantly, the interaction loop between PDA and its stroma greatly contributes to tumor growth and progression. We propose that the extensive stroma of PDA is closely linked to its poor prognosis. An improved understanding of the mechanisms that contribute to pancreatic tumor growth and progression is therefore urgently needed. Targeting the stroma may thus provide novel prevention, earlier detection and therapeutic options to this deadly malignancy. Accordingly, in this review, we will summarize the mechanism of PDA stroma formation, the role of the stroma in tumor progression and therapy resistance and the potential of stroma-targeted therapeutics strategies.
Collapse
|
|
48
|
Apte M, Pirola R, Wilson J. The fibrosis of chronic pancreatitis: new insights into the role of pancreatic stellate cells. Antioxid Redox Signal 2011; 15:2711-2722. [PMID: 21728885 DOI: 10.1089/ars.2011.4079] [Citation(s) in RCA: 104] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
SIGNIFICANCE Prominent fibrosis is a major histological feature of chronic pancreatitis, a progressive necroinflammatory condition of the pancreas, most commonly associated with alcohol abuse. Patients with this disease often develop exocrine and endocrine insufficiency characterized by maldigestion and diabetes. Up until just over a decade ago, there was little understanding of the pathogenesis of pancreatic fibrosis in chronic pancreatitis. RECENT ADVANCES In recent times, significant progress has been made in this area, mostly due to the identification, isolation, and characterization of the cells, namely pancreatic stellate cells (PSCs) that are now established as key players in pancreatic fibrogenesis. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM) proteins. During pancreatic injury, PSCs transform into an activated phenotype that secretes excessive amounts of the ECM proteins that comprise fibrous tissue. CRITICAL ISSUES This Review summarizes current knowledge and critical aspects of PSC biology which have been increasingly well characterized over the past few years, particularly with respect to the response of PSCs to factors that stimulate or inhibit their activation and the intracellular signaling pathways governing these processes. Based on this knowledge, several therapeutic strategies have been examined in experimental models of pancreatic fibrosis, demonstrating that pancreatic fibrosis is a potentially reversible condition, at least in early stages. FUTURE DIRECTIONS These will involve translation of the laboratory findings into effective clinical approaches to prevent/inhibit PSC activation so as to prevent, retard, or reverse the fibrotic process in pancreatitis.
Collapse
Affiliation(s)
- Minoti Apte
- Pancreatic Research Group, South Western Sydney Clinical School, University of New South Wales, Sydney, Australia
| | | | | |
Collapse
|
|
49
|
Won JH, Zhang Y, Ji B, Logsdon CD, Yule DI. Phenotypic changes in mouse pancreatic stellate cell Ca2+ signaling events following activation in culture and in a disease model of pancreatitis. Mol Biol Cell 2011; 22:421-36. [PMID: 21148289 PMCID: PMC3031471 DOI: 10.1091/mbc.e10-10-0807] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The specific characteristics of intracellular Ca 2+ signaling and the downstream consequences of these events were investigated in mouse pancreatic stellate cells (PSC) in culture and in situ using multiphoton microscopy in pancreatic lobules. PSC undergo a phenotypic transformation from a quiescent state to a myofibroblast-like phenotype in culture. This is believed to parallel the induction of an activated state observed in pancreatic disease such as chronic pancreatitis and pancreatic cancer. By day 7 in culture, the complement of cell surface receptors coupled to intracellular Ca 2+ signaling was shown to be markedly altered. Specifically, protease-activated receptors (PAR) 1 and 2, responsive to thrombin and trypsin, respectively, and platelet-derived growth factor (PDGF) receptors were expressed only in activated PSC (aPSC). PAR-1, ATP, and PDGF receptor activation resulted in prominent nuclear Ca 2+ signals. Nuclear Ca 2+ signals and aPSC proliferation were abolished by expression of parvalbumin targeted to the nucleus. In pancreatic lobules, PSC responded to agonists consistent with the presence of only quiescent PSC. aPSC were observed following induction of experimental pancreatitis. In contrast, in a mouse model of pancreatic disease harboring elevated K-Ras activity in acinar cells, aPSC were present under control conditions and their number greatly increased following induction of pancreatitis. These data are consistent with nuclear Ca 2+ signaling generated by agents such as trypsin and thrombin, likely present in the pancreas in disease states, resulting in proliferation of "primed" aPSC to contribute to the severity of pancreatic disease.
Collapse
Affiliation(s)
- Jong Hak Won
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | | | | | | | | |
Collapse
|
|
50
|
Bilezikjian LM, Vale WW. The Local Control of the Pituitary by Activin Signaling and Modulation. OPEN NEUROENDOCRINOLOGY JOURNAL (ONLINE) 2011; 4:90-101. [PMID: 21927629 PMCID: PMC3173763 DOI: 10.2174/1876528901104010090] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The pituitary gland plays a prominent role in the control of many physiological processes. This control is achieved through the actions and interactions of hormones and growth factors that are produced and secreted by the endocrine cell types and the non-endocrine constituents that collectively and functionally define this complex organ. The five endocrine cell types of the anterior lobe of the pituitary, somatotropes, lactotropes, corticotropes, thyrotropes and gonadotropes, are defined by their primary product, growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH) and follicle stimulating hormone (FSH)/luteinizing hormone (LH). They are further distinguishable by the presence of cell surface receptors that display high affinity and selectivity for specific hypothalamic hormones and couple to appropriate downstream signaling pathways involved in the control of cell type specific responses, including the release and/or synthesis of pituitary hormones. Central control of the pituitary via the hypothalamus is further fine-tuned by the positive or negative actions of peripheral feedback signals and of a variety of factors that originate from sources within the pituitary. The focus of this review is the latter category of intrinsic factors that exert local control. Special emphasis is given to the TGF-β family of growth factors, in particular activin effects on the gonadotrope population, because a considerable body of evidence supports their contribution to the local modulation of the embryonic and postnatal pituitary as well as pituitary pathogenesis. A number of other substances, including members of the cytokine and FGF families, VEGF, IGF1, PACAP, Ghrelin, adenosine and nitric oxide have also been shown or implicated to function as autocrine/paracrine factors, though, definitive proof remains lacking in some cases. The ever-growing list of putative autocrine/paracrine factors of the pituitary nevertheless has highlighted the complexity of the local network and its impact on pituitary functions.
Collapse
Affiliation(s)
- Louise M Bilezikjian
- Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California, USA
| | | |
Collapse
|