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Schleinhege R, Neumann I, Oeckinghaus A, Schwab A, Pethő Z. A CNA-35-based high-throughput fibrosis assay reveals ORAI1 as a regulator of collagen release from pancreatic stellate cells. Matrix Biol 2025; 135:70-86. [PMID: 39662708 DOI: 10.1016/j.matbio.2024.12.004] [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: 07/03/2024] [Revised: 11/22/2024] [Accepted: 12/08/2024] [Indexed: 12/13/2024]
Abstract
RATIONALE Pancreatic stellate cells (PSCs) produce a collagen-rich connective tissue in chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Ca2+-permeable ion channels such as ORAI1 are known to affect PSC proliferation and myofibroblastic phenotype. However, it is unknown whether these channels play a role in collagen secretion. METHODS Using the PSC cell line PS-1, we characterized their cell-derived matrices using staining, mass spectroscopy, and cell migration assays. We developed and validated a high-throughput in vitro fibrosis assay to rapidly determine collagen quantity either with Sirius Red or, in the optimized version, with the collagen-binding peptide CNA-35-tdTomato. We assessed collagen deposition upon stimulating cells with transforming growth factor β1 (TGF-β1) and/or vitamin C without or with ORAI1 modulation. Orai1 expression was assessed by immunohistochemistry in the fibrotic tumor tissue of a murine PDAC model (KPfC). RESULTS We found that TGF-β1 and vitamin C promote collagen deposition from PSCs. We used small interfering RNA (siRNA) and the inhibitor Synta-66 to demonstrate that ORAI1 regulates collagen secretion of PSCs but not NIH-3T3 fibroblasts. Physiological levels of vitamin C induce a drastic increase of the intracellular [Ca2+] in PSCs, with Synta-66 inhibiting Ca2+ influx. Lastly, we revealed Orai1 expression in cancer-associated fibroblasts (CAFs) in murine PDAC (KPfC) samples. CONCLUSION In conclusion, our study introduces a robust in vitro assay for fibrosis and identifies ORAI1 as being engaged in PSC-driven fibrosis.
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Affiliation(s)
- Rieke Schleinhege
- Institute of Physiology II, University of Münster, Robert-Koch Str. 27B, 48149, Germany
| | - Ilka Neumann
- Institute of Physiology II, University of Münster, Robert-Koch Str. 27B, 48149, Germany
| | - Andrea Oeckinghaus
- Institute of Molecular Tumor Biology, University of Münster, 48149, Germany
| | - Albrecht Schwab
- Institute of Physiology II, University of Münster, Robert-Koch Str. 27B, 48149, Germany
| | - Zoltán Pethő
- Institute of Physiology II, University of Münster, Robert-Koch Str. 27B, 48149, Germany.
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Wang H, Qi L, Han H, Li X, Han M, Xing L, Li L, Jiang H. Nanomedicine regulating PSC-mediated intercellular crosstalk: Mechanisms and therapeutic strategies. Acta Pharm Sin B 2024; 14:4756-4775. [PMID: 39664424 PMCID: PMC11628839 DOI: 10.1016/j.apsb.2024.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/15/2024] [Accepted: 06/04/2024] [Indexed: 12/13/2024] Open
Abstract
Pancreatic fibrosis (PF) is primarily distinguished by the stimulation of pancreatic stellate cells (PSCs) and excessive extracellular matrix deposition, which is the main barrier impeding drug delivery and distribution. Recently, nanomedicine, with efficient, targeted, and controllable drug release characteristics, has demonstrated enormous advantages in the regression of pancreas fibrotic diseases. Notably, paracrine signals from parenchymal and immune cells such as pancreatic acinar cells, islet cells, pancreatic cancer cells, and immune cells can directly or indirectly modulate PSC differentiation and activation. The intercellular crosstalk between PSCs and these cells has been a critical event involved in fibrogenesis. However, the connections between PSCs and other pancreatic cells during the progression of diseases have yet to be discussed. Herein, we summarize intercellular crosstalk in the activation of PSCs and its contribution to the development of common pancreatic diseases, including pancreatitis, pancreatic cancer, and diabetes. Then, we also examine the latest treatment strategies of nanomedicine and potential targets for PSCs crosstalk in fibrosis, thereby offering innovative insights for the design of antifibrotic nanomedicine. Ultimately, the enhanced understanding of PF will facilitate the development of more precise intervention strategies and foster individually tailored therapeutic approaches for pancreatic diseases.
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Affiliation(s)
- Hui Wang
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Liang Qi
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Han Han
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Xuena Li
- College of Pharmacy, Yanbian University, Yanji 133000, China
| | - Mengmeng Han
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Lei Xing
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
- Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing 210009, China
- Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Hulin Jiang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- College of Pharmacy, Yanbian University, Yanji 133000, China
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China
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Doctor A, Laube M, Meister S, Kiss OC, Kopka K, Hauser S, Pietzsch J. Combined PET Radiotracer Approach Reveals Insights into Stromal Cell-Induced Metabolic Changes in Pancreatic Cancer In Vitro and In Vivo. Cancers (Basel) 2024; 16:3393. [PMID: 39410013 PMCID: PMC11475921 DOI: 10.3390/cancers16193393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/25/2024] [Accepted: 09/29/2024] [Indexed: 10/20/2024] Open
Abstract
Background/Objective Pancreatic stellate cells (PSCs) in pancreatic adenocarcinoma (PDAC) are producing extracellular matrix, which promotes the formation of a dense fibrotic microenvironment. This makes PDAC a highly heterogeneous tumor-stroma-driven entity, associated with reduced perfusion, limited oxygen supply, high interstitial fluid pressure, and limited bioavailability of therapeutic agents. Methods In this study, spheroid and tumor xenograft models of human PSCs and PanC-1 cells were characterized radiopharmacologically using a combined positron emission tomography (PET) radiotracer approach. [18F]FDG, [18F]FMISO, and [18F]FAPI-74 were employed to monitor metabolic activity, hypoxic metabolic state, and functional expression of fibroblast activation protein alpha (FAPα), a marker of activated PSCs. Results In vitro, PanC-1 and multi-cellular tumor spheroids demonstrated comparable glucose uptake and hypoxia, whereas FAPα expression was significantly higher in PSC spheroids. In vivo, glucose uptake as well as the transition to hypoxia were comparable in PanC-1 and multi-cellular xenograft models. In mice injected with PSCs, FAPα expression decreased over a period of four weeks post-injection, which was attributed to the successive death of PSCs. In contrast, FAPα expression increased in both PanC-1 and multi-cellular xenograft models over time due to invasion of mouse fibroblasts. Conclusion The presented models are suitable for subsequently characterizing stromal cell-induced metabolic changes in tumors using noninvasive molecular imaging techniques.
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Affiliation(s)
- Alina Doctor
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany; (A.D.); (M.L.); (S.M.); (K.K.); (S.H.)
- School of Science, Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, Mommsenstraße 4, 01069 Dresden, Germany
| | - Markus Laube
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany; (A.D.); (M.L.); (S.M.); (K.K.); (S.H.)
| | - Sebastian Meister
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany; (A.D.); (M.L.); (S.M.); (K.K.); (S.H.)
| | - Oliver C. Kiss
- Department of Targetry, Target Chemistry and Radiopharmacy, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany;
| | - Klaus Kopka
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany; (A.D.); (M.L.); (S.M.); (K.K.); (S.H.)
- School of Science, Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, Mommsenstraße 4, 01069 Dresden, Germany
- National Center for Tumor Diseases (NCT) Dresden, Partner Site Dresden, University Cancer Center (UCC), Fetscherstraße 74, 01307 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Sandra Hauser
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany; (A.D.); (M.L.); (S.M.); (K.K.); (S.H.)
| | - Jens Pietzsch
- Department of Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany; (A.D.); (M.L.); (S.M.); (K.K.); (S.H.)
- School of Science, Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, Mommsenstraße 4, 01069 Dresden, Germany
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Sultanova TR, Mukhlynina EA, Danilova IG. Morphofunctional Characteristics of Primary Culture of Rat Pancreatic Stellate Cells in the Dynamics of Short-Term Culture. CELL AND TISSUE BIOLOGY 2024; 18:528-534. [DOI: 10.1134/s1990519x24700494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 02/19/2024] [Accepted: 03/06/2024] [Indexed: 01/03/2025]
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Geister E, Ard D, Patel H, Findley A, DeSouza G, Martin L, Knox H, Gavara N, Lugea A, Sabbatini ME. The Role of Twist1 in Chronic Pancreatitis-Associated Pancreatic Stellate Cells. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:1879-1897. [PMID: 39032603 PMCID: PMC11423762 DOI: 10.1016/j.ajpath.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 06/18/2024] [Accepted: 06/28/2024] [Indexed: 07/23/2024]
Abstract
In healthy pancreas, pancreatic stellate cells (PaSCs) synthesize the basement membrane, which is mainly composed of type IV collagen and laminin. In chronic pancreatitis (CP), PaSCs are responsible for the production of a rigid extracellular matrix (ECM) that is mainly composed of fibronectin and type I/III collagen. Reactive oxygen species evoke the formation of the rigid ECM by PaSCs. One source of reactive oxygen species is NADPH oxidase (Nox) enzymes. Nox1 up-regulates the expression of Twist1 and matrix metalloproteinase-9 (MMP-9) in PaSCs from mice with CP. This study determined the functional relationship between Twist1 and MMP-9, and other PaSC-produced proteins, and the extent to which Twist1 regulates digestion of ECM proteins in CP. Twist1 induced the expression of MMP-9 in mouse PaSCs. The action of Twist1 was not selective to MMP-9 because Twist1 induced the expression of types I and IV collagen, fibronectin, transforming growth factor, and α-smooth muscle actin. Luciferase assay indicated that Twist1 in human primary PaSCs increased the expression of MMP-9 at the transcriptional level in an NF-κB dependent manner. The digestion of type I/III collagen by MMP-9 secreted by PaSCs from mice with CP depended on Twist1. Thus, Twist1 in PaSCs from mice with CP induced rigid ECM production and MMP-9 transcription in an NF-κB-dependent mechanism that selectively displayed proteolytic activity toward type I/III collagen.
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Affiliation(s)
- Emma Geister
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Dalton Ard
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Heer Patel
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Alyssa Findley
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Godfrey DeSouza
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Lyndsay Martin
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Henry Knox
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Natasha Gavara
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Aurelia Lugea
- Cedars-Sinai Medical Center, Los Angeles, California
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Zhou Z, Zhang L, Wei X, Wang A, Hu Y, Xiao M, Zheng Y. 1,25(OH) 2D 3 inhibits pancreatic stellate cells activation and promotes insulin secretion in T2DM. Endocrine 2024; 85:1193-1205. [PMID: 38656750 DOI: 10.1007/s12020-024-03833-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 04/11/2024] [Indexed: 04/26/2024]
Abstract
PURPOSE To evaluate the effect and mechanism of 1,25(OH)2D3 on pancreatic stellate cells (PSCs) in type 2 diabetes mellitus (T2DM). METHODS A mouse model of T2DM was successfully established by high-fat diet (HFD) /streptozotocin (STZ) and administered 1,25(OH)2D3 for 3 weeks. Fasting blood glucose (FBG), glycated hemoglobin A1c (GHbA1c), insulin (INS) and glucose tolerance were measured. Histopathology changes and fibrosis of pancreas were examined by hematoxylin and eosin staining and Masson staining. Mouse PSCs were extracted, co-cultured with mouse insulinoma β cells (MIN6 cells) and treated with 1,25(OH)2D3. ELISA detection of inflammatory factor expression. Tissue reactive oxygen species (ROS) levels were also measured. Immunofluorescence or Western blotting were used to measure fibrosis and inflammation-related protein expression. RESULTS PSCs activation and islets fibrosis in T2DM mice. Elevated blood glucose was accompanied by significant increases in serum inflammatory cytokines and tissue ROS levels. 1,25(OH)2D3 attenuated islet fibrosis by reducing hyperglycemia, ROS levels, and inflammatory factors expression. Additionally, the co-culture system confirmed that 1,25(OH)2D3 inhibited PSCs activation, reduced the secretion of pro-inflammatory cytokines, down-regulated the expression of fibrosis and inflammation-related proteins, and promoted insulin secretion. CONCLUSION Our findings identify that PSCs activation contributes to islet fibrosis and β-cell dysfunction. 1,25(OH)2D3 exerts beneficial effects on T2DM potentially by inhibiting PSCs activation and inflammatory response, highlighting promising control strategies of T2DM by vitamin D.
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Affiliation(s)
- Zhengyu Zhou
- Laboratory Animal Center of Suzhou Medical college, Soochow University, Suzhou, China.
| | - Lewen Zhang
- Laboratory Animal Center of Suzhou Medical college, Soochow University, Suzhou, China
| | - Xun Wei
- Center of Laboratory Animal, Shanghai Jiao Tong University, Shanghai, China
| | - Aiqing Wang
- Suzhou Medical college of Soochow University, Suzhou, China
| | - Yudie Hu
- Laboratory Animal Center of Suzhou Medical college, Soochow University, Suzhou, China
| | - Min Xiao
- Laboratory Animal Center of Suzhou Medical college, Soochow University, Suzhou, China
| | - Yuxuan Zheng
- Laboratory Animal Center of Suzhou Medical college, Soochow University, Suzhou, China
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Sgarminato V, Madrid-Wolff J, Boniface A, Ciardelli G, Tonda-Turo C, Moser C. 3D in vitromodeling of the exocrine pancreatic unit using tomographic volumetric bioprinting. Biofabrication 2024; 16:045034. [PMID: 39121863 DOI: 10.1088/1758-5090/ad6d8d] [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: 04/03/2024] [Accepted: 08/09/2024] [Indexed: 08/12/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, a leading cause of cancer-related deaths globally. Initial lesions of PDAC develop within the exocrine pancreas' functional units, with tumor progression driven by interactions between PDAC and stromal cells. Effective therapies require anatomically and functionally relevantin vitrohuman models of the pancreatic cancer microenvironment. We employed tomographic volumetric bioprinting, a novel biofabrication method, to create human fibroblast-laden constructs mimicking the tubuloacinar structures of the exocrine pancreas. Human pancreatic ductal epithelial (HPDE) cells overexpressing the KRAS oncogene (HPDE-KRAS) were seeded in the multiacinar cavity to replicate pathological tissue. HPDE cell growth and organization within the structure were assessed, demonstrating the formation of a thin epithelium covering the acini inner surfaces. Immunofluorescence assays showed significantly higher alpha smooth muscle actin (α-SMA) vs. F-actin expression in fibroblasts co-cultured with cancerous versus wild-type HPDE cells. Additionally,α-SMA expression increased over time and was higher in fibroblasts closer to HPDE cells. Elevated interleukin (IL)-6 levels were quantified in supernatants from co-cultures of stromal and HPDE-KRAS cells. These findings align with inflamed tumor-associated myofibroblast behavior, serving as relevant biomarkers to monitor early disease progression and target drug efficacy. To our knowledge, this is the first demonstration of a 3D bioprinted model of exocrine pancreas that recapitulates its true 3-dimensional microanatomy and shows tumor triggered inflammation.
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Affiliation(s)
- Viola Sgarminato
- Laboratory of Applied Photonics Devices, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
| | - Jorge Madrid-Wolff
- Laboratory of Applied Photonics Devices, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Antoine Boniface
- Laboratory of Applied Photonics Devices, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Gianluca Ciardelli
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
| | - Chiara Tonda-Turo
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
| | - Christophe Moser
- Laboratory of Applied Photonics Devices, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Zhao Y, Feng Y, Sun F, Li L, Chen J, Song Y, Zhu W, Hu X, Li Z, Kong F, Du Y, Kong X. Optimized rAAV8 targeting acinar KLF4 ameliorates fibrosis in chronic pancreatitis via exosomes-enriched let-7s suppressing pancreatic stellate cells activation. Mol Ther 2024; 32:2624-2640. [PMID: 38956871 PMCID: PMC11405174 DOI: 10.1016/j.ymthe.2024.06.030] [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: 11/28/2023] [Revised: 05/14/2024] [Accepted: 06/20/2024] [Indexed: 07/04/2024] Open
Abstract
Chronic pancreatitis (CP) is marked by progressive fibrosis and the activation of pancreatic stellate cells (PSCs), accompanied by the destruction of pancreatic parenchyma, leading to the loss of acinar cells (ACs). Few research studies have explored the mechanism by which damaged ACs (DACs) contribute to PSCs activation and pancreatic fibrosis. Currently, there are no effective drugs for curing CP or limiting the progression of pancreatic fibrosis. In this research, co-culture with intact acinar cells (IACs) suppressed PSC activation, while co-culture with DACs did the opposite. Krüppel-like factor 4 (KLF4) was significantly upregulated in DACs and was established as the key molecule that switches ACs from PSCs-suppressor to PSCs-activator. We revealed the exosomes of IACs contributed to the anti-activated function of IACs-CS on PSCs. MiRNome profiling showed that let-7 family is significantly enriched in IAC-derived exosomes (>30% miRNome), which partially mediates IACs' suppressive impacts on PSCs. Furthermore, it has been observed that the enrichment of let-7 in exosomes was influenced by the expression level of KLF4. Mechanistic studies demonstrated that KLF4 in ACs upregulated Lin28A, thereby decreasing let-7 levels in AC-derived exosomes, and thus promoting PSCs activation. We utilized an adeno-associated virus specifically targeting KLF4 in ACs (shKLF4-pAAV) to suppress PSCs activation in CP, resulting in reduced pancreatic fibrosis. IAC-derived exosomes hold potential as potent weapons against PSCs activation via let-7s, while activated KLF4/Lin28A signaling in DACs diminished such functions. ShKLF4-pAAV holds promise as a novel therapeutic approach for CP.
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Affiliation(s)
- Yating Zhao
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Yongpu Feng
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Fengyuan Sun
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Lei Li
- Digestive Endoscopy Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Jiayu Chen
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Yingxiao Song
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Wenbo Zhu
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Xiulin Hu
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China
| | - Zhaoshen Li
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China.
| | - Fanyang Kong
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China.
| | - Yiqi Du
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China.
| | - Xiangyu Kong
- Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China.
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Qin C, Zhao B, Wang Y, Li Z, Li T, Zhao Y, Wang W, Zhao Y. Extracellular vesicles miR-31-5p promotes pancreatic cancer chemoresistance via regulating LATS2-Hippo pathway and promoting SPARC secretion from pancreatic stellate cells. J Extracell Vesicles 2024; 13:e12488. [PMID: 39104296 DOI: 10.1002/jev2.12488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 07/01/2024] [Indexed: 08/07/2024] Open
Abstract
Pancreatic cancer remains one of the most lethal malignant diseases. Gemcitabine-based chemotherapy is still one of the first-line systemic treatments, but chemoresistance occurs in the majority of patients. Recently, accumulated evidence has demonstrated the role of the tumour microenvironment in promoting chemoresistance. In the tumour microenvironment, pancreatic stellate cells (PSCs) are among the main cellular components, and extracellular vesicles (EVs) are common mediators of cell‒cell communication. In this study, we showed that SP1-transcribed miR-31-5p not only targeted LATS2 in pancreatic cancer cells but also regulated the Hippo pathway in PSCs through EV transfer. Consequently, PSCs synthesized and secreted protein acidic and rich in cysteins (SPARC), which was preferentially expressed in stromal cells, stimulating Extracellular Signal regulated kinase (ERK) signalling in pancreatic cancer cells. Therefore, pancreatic cancer cell survival and chemoresistance were improved due to both the intrinsic Hippo pathway regulated by miR-31-5p and external SPARC-induced ERK signalling. In mouse models, miR-31-5p overexpression in pancreatic cancer cells promoted the chemoresistance of coinjected xenografts. In a tissue microarray, pancreatic cancer patients with higher miR-31-5p expression had shorter overall survival. Therefore, miR-31-5p regulates the Hippo pathway in multiple cell types within the tumour microenvironment via EVs, ultimately contributing to the chemoresistance of pancreatic cancer cells.
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Affiliation(s)
- Cheng Qin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P. R. China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, P.R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, P. R. China
| | - Bangbo Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P. R. China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, P.R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, P. R. China
| | - Yuanyang Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P. R. China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, P.R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, P. R. China
| | - Zeru Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P. R. China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, P.R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, P. R. China
| | - Tianyu Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P. R. China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, P.R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, P. R. China
| | - Yutong Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P. R. China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, P.R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, P. R. China
| | - Weibin Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P. R. China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, P.R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, P. R. China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P. R. China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, P.R. China
- National Science and Technology Key Infrastructure on Translational Medicine in Peking Union Medical College Hospital, Beijing, P. R. China
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Gupta P, Bermejo-Rodriguez C, Kocher H, Pérez-Mancera PA, Velliou EG. Chemotherapy Assessment in Advanced Multicellular 3D Models of Pancreatic Cancer: Unravelling the Importance of Spatiotemporal Mimicry of the Tumor Microenvironment. Adv Biol (Weinh) 2024; 8:e2300580. [PMID: 38327154 DOI: 10.1002/adbi.202300580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 01/10/2024] [Indexed: 02/09/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a challenge for global health with very low survival rate and high therapeutic resistance. Hence, advanced preclinical models for treatment screening are of paramount importance. Herein, chemotherapeutic (gemcitabine) assessment on novel (polyurethane) scaffold-based spatially advanced 3D multicellular PDAC models is carried out. Through comprehensive image-based analysis at the protein level, and expression analysis at the mRNA level, the importance of stromal cells is confirmed, primarily activated stellate cells in the chemoresistance of PDAC cells within the models. Furthermore, it is demonstrated that, in addition to the presence of activated stellate cells, the spatial architecture of the scaffolds, i.e., segregation/compartmentalization of the cancer and stromal zones, affect the cellular evolution and is necessary for the development of chemoresistance. These results highlight that, further to multicellularity, mapping the tumor structure/architecture and zonal complexity in 3D cancer models is important for better mimicry of the in vivo therapeutic response.
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Affiliation(s)
- Priyanka Gupta
- Centre for 3D Models of Health and Disease, Division of Surgery and Interventional Science, University College London, London, W1W 7TY, UK
| | - Camino Bermejo-Rodriguez
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK
| | - Hemant Kocher
- Centre for Tumour Biology and Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Pedro A Pérez-Mancera
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool, L69 3GE, UK
| | - Eirini G Velliou
- Centre for 3D Models of Health and Disease, Division of Surgery and Interventional Science, University College London, London, W1W 7TY, UK
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11
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Wang Y, Li HT, Liu G, Jiang CS, Ni YH, Zeng JH, Lin X, Wang QY, Li DZ, Wang W, Zeng XP. COMP promotes pancreatic fibrosis by activating pancreatic stellate cells through CD36-ERK/AKT signaling pathways. Cell Signal 2024; 118:111135. [PMID: 38479555 DOI: 10.1016/j.cellsig.2024.111135] [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: 11/25/2023] [Revised: 02/22/2024] [Accepted: 03/08/2024] [Indexed: 03/18/2024]
Abstract
BACKGROUND Pancreatic fibrosis is one of the most important pathological features of chronic pancreatitis (CP) and pancreatic stellate cells (PSCs) are the key cells of fibrosis. As an extracellular matrix (ECM) glycoprotein, cartilage oligomeric matrix protein (COMP) is critical for collagen assembly and ECM stability and recent studies showed that COMP exert promoting fibrosis effect in the skin, lungs and liver. However, the role of COMP in activation of PSCs and pancreatic fibrosis remain unclear. We aimed to investigate the role and specific mechanisms of COMP in regulating the profibrotic phenotype of PSCs and pancreatic fibrosis. METHODS ELISA method was used to determine serum COMP in patients with CP. Mice model of CP was established by repeated intraperitoneal injection of cerulein and pancreatic fibrosis was evaluated by Hematoxylin-Eosin staining (H&E) and Sirius red staining. Immunohistochemical staining was used to detect the expression changes of COMP and fibrosis marker such as α-SMA and Fibronectin in pancreatic tissue of mice. Cell Counting Kit-8, Wound Healing and Transwell assessed the proliferation and migration of human pancreatic stellate cells (HPSCs). Western blotting, qRT-PCR and immunofluorescence staining were performed to detect the expression of fibrosis marker, AKT and MAPK family proteins in HPSCs. RNA-seq omics analysis as well as small interfering RNA of COMP, recombinant human COMP (rCOMP), MEK inhibitors and PI3K inhibitors were used to study the effect and mechanism of COMP on activation of HPSCs. RESULTS ELISA showed that the expression of COMP significantly increased in the serum of CP patients. H&E and Sirius red staining analysis showed that there was a large amount of collagen deposition in the mice in the CP model group and high expression of COMP, α-SMA, Fibronectin and Vimentin were observed in fibrotic tissues. TGF-β1 stimulates the activation of HPSCs and increases the expression of COMP. Knockdown of COMP inhibited proliferation and migration of HPSCs. Further, RNA-seq omics analysis and validation experiments in vitro showed that rCOMP could significantly promote the proliferation and activation of HPSCs, which may be due to promoting the phosphorylation of ERK and AKT through membrane protein receptor CD36. rCOMP simultaneously increased the expression of α-SMA, Fibronectin and Collagen I in HPSCs. CONCLUSION In conclusion, this study showed that COMP was up-regulated in CP fibrotic tissues and COMP induced the activation, proliferation and migration of PSCs through the CD36-ERK/AKT signaling pathway. COMP may be a potential therapeutic candidate for the treatment of CP. Interfering with the expression of COMP or the communication between COMP and CD36 on PSCs may be the next direction for therapeutic research.
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Affiliation(s)
- 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
| | - Hai-Tao 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, Fuzhou, 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, Fuzhou, 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, Fuzhou, China; Department of Digestive Diseases, Dongfang Hospital, Xiamen University, Fuzhou, China
| | - 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
| | - Jing-Hui Zeng
- Department of Presbyatrics, 900TH Hospital of Joint Logistics Support Force, Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Xia Lin
- Department of Digestive Diseases, Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, China
| | - Qing-Yun Wang
- 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, Fuzhou, 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, Fuzhou, China; Department of Digestive Diseases, Dongfang Hospital, Xiamen University, Fuzhou, 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, Fuzhou, China; Department of Digestive Diseases, Dongfang Hospital, Xiamen University, Fuzhou, China.
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12
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Hagn-Meincke R, Yadav D, Andersen DK, Vege SS, Fogel EL, Serrano J, Bellin MD, Topazian MD, Conwell DL, Li L, Van Den Eeden SK, Drewes AM, Pandol SJ, Forsmark CE, Fisher WE, Hart PA, Olesen SS, Park WG. Circulating immune signatures in chronic pancreatitis with and without preceding acute pancreatitis: A pilot study. Pancreatology 2024; 24:384-393. [PMID: 38461145 PMCID: PMC11023786 DOI: 10.1016/j.pan.2024.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 02/05/2024] [Accepted: 02/21/2024] [Indexed: 03/11/2024]
Abstract
OBJECTIVE To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP). METHODS We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons of analytes were performed between the subgroups. RESULTS In total, 133 patients with CP (111 with AP and 22 without AP) and 50 healthy controls were included. Among the 80 analytes studied, CP patients with a history of AP had significantly higher serum levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (Cutaneous T-Cell Attracting Chemokine (CTACK), Monokine induced Gamma Interferon (MIG), Macrophage-derived Chemokine (MDC), Monocyte Chemoattractant Protein-1 (MCP-1)) compared to CP without preceding AP and controls. In contrast, CP patients without AP had immune profiles characterized by low systemic inflammation and downregulation of anti-inflammatory mediators, including IL-10. CONCLUSION CP patients with a preceding history of AP have signs of systemic inflammatory activity even during a clinically quiescent phase. In contrast, CP patients without a history of AP have low systemic inflammatory activity. These findings suggest the presence of two immunologically diverse subtypes of CP.
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Affiliation(s)
- Rasmus Hagn-Meincke
- Centre for Pancreatic Diseases and Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark; Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Dhiraj Yadav
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA
| | - Dana K Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Santhi Swaroop Vege
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Evan L Fogel
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jose Serrano
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Melena D Bellin
- Division of Pediatric Endocrinology, University of Minnesota, Minnesota, MN, USA
| | - Mark D Topazian
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Darwin L Conwell
- Department of Medicine, University of Kentucky, Lexington, KY, USA
| | - Liang Li
- Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Asbjørn M Drewes
- Centre for Pancreatic Diseases and Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Stephen J Pandol
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Chris E Forsmark
- Division of Gastroenterology, Hepatology, and Nutrition. University of Florida, Gainesville, FL, USA
| | - William E Fisher
- Division of General Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Søren S Olesen
- Centre for Pancreatic Diseases and Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Walter G Park
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
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Tsomidis I, Voumvouraki A, Kouroumalis E. The Pathogenesis of Pancreatitis and the Role of Autophagy. GASTROENTEROLOGY INSIGHTS 2024; 15:303-341. [DOI: 10.3390/gastroent15020022] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The pathogenesis of acute and chronic pancreatitis has recently evolved as new findings demonstrate a complex mechanism operating through various pathways. In this review, the current evidence indicating that several mechanisms act in concert to induce and perpetuate pancreatitis were presented. As autophagy is now considered a fundamental mechanism in the pathophysiology of both acute and chronic pancreatitis, the fundamentals of the autophagy pathway were discussed to allow for a better understanding of the pathophysiological mechanisms of pancreatitis. The various aspects of pathogenesis, including trypsinogen activation, ER stress and mitochondrial dysfunction, the implications of inflammation, and macrophage involvement in innate immunity, as well as the significance of pancreatic stellate cells in the development of fibrosis, were also analyzed. Recent findings on exosomes and the miRNA regulatory role were also presented. Finally, the role of autophagy in the protection and aggravation of pancreatitis and possible therapeutic implications were reviewed.
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Affiliation(s)
- Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
| | - Elias Kouroumalis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
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14
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Iyer S, Enman M, Sahay P, Dudeja V. Novel therapeutics to treat chronic pancreatitis: targeting pancreatic stellate cells and macrophages. Expert Rev Gastroenterol Hepatol 2024; 18:171-183. [PMID: 38761167 DOI: 10.1080/17474124.2024.2355969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 05/13/2024] [Indexed: 05/20/2024]
Abstract
INTRODUCTION Chronic pancreatitis (CP) is a persistent, recurrent, and progressive disorder that is characterized by chronic inflammation and irreversible fibrosis of the pancreas. It is associated with severe morbidity, resulting in intense abdominal pain, diabetes, exocrine and endocrine dysfunction, and an increased risk of pancreatic cancer. The etiological factors are diverse and the major risk factors include smoking, chronic alcoholism, as well as other environmental and genetic factors. The treatment and management of CP is challenging, and no definitive curative therapy is currently available. AREAS COVERED This review paper aims to provide an overview of the different cell types in the pancreas that is known to mediate disease progression and outline potential novel therapeutic approaches and drug targets that may be effective in treating and managing CP. The information presented in this review was obtained by conducting a NCBI PubMed database search, using relevant keywords. EXPERT OPINION In recent years, there has been an increased interest in the development of novel therapeutics for CP. A collaborative multi-disciplinary approach coupled with a consistent funding for research can expedite progress of translating the findings from bench to bedside.
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Affiliation(s)
- Srikanth Iyer
- Department of Surgery, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
| | - Macie Enman
- Department of Surgery, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
| | - Preeti Sahay
- Department of Surgery, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
| | - Vikas Dudeja
- Department of Surgery, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
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15
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Guo HL, Liang XS, Zeng XP, Liu Y, Li ZS, Wang LJ, Hu LH. Pirfenidone alleviates chronic pancreatitis via suppressing the activation of pancreatic stellate cells and the M1 polarization of macrophages. Int Immunopharmacol 2024; 130:111691. [PMID: 38367466 DOI: 10.1016/j.intimp.2024.111691] [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: 08/10/2023] [Revised: 01/14/2024] [Accepted: 02/09/2024] [Indexed: 02/19/2024]
Abstract
In the realm of fibroinflammatory conditions, chronic pancreatitis (CP) stands out as a particularly challenging ailment, lacking a dedicated, approved treatment. The potential of Pirfenidone (PFD), a drug originally used for treating idiopathic pulmonary fibrosis (IPF), in addressing CP's fibrotic aspects has sparked new interest. This investigation focused on the role of PFD in diminishing fibrosis and immune response in CP, using a mouse model induced by caerulein. The research extended to in vitro studies examining the influence of PFD on pancreatic stellate cells' (PSCs) behavior and the polarization of macrophages into M1 and M2 types. Advanced techniques like RNA sequencing and comprehensive data analyses were employed to decode the molecular interactions of PFD with PSCs. Supplementary experiments using techniques such as quantitative real-time PCR, western blotting, and immunofluorescence were also implemented. Results showed a notable reduction in pancreatic damage in PFD-treated mice, manifested through decreased acinar cell atrophy, lower collagen deposition, and a reduction in macrophage presence. Further investigation revealed PFD's capacity to hinder PSCs' migration, growth, and activation, alongside a reduction in the production and secretion of extracellular matrix proteins. This effect is primarily achieved by interfering with signaling pathways such as TGF-β/Smad, Wnt/β-catenin, and JAK/STAT. Additionally, PFD selectively hampers M1 macrophage polarization through the STAT3 pathway, without impacting M2 polarization. These outcomes highlight PFD's dual mechanism in moderating PSC activity and M1 macrophage polarization, positioning it as a promising candidate for CP therapy.
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Affiliation(s)
- Hong-Lei Guo
- Department of Infectious Diseases, First Affiliated Hospital of Naval Medical University, Shanghai, China; Shanghai Institute of Pancreatic Diseases, Shanghai, China
| | - Xue-Song Liang
- Department of Infectious Diseases, First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Xiang-Peng Zeng
- Department of Digestive Diseases, No. 900 Hospital of the Joint Logistics Support Force, Fuzhou, Fujian, China
| | - Yu Liu
- Department of Gastroenterology and Hepatology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Zhao-Shen Li
- Shanghai Institute of Pancreatic Diseases, Shanghai, China; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Li-Juan Wang
- Shanghai Institute of Pancreatic Diseases, Shanghai, China; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, China.
| | - Liang-Hao Hu
- Shanghai Institute of Pancreatic Diseases, Shanghai, China; Department of Gastroenterology, First Affiliated Hospital of Naval Medical University, Shanghai, China.
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16
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Sun L, Zheng M, Gao Y, Brigstock DR, Gao R. Retinoic acid signaling pathway in pancreatic stellate cells: Insight into the anti-fibrotic effect and mechanism. Eur J Pharmacol 2024; 967:176374. [PMID: 38309676 DOI: 10.1016/j.ejphar.2024.176374] [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: 10/14/2023] [Revised: 01/15/2024] [Accepted: 01/30/2024] [Indexed: 02/05/2024]
Abstract
Pancreatic stellate cells (PSCs) are activated following loss of cytoplasmic vitamin A (retinol)-containing lipid droplets, which is a key event in the process of fibrogenesis of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDCA). PSCs are the major source of cancer-associated fibroblasts (CAFs) that produce stroma to induce PDAC cancer cell growth, invasion, and metastasis. As an active metabolite of retinol, retinoic acid (RA) can regulate target gene expression in PSCs through its nuclear receptor complex (RAR/RXR or RXR/RXR) or transcriptional intermediary factor. Additionally, RA also has extranuclear and non-transcriptional effects. In vitro studies have shown that RA induces PSC deactivation which reduces extracellular matrix production through multiple modes of action, such as inhibiting TβRⅡ, PDGFRβ, β-catenin and Wnt production, downregulating ERK1/2 and JNK phosphorylation and suppressing active TGF-β1 release. RA alone or in combination with other reagents have been demonstrated to have an effective anti-fibrotic effect on cerulein-induced mouse CP models in vivo studies. Clinical trial data have shown that repurposing all-trans retinoic acid (ATRA) as a stromal-targeting agent for human pancreatic cancer is safe and tolerable, suggesting the possibility of using RA for the treatment of CP and PDCA in humans. This review focuses on RA signaling pathways in PSCs and the effects and mechanisms of RA in PSC-mediated fibrogenesis as well as the anti-fibrotic and anti-tumor effects of RA targeting PSCs or CAFs in vitro and in vivo, highlighting the potential therapies of RA against CP and PDAC.
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Affiliation(s)
- Li Sun
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Department of Pathology, First Hospital of Jilin University, Changchun, China
| | - Meifang Zheng
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Yanhang Gao
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China; Department of Infectious Diseases, 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; Department of Infectious Diseases, First Hospital of Jilin University, Changchun, China.
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17
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Bi YW, Li LS, Ru N, Zhang B, Lei X. Nicotinamide adenine dinucleotide phosphate oxidase in pancreatic diseases: Mechanisms and future perspectives. World J Gastroenterol 2024; 30:429-439. [PMID: 38414585 PMCID: PMC10895600 DOI: 10.3748/wjg.v30.i5.429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/17/2023] [Accepted: 01/12/2024] [Indexed: 01/31/2024] Open
Abstract
Pancreatitis and pancreatic cancer (PC) stand as the most worrisome ailments affecting the pancreas. Researchers have dedicated efforts to unraveling the mechanisms underlying these diseases, yet their true nature continues to elude their grasp. Within this realm, oxidative stress is often believed to play a causal and contributory role in the development of pancreatitis and PC. Excessive accumulation of reactive oxygen species (ROS) can cause oxidative stress, and the key enzyme responsible for inducing ROS production in cells is nicotinamide adenine dinucleotide phosphate hydrogen oxides (NOX). NOX contribute to pancreatic fibrosis and inflammation by generating ROS that injure acinar cells, activate pancreatic stellate cells, and mediate macrophage polarization. Excessive ROS production occurs during malignant transformation and pancreatic carcinogenesis, creating an oxidative microenvironment that can cause abnormal apoptosis, epithelial to mesenchymal transition and genomic instability. Therefore, understanding the role of NOX in pancreatic diseases contributes to a more in-depth exploration of the exact pathogenesis of these diseases. In this review, we aim to summarize the potential roles of NOX and its mechanism in pancreatic disorders, aiming to provide novel insights into understanding the mechanisms underlying these diseases.
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Affiliation(s)
- Ya-Wei Bi
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Long-Song Li
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Nan Ru
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Bo Zhang
- Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Xiao Lei
- Department of Radiation Oncology, Chinese PLA General Hospital, Beijing 100853, China
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18
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Wang D, Han S, Lv G, Hu Y, Zhuo W, Zeng Z, Tang J, Huang Y, Wang F, Wang J, Zhao Y, Zhao G. Pancreatic Acinar Cells-Derived Sphingosine-1-Phosphate Contributes to Fibrosis of Chronic Pancreatitis via Inducing Autophagy and Activation of Pancreatic Stellate Cells. Gastroenterology 2023; 165:1488-1504.e20. [PMID: 37634735 DOI: 10.1053/j.gastro.2023.08.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 07/22/2023] [Accepted: 08/11/2023] [Indexed: 08/29/2023]
Abstract
BACKGROUND & AIMS Studies have demonstrated that activated pancreatic stellate cells (PSCs) play a crucial role in pancreatic fibrogenesis in chronic pancreatitis (CP); however, the precise mechanism for PSCs activation has not been fully elucidated. We analyzed the role of injured pancreatic acinar cells (iPACs) in the activation of PSCs of CP. METHODS Sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) signaling was evaluated in experimental CP induced by cerulein injection or pancreatic duct ligation, as well as in PACs injured by cholecystokinin. The activation of PSCs and pancreatic fibrosis in CP samples was evaluated by immunohistochemical and immunofluorescence analyses. In vitro coculture assay of iPACs and PSCs was created to evaluate the effect of the SPHK1/S1P pathway and S1P receptor 2 (SIPR2) on autophagy and activation of PSCs. The pathogenesis of CP was assessed in SPHK1-/- mice or PACs-specific SPHK1-knockdown mice with recombinant adeno-associated virus serotypes 9-SPHK1-knockdown, as well as in mice treated with inhibitor of SPHK1 and S1P receptor 2 (S1PR2). RESULTS SPHK1/S1P was remarkably increased in iPACs and acinar cells in pancreatic tissues of CP mice. Meanwhile, the pathogenesis, fibrosis, and PSCs activation of CP was significantly prevented in SPHK1-/- mice and recombinant adeno-associated virus serotypes 9-SPHK1-knockdown mice. Meanwhile, iPACs obviously activated PSCs, which was prevented by SPHK1 knockdown in iPACs. Moreover, iPACs-derived S1P specifically combined to S1PR2 of PSCs, by which modulated 5' adenosine monophosphate-activated protein kinase/mechanistic target of rapamycin pathway and consequently induced autophagy and activation of PSCs. Furthermore, hypoxia-inducible factor 1-α and -2α promoted SPHK1 transcription of PACs under hypoxia conditions, which is a distinct characteristic of the CP microenvironment. Coincidently, inhibition of SPHK1 and S1PR2 activity with inhibitor PF-543 and JTE-013 obviously impeded pancreatic fibrogenesis of CP mice. CONCLUSIONS The activated SPHK1/S1P pathway in iPACs induces autophagy and activation of PSCs by regulating the S1PR2/5' adenosine monophosphate-activated protein kinase/mammalian target of rapamycin pathway, which promotes fibrogenesis of CP. The hypoxia microenvironment might contribute to the cross talk between PACs and PSCs in pathogenesis of CP.
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Affiliation(s)
- Decai Wang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Shengbo Han
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Guozheng Lv
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Yuhang Hu
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Wenfeng Zhuo
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Zhu Zeng
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Jiang Tang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Yan Huang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Fan Wang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Jie Wang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Yong Zhao
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China
| | - Gang Zhao
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan China.
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Alavi M, Mejia-Bautista A, Tang M, Bandovic J, Rosenberg AZ, Bialkowska AB. Krüppel-like Factor 5 Plays an Important Role in the Pathogenesis of Chronic Pancreatitis. Cancers (Basel) 2023; 15:5427. [PMID: 38001687 PMCID: PMC10670257 DOI: 10.3390/cancers15225427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/06/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
Chronic pancreatitis results in the formation of pancreatic intraepithelial neoplasia (PanIN) and poses a risk of developing pancreatic cancer. Our previous study demonstrated that Krüppel-like factor 5 (KLF5) is necessary for forming acinar-to-ductal metaplasia (ADM) in acute pancreatitis. Here, we investigated the role of KLF5 in response to chronic injury in the pancreas. Human tissues originating from chronic pancreatitis patients showed increased levels of epithelial KLF5. An inducible genetic model combining the deletion of Klf5 and the activation of KrasG12D mutant expression in pancreatic acinar cells together with chemically induced chronic pancreatitis was used. The chronic injury resulted in increased levels of KLF5 in both control and KrasG12D mutant mice. Furthermore, it led to numerous ADM and PanIN lesions and extensive fibrosis in the KRAS mutant mice. In contrast, pancreata with Klf5 loss (with or without KrasG12D) failed to develop ADM, PanIN, or significant fibrosis. Furthermore, the deletion of Klf5 reduced the expression level of cytokines and fibrotic components such as Il1b, Il6, Tnf, Tgfb1, Timp1, and Mmp9. Notably, using ChIP-PCR, we showed that KLF5 binds directly to the promoters of Il1b, Il6, and Tgfb1 genes. In summary, the inactivation of Klf5 inhibits ADM and PanIN formation and the development of pancreatic fibrosis.
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Affiliation(s)
- Maryam Alavi
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA (M.T.)
| | - Ana Mejia-Bautista
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA (M.T.)
| | - Meiyi Tang
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA (M.T.)
| | - Jela Bandovic
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Avi Z. Rosenberg
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21217, USA;
| | - Agnieszka B. Bialkowska
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA (M.T.)
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20
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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.
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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
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21
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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.
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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.
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22
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Yin H, Zhang Z, Zhang D, Peng L, Xia C, Yang X, Wang X, Li Z, Chang J, Huang H. A new method for treating chronic pancreatitis and preventing fibrosis using bioactive calcium silicate ion solution. J Mater Chem B 2023; 11:9163-9178. [PMID: 37642526 DOI: 10.1039/d3tb01287e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Chronic pancreatitis (CP) is a multifactorial fibroinflammatory syndrome. At present, there is no effective way to treat it clinically. In this study, we proposed a new approach by application of a highly active calcium silicate ion solution derived from calcium silicate (CS) bioceramics, which effectively inhibited the development of CP. This bioceramic derived bioactive ionic solution mainly regulated pancreatic acinar cells (PACs), macrophages and pancreatic stellate cells (PSCs) by SiO32- ions to inhibit inflammation and fibrosis and promote acinar regeneration. The possible mechanism of the therapeutic effect of CS ion solution mainly includes the inhibition of PAC apoptosis by down-regulating the c-caspase3 signal pathway and promotion of the regeneration of PACs by up-regulating the WNT/β-catenin signaling pathway. In addition, the CS ion solution also effectively down-regulated the NF-κB signaling pathway to reduce macrophage infiltration and PAC inflammatory factor secretion, thereby reducing PSC mediated pancreatic fibrosis. This bioceramics-based ion solution provides a new idea for disease treatment using biomaterials, which may have the potential for the development of new therapy for CP.
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Affiliation(s)
- Hua Yin
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200433, People's Republic of China.
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Ningxia, 750004, People's Republic of China
| | - Zhaowenbin Zhang
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China
- State Key Laboratory of High-Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, People's Republic of China
| | - Deyu Zhang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200433, People's Republic of China.
| | - Lisi Peng
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200433, People's Republic of China.
| | - Chuanchao Xia
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200433, People's Republic of China.
| | - Xiaoli Yang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200433, People's Republic of China.
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Ningxia, 750004, People's Republic of China
| | - Xinyue Wang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200433, People's Republic of China.
| | - Zhaoshen Li
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200433, People's Republic of China.
| | - Jiang Chang
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China
- State Key Laboratory of High-Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, People's Republic of China
| | - Haojie Huang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200433, People's Republic of China.
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Chang M, Chen W, Xia R, Peng Y, Niu P, Fan H. Pancreatic Stellate Cells and the Targeted Therapeutic Strategies in Chronic Pancreatitis. Molecules 2023; 28:5586. [PMID: 37513458 PMCID: PMC10383437 DOI: 10.3390/molecules28145586] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Chronic pancreatitis (CP) is a disease characterized by inflammatory recurrence that accompanies the development of pancreatic fibrosis. As the mystery of CP pathogenesis is gradually revealed, accumulating evidence suggests that the activation of pancreatic stellate cells (PSCs) and the appearance of a myofibroblast-like phenotype are the key gatekeepers in the development of CP. Targeting PSCs to prevent their activation and conversion to a myofibroblast-like phenotype, as well as increasing antioxidant capacity to counteract ongoing oxidative stress, are effective strategies for preventing or treating CP. Therefore, we reviewed the crosstalk between CP and pancreatic fibrosis, summarized the activation mechanisms of PSCs, and investigated potential CP therapeutic strategies targeting PSCs, including, but not limited to, anti-fibrosis therapy, antioxidant therapy, and gene therapy. Meanwhile, the above therapeutic strategies are selected in order to update the available phytopharmaceuticals as novel complementary or alternative approaches for the prevention and treatment of CP to clarify their potential mechanisms of action and their relevant molecular targets, aiming to provide the most comprehensive therapeutic treatment direction for CP and to bring new hope to CP patients.
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Affiliation(s)
- Man Chang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Wenjuan Chen
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Ruting Xia
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yangyue Peng
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Pandi Niu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Hui Fan
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangzhou 510006, China
- Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangzhou 510006, China
- Key Unit of Modulating Liver to Treat Hyperlipemia SATCM (State Administration of Traditional Chinese Medicine), Guangzhou 510006, China
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
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24
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Zhang Y, Zhang WQ, Liu XY, Zhang Q, Mao T, Li XY. Immune cells and immune cell-targeted therapy in chronic pancreatitis. Front Oncol 2023; 13:1151103. [PMID: 36969002 PMCID: PMC10034053 DOI: 10.3389/fonc.2023.1151103] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 02/27/2023] [Indexed: 03/11/2023] Open
Abstract
In recent years, studies have attempted to understand the immune cells and mechanisms underlying the pathogenesis of chronic pancreatitis (CP) by constructing a model of CP. Based on these studies, the innate immune response is a key factor in disease pathogenesis and inflammation severity. Novel mechanisms of crosstalk between immune and non-immune pancreatic cells, such as pancreatic stellate cells (PSC), have also been explored. Immune cells, immune responses, and signaling pathways in CP are important factors in the development and progression of pancreatitis. Based on these mechanisms, targeted therapy may provide a feasible scheme to stop or reverse the progression of the disease in the future and provide a new direction for the treatment of CP. This review summarizes the recent advances in research on immune mechanisms in CP and the new advances in treatment based on these mechanisms.
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25
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Pi Z, Qiu X, Liu J, Shi Y, Zeng Z, Xiao R. Activating Protein-1 (AP-1): A Promising Target for the Treatment of Fibrotic Diseases. Curr Med Chem 2023; 31:CMC-EPUB-129375. [PMID: 36757030 DOI: 10.2174/0929867330666230209100059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 12/04/2022] [Accepted: 12/29/2022] [Indexed: 02/10/2023]
Abstract
The fibrosis of tissues and organs occurs via an aberrant tissue remodeling process characterized by an excessive deposition of extracellular matrix, which can lead to organ dysfunction, organ failure, and death. Because the pathogenesis of fibrosis remains unclear and elusive, there is currently no medication to reverse it; hence, this process deserves further study. Activating protein-1 (AP-1)-comprising Jun (c-Jun, JunB, JunD), Fos (c-fos, FosB, Fra1, and Fra2), and activating transcription factor-is a versatile dimeric transcription factor. Numerous studies have demonstrated that AP-1 plays a crucial role in advancing tissue and organ fibrosis via induction of the expression of fibrotic molecules and activating fibroblasts. This review focuses on the role of AP-1 in a range of fibrotic disorders as well as on the antifibrotic effects of AP-1 inhibitors. It also discusses the potential of AP-1 as a new therapeutic target in conditions involving tissue and organ fibrosis.
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Affiliation(s)
- Zixin Pi
- Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
- Department of Medical Genetics, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Xiangning Qiu
- Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Jiani Liu
- Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Yaqian Shi
- Second Xiangya Hospital of Central South University Department of Dermatology Changsha China
| | - Zhuotong Zeng
- Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Rong Xiao
- Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
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26
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Are Aspects of Integrative Concepts Helpful to Improve Pancreatic Cancer Therapy? Cancers (Basel) 2023; 15:cancers15041116. [PMID: 36831465 PMCID: PMC9953994 DOI: 10.3390/cancers15041116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/24/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Numerous clinical studies have been conducted to improve the outcomes of patients suffering from pancreatic cancer. Different approaches using targeted therapeutic strategies and precision medicine methods have been investigated, and synergies and further therapeutic advances may be achieved through combinations with integrative methods. For pancreatic tumors, a particular challenge is the presence of a microenvironment and a dense stroma, which is both a physical barrier to drug penetration and a complex entity being controlled by the immune system. Therefore, the state of immunological tolerance in the tumor microenvironment must be overcome, which is a considerable challenge. Integrative approaches, such as hyperthermia, percutaneous irreversible electroporation, intra-tumoral injections, phytotherapeutics, or vitamins, in combination with standard-oncological therapies, may potentially contribute to the control of pancreatic cancer. The combined application of standard-oncological and integrative methods is currently being studied in ongoing clinical trials. An actual overview is given here.
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27
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Zhang F, Hu Q, Li B, Huang Y, Wang M, Shao S, Tang H, Yao Z, Ping Y, Liang T. A biomimetic nanodrug for enhanced chemotherapy of pancreatic tumors. J Control Release 2023; 354:835-850. [PMID: 36627026 DOI: 10.1016/j.jconrel.2023.01.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/30/2022] [Accepted: 01/04/2023] [Indexed: 01/12/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains to be one of the highest malignant tumors due to its poor chemotherapeutic efficacy and multidrug resistance. A major reason for the failure in chemotherapy is poor drug accumulation into PDAC tumor tissues due to the overexpressed extracellular matrix (ECM) stroma, which forms a major obstacle limiting the deep tissue penetration of chemotherapeutics. Herein, we report a tumor microenvironment (TME)-responsive nanodrug, based on PDAC cell membrane-coated gold nanocages (AuNCs), to co-deliver the chemotherapeutics (GEM) and nitrogen oxide (NO) donor (L-Arg) to enhance drug accumulation and reduce chemoresistance. The high glutathione (GSH) level can trigger the cleavage of the disulfide bond on nanodrug to release GEM. Moreover, the elevated ROS level could activate L-Arg to generate NO, which synergistically facilitate GEM to penetrate into deep tissues by means of vasodilation and normalization of blood vessels in the PDAC tumor tissue. In addition, AuNCs not only serve as a photothermal agent for chemotherapy, but also generate photoacoustic signals to monitor drug accumulation and distribution. As expected, the strategy demonstrates to be remarkable in treating different xenograft mice models, especially in orthotopic and patient-derived xenograft (PDX) models. The current study defines a useful therapeutic tool for treating PDAC tumors.
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Affiliation(s)
- Fu Zhang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qida Hu
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China
| | - Bowen Li
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive, Singapore, 117585, Singapore.
| | - Yong Huang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Meng Wang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China
| | - Shiyi Shao
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China
| | - Honglin Tang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Zhuo Yao
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yuan Ping
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310003, China; Innovation Center for the Study of Pancreatic Diseases, Hangzhou 310003, China; Zhejiang Provincial Clinical Research Center for the Study of Hepatobiliary & Pancreatic Diseases, Hangzhou 310003, China; Cancer Center, Zhejiang University, Hangzhou 310058, China; Research Center for Healthcare Data Science, Zhejiang Lab, Hangzhou 311121, China.
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28
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Special issue: 2022 pancreatic cancer and the role of the stroma in the pathophysiology of the gland. J Physiol Biochem 2023; 79:175-177. [PMID: 36604403 DOI: 10.1007/s13105-022-00942-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 12/21/2022] [Indexed: 01/07/2023]
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29
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Velasco RM, García AG, Sánchez PJ, Sellart IM, Sánchez-Arévalo Lobo VJ. Tumour microenvironment and heterotypic interactions in pancreatic cancer. J Physiol Biochem 2023; 79:179-192. [PMID: 35102531 DOI: 10.1007/s13105-022-00875-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 01/18/2022] [Indexed: 12/27/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is a disease with a survival rate of 9%; this is due to its chemoresistance and the large tumour stroma that occupies most of the tumour mass. It is composed of a large number of cells of the immune system, such as Treg cells, tumour-associated macrophages (TAMs), myeloid suppressor cells (MDCs) and tumour-associated neutrophiles (TANs) that generate an immunosuppressive environment by the release of inflammatory cytokines. Moreover, cancer-associated fibroblast (CAFs) provide a protective coverage that would difficult the access of chemotherapy to the tumour. According to this, new therapies that could remodel this heterogeneous tumour microenvironment, such as adoptive T cell therapies (ACT), immune checkpoint inhibitors (ICI), and CD40 agonists, should be developed for targeting PDA. This review organizes the different cell populations found in the tumour stroma involved in tumour progression in addition to the different therapies that are being studied to counteract the tumour.
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Affiliation(s)
- Raúl Muñoz Velasco
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain
- Instituto de Investigación Hospital 12 de Octubre, Pathology Department, Av. Córdoba, s/n, 28041, Madrid, Spain
| | - Ana García García
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain
- Instituto de Investigación Hospital 12 de Octubre, Pathology Department, Av. Córdoba, s/n, 28041, Madrid, Spain
| | - Paula Jiménez Sánchez
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain
- Instituto de Investigación Hospital 12 de Octubre, Pathology Department, Av. Córdoba, s/n, 28041, Madrid, Spain
| | - Inmaculada Montanuy Sellart
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain
| | - Víctor Javier Sánchez-Arévalo Lobo
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain.
- Instituto de Investigación Hospital 12 de Octubre, Pathology Department, Av. Córdoba, s/n, 28041, Madrid, Spain.
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Zhang G, Zhao X, Cai J, Li S, Li X, Li W, Shi P, Liu D, Zheng D, Zhang T, Feng R, Liu H. XCHT alleviates the pancreatic fibrosis via VDR/NLRP3 signaling pathway in a mouse model of CP. JOURNAL OF ETHNOPHARMACOLOGY 2023; 300:115689. [PMID: 36096349 DOI: 10.1016/j.jep.2022.115689] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Xiao Chai Hu Tang (XCHT) derived from the classic medical book Shang Han Lun (Treatise on Febrile Diseases) in the Eastern Han Dynasty, which has been widely used in China and other Asian countries for the treatment of inflammation and fibrosis of chronic pancreatitis (CP), but the therapeutic mechanism of XCHT in pancreatic fibrosis remains unclear. AIM OF THE STUDY This study aimed to evaluate the intervention effects and explore pharmacological mechanism of XCHT on inflammation and fibrosis in cerulein-induced CP model. MATERIALS AND METHODS Fifty male C57BL/6 mice were randomly divided into five main groups, 10 animals in each: Control, CP model (50 μg/kg cerulein), high dose XCHT-treated CP group (60 g/kg XCHT), medium dose XCHT-treated CP group (30 g/kg XCHT) and low dose XCHT-treated CP group (15 g/kg XCHT). Different doses of XCHT were given to mice by gavage twice a day for 2 weeks after the CP model induction. Pancreatic tissues were harvested and the pancreatic inflammation and fibrosis were evaluated by histological score, Sirius red staining, and alpha-smooth muscle actin (α-SMA) immunohistochemical staining. ELISA, IHC and RT-qPCR were performed to detect the expression of Vitamin D3 (VD3) and Vitamin D receptor (VDR) in serum and pancreatic tissues, respectively. The expressions of NLRP3 inflammasome related genes and molecules were assayed by WB, IHC and RT-qPCR. RESULTS The pathohistological results demonstrated that XCHT markedly inhibited the fibrosis and chronic inflammation of cerulein-induced CP, indicated by reduction of collagen I, collagen III, α-SMA, and NLRP3 expressions. XCHT significantly increased VD3 and VDR expression while reduced the pancreatic NLRP3 expression. Correspondingly, XCHT decreased the levels of NLRP3 downstream targets IL-1β, TNF-α and IL-6. CONCLUSIONS These results revealed that XCHT suppressed the pancreatic fibrosis and chronic inflammation in cerulein-induced CP model by enhancing the VD3/VDR expression and inhibiting the secretion of NLRP3-assoicated inflammatory factors.
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Affiliation(s)
- Guixian Zhang
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Xiumei Zhao
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Jun Cai
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Sainan Li
- Graduate School of Tianjin Medical University, Tianjin, 300070, China
| | - Xijing Li
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Wenchang Li
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Pengcheng Shi
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Dawei Liu
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Duo Zheng
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Ting Zhang
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Renrui Feng
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China
| | - Hongbin Liu
- Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Rd, Tianjin, 300020, China.
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Singh M, Pal P, Dutta RS, Marbaniang D, Ray S, Mazumder B. Nanodiamond Mediated Molecular Targeting in Pancreatic Ductal Adenocarcinoma: Disrupting the Tumor-stromal Cross-talk, Next Hope on the Horizon? Curr Cancer Drug Targets 2023; 23:620-633. [PMID: 36843367 DOI: 10.2174/1568009623666230227120837] [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: 03/11/2022] [Revised: 12/21/2022] [Accepted: 12/21/2022] [Indexed: 02/28/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the foremost causes of cancer-related morbidities worldwide. Novel nanotechnology-backed drug delivery stratagems, including molecular targeting of the chemotherapeutic payload, have been considered. However, no quantum leap in the gross survival rate of patients with PDAC has been realized. One of the predominant causes behind this is tumor desmoplasia, a dense and heterogenous stromal extracellular matrix of the tumor, aptly termed tumor microenvironment (TME). It plays a pivotal role in the tumor pathogenesis of PDAC as it occupies most of the tumor mass, making PDAC one of the most stromal-rich cancers. The complex crosstalk between the tumor and dynamic components of the TME impacts tumor progression and poses a potential barrier to drug delivery. Understanding and deciphering the complex cascade of tumorstromal interactions are the need of the hour so that we can develop neoteric nano-carriers to disrupt the stroma and target the tumor. Nanodiamonds (NDs), due to their unique surface characteristics, have emerged as a promising nano delivery system in various pre-clinical cancer models and have the potential to deliver the chemotherapeutic payload by moving beyond the dynamic tumor-stromal barrier. It can be the next revolution in nanoparticle-mediated pancreatic cancer targeting.
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Affiliation(s)
- Mohini Singh
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, 786004, Assam, India
| | - Paulami Pal
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, 786004, Assam, India
| | - Rajat Subhra Dutta
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, 786004, Assam, India
| | - Daphisha Marbaniang
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, 786004, Assam, India
| | - Subhabrata Ray
- Dr. B.C. Roy College of Pharmacy & AHS, Durgapur, WB, India
| | - Bhaskar Mazumder
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, 786004, Assam, India
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Lin H, Ye Z, Xu R, Li XE, Sun B. The transcription factor JUN is a major regulator of quiescent pancreatic stellate cell maintenance. Gene X 2023; 851:147000. [DOI: 10.1016/j.gene.2022.147000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 10/01/2022] [Accepted: 10/18/2022] [Indexed: 11/27/2022] Open
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Li BQ, Liu XY, Mao T, Zheng TH, Zhang P, Zhang Q, Zhang Y, Li XY. The research progress of anti-inflammatory and anti-fibrosis treatment of chronic pancreatitis. Front Oncol 2022; 12:1050274. [PMID: 36505827 PMCID: PMC9730810 DOI: 10.3389/fonc.2022.1050274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 11/11/2022] [Indexed: 11/27/2022] Open
Abstract
Chronic pancreatitis (CP) is a chronic progressive inflammatory disease of the pancreas, caused by multiple factors and accompanied by irreversible impairment of pancreatic internal and external secretory functions. Pathologically, atrophy of the pancreatic acini, tissue fibrosis or calcification, focal edema, inflammation, and necrosis are observed. Clinical manifestations include recurrent or persistent abdominal pain, diarrhea, emaciation, and diabetes. In addition, CP is prone to develop into pancreatic cancer(PC) due to persistent inflammation and fibrosis. The disease course is prolonged and the clinical prognosis is poor. Currently, clinical treatment of CP is still based on symptomatic treatment and there is a lack of effective etiological treatment. Encouragingly, experiments have shown that a variety of active substances have great potential in the etiological treatment of chronic pancreatitis. In this paper, we will review the pathogenesis of CP, as well as the research progress on anti-inflammatory and anti-fibrotic therapies, which will provide new ideas for the development of subsequent clinical studies and formulation of effective treatment programs, and help prevent CP from developing into pancreatic cancer and reduce the prevalence of PC as much as possible.
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Mukherjee AG, Wanjari UR, Gopalakrishnan AV, Bradu P, Sukumar A, Patil M, Renu K, Dey A, Vellingiri B, George A, Ganesan R. Implications of cancer stem cells in diabetes and pancreatic cancer. Life Sci 2022; 312:121211. [PMID: 36414089 DOI: 10.1016/j.lfs.2022.121211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 11/21/2022]
Abstract
This review provides a detailed study of pancreatic cancer (PC) and the implication of different types of cancers concerning diabetes. The combination of anti-diabetic drugs with other anti-cancer drugs and phytochemicals can help prevent and treat this disease. PC cancer stem cells (CSCs) and how they migrate and develop into malignant tumors are discussed. A detailed explanation of the different mechanisms of diabetes development, which can enhance the pancreatic CSCs' proliferation by increasing the IGF factor levels, epigenetic modifications, DNA damage, and the influence of lifestyle factors like obesity, and inflammation, has been discussed. It also explains how cancer due to diabetes is associated with high mortality rates. One of the well-known diabetic drugs, metformin, can be combined with other anti-cancer drugs and prevent the development of PC and has been taken as one of the prime focus in this review. Overall, this paper provides insight into the relationship between diabetes and PC and the methods that can be employed to diagnose this disease at an earlier stage successfully.
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Affiliation(s)
- Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India.
| | - Pragya Bradu
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Aarthi Sukumar
- Department of Integrative Biology, School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Megha Patil
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, 632014, India
| | - Kaviyarasi Renu
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, Tamil Nadu, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata, West Bengal, 700073, India
| | - Balachandar Vellingiri
- Stem cell and Regenerative Medicine/Translational Research, Department of Zoology, School of Basic Sciences, Central University of Punjab (CUPB), Bathinda - 151401, Punjab, India
| | - Alex George
- Jubilee Centre for Medical Research, Jubilee Mission Medical College and Research Institute, Thrissur, 680005, Kerala, India
| | - Raja Ganesan
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, 24252, Republic of Korea
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Li Z, Du Y, Wang X. Pancreatic Lineage Cell Differentiation of Bone Marrow Mesenchymal Stromal Cells on Acellular Pancreatic Bioscaffold. Pancreas 2022; 51:1411-1426. [PMID: 37099787 DOI: 10.1097/mpa.0000000000002184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/28/2023]
Abstract
OBJECTIVES We evaluated the potential differentiation ability of bone mesenchymal stromal cells (BMSCs) into pancreatic lineage cells on a rat acellular pancreatic bioscaffold (APB) and the effect of differentiated BMSCs in vivo. METHODS The BMSCs were dynamically or statically cultured with or without growth factor in both culture systems. We assessed the cytological behavior and differentiation. We also evaluated the pancreatic fibrosis and pathological scores. RESULTS The proliferation rates of BMSCs were significantly higher in the APB groups. The APB induced BMSCs to express mRNA markers at higher levels. All tested pancreatic functional proteins were also expressed at higher levels in the APB group. The secretion of metabolic enzymes was higher in the APB system. The ultrastructure of BMSCs in the APB group further revealed the morphological characteristics of pancreatic-like cells. For the in vivo study, the pancreatic fibrosis and pathological scores were significantly lower in the differentiated BMSCs group. In addition, in both the in vitro and the in vivo study, growth factor significantly improved proliferation, differentiation, and pancreatic cell therapy. CONCLUSIONS The APB can promote BMSC differentiation toward pancreatic lineage and pancreatic-like phenotypes, giving it the potential for use in pancreatic cell therapies and tissue engineering.
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Affiliation(s)
| | - Yue Du
- Department of Public Health, Tianjin Medical University, Tianjin, China
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36
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The microbiota and aging microenvironment in pancreatic cancer: Cell origin and fate. Biochim Biophys Acta Rev Cancer 2022; 1877:188826. [DOI: 10.1016/j.bbcan.2022.188826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 10/14/2022] [Accepted: 10/15/2022] [Indexed: 11/30/2022]
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Xiang H, Yu H, Zhou Q, Wu Y, Ren J, Zhao Z, Tao X, Dong D. Macrophages: A rising star in immunotherapy for chronic pancreatitis. Pharmacol Res 2022; 185:106508. [DOI: 10.1016/j.phrs.2022.106508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 10/10/2022] [Indexed: 11/29/2022]
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Wu Y, Zhang C, Guo M, Hu W, Qiu Y, Li M, Xu D, Wu P, Sun J, Shi R, Zhang Z, Jiang K. Targeting pancreatic stellate cells in chronic pancreatitis: Focus on therapeutic drugs and natural compounds. Front Pharmacol 2022; 13:1042651. [PMID: 36339568 PMCID: PMC9627273 DOI: 10.3389/fphar.2022.1042651] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/10/2022] [Indexed: 11/21/2022] Open
Abstract
Chronic pancreatitis (CP) is a precancerous illness linked to pancreatic ductal adenocarcinoma (PDAC), although the evolutionary mechanism is uncertain. CP is distinguished by severe fibrosis caused by the activation of pancreatic stellate cells (PSCs). The current clinical therapeutic protocol for CP lacks specific therapeutic medicines for the prevention and suppression of inflammation and fibrosis aggravating in CP. More research on specifically targeting PSCs would help facilitate the development of novel therapies for pancreatic fibrosis. Notably, using natural compounds from medicinal plants as new antifibrotic agents has become a focus of recent research and is widely employed as an alternative and complementary approach. Our goal was to shed light on the role of PSCs in the development of CP and provide a focused update on the new potential therapeutic strategies against PSCs in CP models. Future studies can refer to these possible strategies for drug design, bioavailability, pharmacokinetics, and other issues to obtain better clinical outcomes for treating CP.
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Affiliation(s)
- Yang Wu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chun Zhang
- Gastroenterology Department, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Mei Guo
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Weikang Hu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yangling Qiu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mengran Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Dong Xu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Pengfei Wu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jing Sun
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Run Shi
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Zili Zhang, ; Kuirong Jiang,
| | - Kuirong Jiang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Zili Zhang, ; Kuirong Jiang,
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Liu Y, Wu X, Chen F, Li H, Wang T, Liu N, Sun K, Zhou G, Tao K. Modulating cancer-stroma crosstalk by a nanoparticle-based photodynamic method to pave the way for subsequent therapies. Biomaterials 2022; 289:121813. [PMID: 36152513 DOI: 10.1016/j.biomaterials.2022.121813] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 11/02/2022]
Abstract
Cancer cells and their stromal microenvironment are mutually supportive. Either destroying cancer cells or damaging stromal components cannot guarantee a satisfactory outcome in the long-term treatment. Herein, we showed that the tumor-stroma crosstalk was disturbed by nanoparticle-based photodynamic therapy (PDT) in pancreatic tumor models, leading to the persistent inhibition of extracellular matrix (ECM) secretion and the enhanced therapeutic effect. By employing a conditioned medium method, we found that the nanoparticulate PDT at a sub-lethal dosage down-regulated TGFβ signaling pathways, leading to the decrease in drug resistance, proliferation, and migration of the cancer cells. Meanwhile, pancreatic stellate cells (PSCs) were inactivated by PDT, hindering the secretion of ECM. Combining the results that PDT indiscriminately killed PSCs and cancer cells, we showed that the mutual support between the cancer cells and the stroma was interrupted. We further presented the inhibition of the crosstalk persistently enhanced tumor penetration in stroma-rich pancreatic tumor models. The loosened stroma not only facilitated tumor eradication by subsequent therapy but also improved the efficiency of gemcitabine treatment on monthly later recurrent tumors. Therefore, our work may boost the potential of PDT to be a valuable individual or adjuvant treatment for desmoplastic cancers.
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Affiliation(s)
- Yan Liu
- Shanghai Key Laboratory of Tissue Engineering, Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China; State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, PR China
| | - Xiaodi Wu
- Research Institute of Plastic Surgery, Wei Fang Medical College, Wei Fang, Shandong, 261042, PR China
| | - Feifan Chen
- Research Institute of Plastic Surgery, Wei Fang Medical College, Wei Fang, Shandong, 261042, PR China
| | - Hao Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China
| | - Tao Wang
- Research Institute of Plastic Surgery, Wei Fang Medical College, Wei Fang, Shandong, 261042, PR China
| | - Ningning Liu
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, PR China
| | - Kang Sun
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
| | - Guangdong Zhou
- Shanghai Key Laboratory of Tissue Engineering, Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China; Research Institute of Plastic Surgery, Wei Fang Medical College, Wei Fang, Shandong, 261042, PR China.
| | - Ke Tao
- State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, PR China.
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Abstract
It has been 30 years since the first member of the protease-activated receptor (PAR) family was discovered. This was followed by the discovery of three other receptors, including PAR2. PAR2 is a G protein-coupled receptor activated by trypsin site-specific proteolysis. The process starts with serine proteases acting between arginine and serine, creating an N-terminus that functions as a tethered ligand that binds, after a conformational change, to the second extracellular loop of the receptor, leading to activation of G-proteins. The physiological and pathological functions of this ubiquitous receptor are still elusive. This review focuses on PAR2 activation and its distribution under physiological and pathological conditions, with a particular focus on the pancreas, a significant producer of trypsin, which is the prototype activator of the receptor. The role in acute or chronic pancreatitis, pancreatic cancer, and diabetes mellitus will be highlighted.
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Affiliation(s)
- Petr SUHAJ
- Department of Pathology and Molecular Medicine, Thomayer University Hospital, Prague, Czech Republic,Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Tomas OLEJAR
- Department of Pathology and Molecular Medicine, Thomayer University Hospital, Prague, Czech Republic,Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Radoslav MATEJ
- Department of Pathology and Molecular Medicine, Thomayer University Hospital, Prague, Czech Republic,Department of Pathology, University Hospital Kralovske Vinohrady, Prague, Czech Republic,Third Faculty of Medicine, Charles University, Prague, Czech Republic
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Chu X, Yang Y, Tian X. Crosstalk between Pancreatic Cancer Cells and Cancer-Associated Fibroblasts in the Tumor Microenvironment Mediated by Exosomal MicroRNAs. Int J Mol Sci 2022; 23:ijms23179512. [PMID: 36076911 PMCID: PMC9455258 DOI: 10.3390/ijms23179512] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/15/2022] [Accepted: 08/19/2022] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant digestive tumors, characterized by a low rate of early diagnosis, strong invasiveness, and early metastasis. The abundant stromal cells, dense extracellular matrix, and lack of blood supply in PDAC limit the penetration of chemotherapeutic drugs, resulting in poor efficacy of the current treatment regimens. Cancer-associated fibroblasts (CAFs) are the major stromal cells in the tumor microenvironment. Tumor cells can secrete exosomes to promote the generation of activated CAFs, meanwhile exosomes secreted by CAFs help promote tumor progression. The aberrant expression of miRNAs in exosomes is involved in the interaction between tumor cells and CAFs, which provides the possibility for the application of exosomal miRNAs in the diagnosis and treatment of PDAC. The current article reviews the mechanism of exosomal miRNAs in the crosstalk between PDAC cells and CAFs in the tumor microenvironment, in order to improve the understanding of TME regulation and provide evidence for designing diagnostic and therapeutic targets against exosome miRNA in human PDAC.
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Monteiro MV, Ferreira LP, Rocha M, Gaspar VM, Mano JF. Advances in bioengineering pancreatic tumor-stroma physiomimetic Biomodels. Biomaterials 2022; 287:121653. [PMID: 35803021 DOI: 10.1016/j.biomaterials.2022.121653] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 06/20/2022] [Accepted: 06/24/2022] [Indexed: 01/18/2023]
Abstract
Pancreatic cancer exhibits a unique bioarchitecture and desmoplastic cancer-stoma interplay that governs disease progression, multi-resistance, and metastasis. Emulating the biological features and microenvironment heterogeneity of pancreatic cancer stroma in vitro is remarkably complex, yet highly desirable for advancing the discovery of innovative therapeutics. Diverse bioengineering approaches exploiting patient-derived organoids, cancer-on-a-chip platforms, and 3D bioprinted living constructs have been rapidly emerging in an endeavor to seamlessly recapitulate major tumor-stroma biodynamic interactions in a preclinical setting. Gathering on this, herein we showcase and discuss the most recent advances in bio-assembling pancreatic tumor-stroma models that mimic key disease hallmarks and its desmoplastic biosignature. A reverse engineering perspective of pancreatic tumor-stroma key elementary units is also provided and complemented by a detailed description of biodesign guidelines that are to be considered for improving 3D models physiomimetic features. This overview provides valuable examples and starting guidelines for researchers envisioning to engineer and characterize stroma-rich biomimetic tumor models. All in all, leveraging advanced bioengineering tools for capturing stromal heterogeneity and dynamics, opens new avenues toward generating more predictive and patient-personalized organotypic 3D in vitro platforms for screening transformative therapeutics targeting the tumor-stroma interplay.
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Affiliation(s)
- Maria V Monteiro
- Department of Chemistry, CICECO, University of Aveiro, Campus Universitário de Santiago, 3810-193, Aveiro, Portugal
| | - Luís P Ferreira
- Department of Chemistry, CICECO, University of Aveiro, Campus Universitário de Santiago, 3810-193, Aveiro, Portugal
| | - Marta Rocha
- Department of Chemistry, CICECO, University of Aveiro, Campus Universitário de Santiago, 3810-193, Aveiro, Portugal
| | - Vítor M Gaspar
- Department of Chemistry, CICECO, University of Aveiro, Campus Universitário de Santiago, 3810-193, Aveiro, Portugal.
| | - João F Mano
- Department of Chemistry, CICECO, University of Aveiro, Campus Universitário de Santiago, 3810-193, Aveiro, Portugal.
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Li M, Yuan Y, Han X, Liu X, Zhang W, Hao J. Antioxidant Mitoquinone Alleviates Chronic Pancreatitis via Anti-Fibrotic and Antioxidant Effects. J Inflamm Res 2022; 15:4409-4420. [PMID: 35945990 PMCID: PMC9357395 DOI: 10.2147/jir.s357394] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 07/04/2022] [Indexed: 12/06/2022] Open
Abstract
Background Chronic pancreatitis (CP) is a long-term inflammatory disease of the pancreas that can be caused by various pathogenic factors. Oxidative stress (OS), which is associated with several pancreatic diseases, can induce pancreatic stellate cell (PSC) activation, leading to pancreatic fibrosis. Given the inefficacy of existing treatments for CP, in this study, our objective was to evaluate the therapeutic effect of the antioxidant, mitoquinone (MitoQ). Methods First, in vivo, we established a CP mouse model via the repeated injection of cerulein. Mice in the MitoQ group simultaneously received MitoQ daily. After 4 weeks of cerulein injection, pancreatic tissues from mice were evaluated by morphological changes and the expression of fibrosis markers. Further, OS in the collected pancreatic tissue samples was evaluated by determining the level of malondialdehyde (MDA) as well as the expression levels and activities of antioxidants. Furthermore, in vitro, the effect of MitoQ on human PSCs (hPSCs) was evaluated based on PSC activation markers and fibrotic phenotypes, and OS in these treated hPSCs was evaluated by measuring reactive oxygen species (ROS), MDA, and antioxidant levels. Results In vivo, MitoQ alleviated pancreatic fibrosis and inhibited OS in the cerulein-induced murine CP model. In vitro, it inhibited PSC activation as well as the subsequent development of the profibrogenic phenotypes by balancing out the levels of free radicals and the intracellular antioxidant system. Conclusion MitoQ is a potential candidate for CP treatment.
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Affiliation(s)
- Miaomiao Li
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Yue Yuan
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Xue Han
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, People’s Republic of China
| | - Xinjuan Liu
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, People’s Republic of China
- Weizhen Zhang, Department of Physiology and Pathophysiology, Peking University Health Science Center, No. 38, Xueyuan Road, Haidian District, Beijing, 100191, Email
| | - Jianyu Hao
- Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China
- Correspondence: Jianyu Hao, Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, South Road of Workers Stadium, Chaoyang District, Beijing, 100020, Email
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Yao W, Luo D, Lv Z, Yang Y, Wang L, Ma B, Xue D, Hao C, Zhang Y. The Rabep1-Mediated Endocytosis and Activation of Trypsinogen to Promote Pancreatic Stellate Cell Activation. Biomolecules 2022; 12:biom12081063. [PMID: 36008957 PMCID: PMC9406084 DOI: 10.3390/biom12081063] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/26/2022] [Accepted: 07/29/2022] [Indexed: 02/01/2023] Open
Abstract
Background: The pathogenesis of chronic pancreatitis is still unclear. Trypsinogen activation is an active factor in acute pancreatitis that has not been studied in the occurrence of chronic pancreatitis. Methods: Immunofluorescence was used to detect the location and expression of trypsinogen in chronic pancreatitis and normal tissues. Microarray and single-cell RNA-seq (scRNA-seq) were used to screen core genes and pathways in pancreatic stellate cells (PSCs). Western blotting and immunofluorescence were used to verify trypsinogen expression in PSCs after silencing Rabep1. Immunofluorescence and flow cytometry were used to validate trypsinogen activation and PSC activation after intervening in the endocytosis pathway. Results: Endocytosed trypsinogen was found in PSCs in CP clinical samples. Bioinformatic analysis showed that Rabep1 is a core gene that regulates trypsinogen endocytosis through the endocytosis pathway, verified by Western blot and immunofluorescence. Immunofluorescence and flow cytometry analyses confirmed the activation of trypsinogen and PSCs through the endocytosis pathway in PSCs. Conclusion: This study discovered a new mechanism by which trypsinogen affects the activation of PSCs and the occurrence and development of CP. Through communication between pancreatic acinar cells and PSCs, trypsinogen can be endocytosed by PSCs and activated by the Rabep1 gene.
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Affiliation(s)
- Wenchao Yao
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; (W.Y.); (D.L.); (Z.L.); (Y.Y.); (L.W.); (B.M.); (D.X.)
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Dankun Luo
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; (W.Y.); (D.L.); (Z.L.); (Y.Y.); (L.W.); (B.M.); (D.X.)
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Zhenyi Lv
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; (W.Y.); (D.L.); (Z.L.); (Y.Y.); (L.W.); (B.M.); (D.X.)
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Yang Yang
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; (W.Y.); (D.L.); (Z.L.); (Y.Y.); (L.W.); (B.M.); (D.X.)
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Liyi Wang
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; (W.Y.); (D.L.); (Z.L.); (Y.Y.); (L.W.); (B.M.); (D.X.)
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Biao Ma
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; (W.Y.); (D.L.); (Z.L.); (Y.Y.); (L.W.); (B.M.); (D.X.)
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Dongbo Xue
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; (W.Y.); (D.L.); (Z.L.); (Y.Y.); (L.W.); (B.M.); (D.X.)
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Chenjun Hao
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; (W.Y.); (D.L.); (Z.L.); (Y.Y.); (L.W.); (B.M.); (D.X.)
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
- Correspondence: (C.H.); (Y.Z.)
| | - Yingmei Zhang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
- Correspondence: (C.H.); (Y.Z.)
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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.
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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.
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Yang Z, Xie Z, Wan J, Yi B, Xu T, Shu X, Zhao Z, Tang C. Current Trends and Research Hotspots in Pancreatic Stellate Cells: A Bibliometric Study. Front Oncol 2022; 12:896679. [PMID: 35719926 PMCID: PMC9198254 DOI: 10.3389/fonc.2022.896679] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 05/04/2022] [Indexed: 12/19/2022] Open
Abstract
Background Pancreatic stellate cells (PSCs) play crucial roles in acute/chronic pancreatitis and pancreatic cancer. In this study, bibliometric analysis was used to quantitatively and qualitatively analyze the literature related to PSCs from 1998-2021 to summarize the current trends and research topics in this field. Methods Relevant literature data were downloaded from the Science Citation Index Expanded Web of Science Core Collection (WoSCC) on April 07, 2021, using Clarivate Analytics. Biblioshiny R packages, VOSviewer, Citespace, BICOMB, gCLUTO, and the Online Analysis Platform of Literature Metrology (http://bibliometric.com) were used to analyze the manually selected data. Results A total of 958 relevant studies published in 48 countries or regions were identified. The United States of America (USA) had the highest number of publications, followed by the People's Republic of China, Germany, and Japan. Tohoku University (Japan), the University of New South Wales (Australia), the University of Texas MD Anderson Cancer Center (USA), Technical University of Munich (Germany), and University of Rostock (Germany) were the top five institutions with most publications. Nine major clusters were generated using reference co-citation analysis. Keyword burst detection revealed that progression (2016-2021), microenvironment (2016-2021), and tumor microenvironment (2017-2021) were the current frontier keywords. Biclustering analysis identified five research hotspots in the field of PSCs during 1998-2021. Conclusion In this study, a scientometric analysis of 958 original documents related to PSCs showed that the research topics of these studies are likely in the transition from acute/chronic pancreatitis to pancreatic cancer. The current research trends regarding PSCs are related to pancreatic cancer, such as tumor microenvironment. This study summarizes five research hotspots in the field of PSCs between 1998 and 2021 and thus may provide insights for future research.
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Affiliation(s)
- Zhaoming Yang
- Department of Hepatobiliary, Pancreatic and Splenic Surgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Zhiqin Xie
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jian Wan
- Department of Hepatobiliary, Pancreatic and Splenic Surgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Bo Yi
- Department of Hepatobiliary, Pancreatic and Splenic Surgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Tao Xu
- Department of Hepatobiliary, Pancreatic and Splenic Surgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Xiaorong Shu
- Medical Records Statistics Center, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Zhijian Zhao
- Department of Hepatobiliary, Pancreatic and Splenic Surgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
| | - Caixi Tang
- Department of Hepatobiliary, Pancreatic and Splenic Surgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China
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Zheng M, Gao R. Vitamin D: A Potential Star for Treating Chronic Pancreatitis. Front Pharmacol 2022; 13:902639. [PMID: 35734414 PMCID: PMC9207250 DOI: 10.3389/fphar.2022.902639] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 05/13/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic pancreatitis (CP) is a chronic inflammatory and fibrotic disease of the pancreas. The incidence of CP is increasing worldwide but the effective therapies are lacking. Hence, it is necessary to identify economical and effective agents for the treatment of CP patients. Vitamin D (VD) and its analogues have been confirmed as pleiotropic regulators of cell proliferation, apoptosis, differentiation and autophagy. Clinical studies show that VD deficiency is prevalent in CP patients. However, the correlation between VD level and the risk of CP remains controversial. VD and its analogues have been demonstrated to inhibit pancreatic fibrosis by suppressing the activation of pancreatic stellate cells and the production of extracellular matrix. Limited clinical trials have shown that the supplement of VD can improve VD deficiency in patients with CP, suggesting a potential therapeutic value of VD in CP. However, the mechanisms by which VD and its analogues inhibit pancreatic fibrosis have not been fully elucidated. We are reviewing the current literature concerning the risk factors for developing CP, prevalence of VD deficiency in CP, mechanisms of VD action in PSC-mediated fibrogenesis during the development of CP and potential therapeutic applications of VD and its analogues in the treatment of CP.
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Zhang J, Bai J, Zhou Q, Hu Y, Wang Q, Yang L, Chen H, An H, Zhou C, Wang Y, Chen X, Li M. Glutathione prevents high glucose-induced pancreatic fibrosis by suppressing pancreatic stellate cell activation via the ROS/TGFβ/SMAD pathway. Cell Death Dis 2022; 13:440. [PMID: 35523788 PMCID: PMC9076672 DOI: 10.1038/s41419-022-04894-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 04/25/2022] [Accepted: 04/28/2022] [Indexed: 12/14/2022]
Abstract
The activation of pancreatic stellate cells (PSCs) is the key mechanism of pancreatic fibrosis, which can lead to β-cell failure. Oxidative stress is an important risk factor for PSC activation. There is no direct evidence proving if administration of glutathione can inhibit fibrosis and β-cell failure. To explore the role of glutathione in pancreatic fibrosis and β-cell failure induced by hyperglycaemia, we established a rat model of pancreatic fibrosis and β-cell failure. The model was founded through long-term oscillating glucose (LOsG) intake and the setup of a sham group and a glutathione intervention group. In vitro, rat PSCs were treated with low glucose, high glucose, or high glucose plus glutathione to explore the mechanism of high glucose-induced PSC activation and the downstream effects of glutathione. Compared with sham rats, LOsG-treated rats had higher reactive oxygen species (ROS) levels in peripheral leukocytes and pancreatic tissue while TGFβ signalling was upregulated. In addition, as the number of PSCs and pancreatic fibrosis increased, β-cell function was significantly impaired. Glutathione evidently inhibited the upregulation of TGFβ signalling and several unfavourable outcomes caused by LOsG. In vitro treatment of high glucose for 72 h resulted in higher ROS accumulation and potentiated TGFβ pathway activation in PSCs. PSCs showed myofibroblast phenotype transformation with upregulation of α-SMA expression and increased cell proliferation and migration. Treatment with either glutathione or TGFβ pathway inhibitors alleviated these changes. Together, our findings suggest that glutathione can inhibit PSC activation-induced pancreatic fibrosis via blocking ROS/TGFβ/SMAD signalling in vivo and in vitro.
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Affiliation(s)
- Jitai Zhang
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Juan Bai
- grid.268099.c0000 0001 0348 3990Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qian Zhou
- grid.268099.c0000 0001 0348 3990Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yuxin Hu
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qian Wang
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Lanting Yang
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Huamin Chen
- grid.268099.c0000 0001 0348 3990Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Hui An
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China ,grid.417384.d0000 0004 1764 2632Department of Anesthesia and Critical Care, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chuanzan Zhou
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yongyu Wang
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Xiufang Chen
- grid.268099.c0000 0001 0348 3990Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ming Li
- grid.268099.c0000 0001 0348 3990Cardiac Regeneration Research Institute, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China ,grid.417384.d0000 0004 1764 2632The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
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Hrabák P, Kalousová M, Krechler T, Zima T. Pancreatic stellate cells - rising stars in pancreatic pathologies. Physiol Res 2021. [DOI: 10.33549//physiolres.934783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Pluripotent pancreatic stellate cells (PSCs) receive growing interest in past decades. Two types of PSCs are recognized –vitamin A accumulating quiescent PSCs and activated PSCs- the main producents of extracellular matrix in pancreatic tissue. PSCs plays important role in pathogenesis of pancreatic fibrosis in pancreatic cancer and chronic pancreatitis. PSCs are intensively studied as potential therapeutical target because of their important role in developing desmoplastic stroma in pancreatic cancer. There also exists evidence that PSC are involved in other pathologies like type-2 diabetes mellitus. This article brings brief characteristics of PSCs and recent advances in research of these cells.
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Affiliation(s)
| | - M Kalousová
- 2Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic.
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Herring B, Jang S, Whitt J, Goliwas K, Aburjania Z, Dudeja V, Ren B, Berry J, Bibb J, Frost A, Chen H, Rose JB, Jaskula-Sztul R. Ex Vivo Modeling of Human Neuroendocrine Tumors in Tissue Surrogates. Front Endocrinol (Lausanne) 2021; 12:710009. [PMID: 35002949 PMCID: PMC8734644 DOI: 10.3389/fendo.2021.710009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 11/10/2021] [Indexed: 12/24/2022] Open
Abstract
Few models exist for studying neuroendocrine tumors (NETs), and there are mounting concerns that the currently available array of cell lines is not representative of NET biology. The lack of stable patient-derived NET xenograft models further limits the scientific community's ability to make conclusions about NETs and their response to therapy in patients. To address these limitations, we propose the use of an ex vivo 3D flow-perfusion bioreactor system for culturing and studying patient-derived NET surrogates. Herein, we demonstrate the utility of the bioreactor system for culturing NET surrogates and provide methods for evaluating the efficacy of therapeutic agents on human NET cell line xenograft constructs and patient-derived NET surrogates. We also demonstrate that patient-derived NET tissues can be propagated using the bioreactor system and investigate the near-infrared (NIR) dye IR-783 for its use in monitoring their status within the bioreactor. The results indicate that the bioreactor system and similar 3D culture models may be valuable tools for culturing patient-derived NETs and monitoring their response to therapy ex vivo.
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Affiliation(s)
- Brendon Herring
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Samuel Jang
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Jason Whitt
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Kayla Goliwas
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Zviadi Aburjania
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Vikas Dudeja
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Bin Ren
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Joel Berry
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, United States
| | - James Bibb
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Andra Frost
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Herbert Chen
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - John Bart Rose
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Renata Jaskula-Sztul
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
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