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Zou J, Jiang C, Hu Q, Jia X, Wang S, Wan S, Mao Y, Zhang D, Zhang P, Dai B, Li Y. Tumor microenvironment-responsive engineered hybrid nanomedicine for photodynamic-immunotherapy via multi-pronged amplification of reactive oxygen species. Nat Commun 2025; 16:424. [PMID: 39762214 PMCID: PMC11704041 DOI: 10.1038/s41467-024-55658-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Reactive oxygen species (ROS) is promising in cancer therapy by accelerating tumor cell death, whose therapeutic efficacy, however, is greatly limited by the hypoxia in the tumor microenvironment (TME) and the antioxidant defense. Amplification of oxidative stress has been successfully employed for tumor therapy, but the interactions between cancer cells and the other factors of TME usually lead to inadequate tumor treatments. To tackle this issue, we develop a pH/redox dual-responsive nanomedicine based on the remodeling of cancer-associated fibroblasts (CAFs) for multi-pronged amplification of ROS (ZnPP@FQOS). It is demonstrated that ROS generated by ZnPP@FQOS is endogenously/exogenously multiply amplified owing to the CAFs remodeling and down-regulation of anti-oxidative stress in cancer cells, ultimately achieving the efficient photodynamic therapy in a female tumor-bearing mouse model. More importantly, ZnPP@FQOS is verified to enable the stimulation of enhanced immune responses and systemic immunity. This strategy remarkably potentiates the efficacy of photodynamic-immunotherapy, thus providing a promising enlightenment for tumor therapy.
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Grants
- This work was financially supported by the National Key Research and Development Program of China (No. 2022YFC2403203, Y.L.), the National Natural Science Foundation of China (No. 22305081, D.Z.), Basic Research Program of Shanghai (No. 21JC1406003, Y.L.), Leading Talents in Shanghai in 2018, the Key Field Research Program (No. 2023AB054, Y.L.), Shanghai Sailing Program (23YF1408600, D.Z.) and the Innovation Program of Shanghai Municipal Education Commission (No. 2023ZKZD33, P.Z.)
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Affiliation(s)
- Jinglin Zou
- Lab of Low-Dimensional Materials Chemistry, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontier Science Center of the Materials Biology and Dynamic Chemistry, Shanghai Engineering Research Center of Hierarchical Nanomaterials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China
| | - Cong Jiang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qiangsheng Hu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xinlin Jia
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuqi Wang
- Lab of Low-Dimensional Materials Chemistry, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontier Science Center of the Materials Biology and Dynamic Chemistry, Shanghai Engineering Research Center of Hierarchical Nanomaterials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China
| | - Shiyue Wan
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuanqing Mao
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dapeng Zhang
- Lab of Low-Dimensional Materials Chemistry, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontier Science Center of the Materials Biology and Dynamic Chemistry, Shanghai Engineering Research Center of Hierarchical Nanomaterials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China
| | - Peng Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Bin Dai
- Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and Chemical Engineering, Shihezi University, Shihezi, China
| | - Yongsheng Li
- Lab of Low-Dimensional Materials Chemistry, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontier Science Center of the Materials Biology and Dynamic Chemistry, Shanghai Engineering Research Center of Hierarchical Nanomaterials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China.
- Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and Chemical Engineering, Shihezi University, Shihezi, China.
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2
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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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3
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Wang Y, Jiao L, Qiang C, Chen C, Shen Z, Ding F, Lv L, Zhu T, Lu Y, Cui X. The role of matrix metalloproteinase 9 in fibrosis diseases and its molecular mechanisms. Biomed Pharmacother 2024; 171:116116. [PMID: 38181715 DOI: 10.1016/j.biopha.2023.116116] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/25/2023] [Accepted: 12/29/2023] [Indexed: 01/07/2024] Open
Abstract
Fibrosis is a process of tissue repair that results in the slow creation of scar tissue to replace healthy tissue and can affect any tissue or organ. Its primary feature is the massive deposition of extracellular matrix (mainly collagen), eventually leading to tissue dysfunction and organ failure. The progression of fibrotic diseases has put a significant strain on global health and the economy, and as a result, there is an urgent need to find some new therapies. Previous studies have identified that inflammation, oxidative stress, some cytokines, and remodeling play a crucial role in fibrotic diseases and are essential avenues for treating fibrotic diseases. Among them, matrix metalloproteinases (MMPs) are considered the main targets for the treatment of fibrotic diseases since they are the primary driver involved in ECM degradation, and tissue inhibitors of metalloproteinases (TIMPs) are natural endogenous inhibitors of MMPs. Through previous studies, we found that MMP-9 is an essential target for treating fibrotic diseases. However, it is worth noting that MMP-9 plays a bidirectional regulatory role in different fibrotic diseases or different stages of the same fibrotic disease. Previously identified MMP-9 inhibitors, such as pirfenidone and nintedanib, suffer from some rather pronounced side effects, and therefore, there is an urgent need to investigate new drugs. In this review, we explore the mechanism of action and signaling pathways of MMP-9 in different tissues and organs, hoping to provide some ideas for developing safer and more effective biologics.
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Affiliation(s)
- Yuling Wang
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Linke Jiao
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Caoxia Qiang
- Department of Traditional Chinese Medicine, Tumor Hospital Affiliated to Nantong University, Jiangsu, China
| | - Chen Chen
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zihuan Shen
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Fan Ding
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China; Graduate School of Beijing University of Chinese Medicine, Beijing, China
| | - Lifei Lv
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Tingting Zhu
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yingdong Lu
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiangning Cui
- Department of Cardiovascular Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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McCarthy GA, Di Niro R, Finan JM, Jain A, Guo Y, Wyatt C, Guimaraes A, Waugh T, Keith D, Morgan T, Sears R, Brody J. Deletion of the mRNA stability factor ELAVL1 (HuR) in pancreatic cancer cells disrupts the tumor microenvironment integrity. NAR Cancer 2023; 5:zcad016. [PMID: 37089813 PMCID: PMC10113877 DOI: 10.1093/narcan/zcad016] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 03/08/2023] [Accepted: 04/06/2023] [Indexed: 04/25/2023] Open
Abstract
Stromal cells promote extensive fibrosis in pancreatic ductal adenocarcinoma (PDAC), which is associated with poor prognosis and therapeutic resistance. We report here for the first time that loss of the RNA-binding protein human antigen R (HuR, ELAVL1) in PDAC cells leads to reprogramming of the tumor microenvironment. In multiple in vivo models, CRISPR deletion of ELAVL1 in PDAC cells resulted in a decrease of collagen deposition, accompanied by a decrease of stromal markers (i.e. podoplanin, α-smooth muscle actin, desmin). RNA-sequencing data showed that HuR plays a role in cell-cell communication. Accordingly, cytokine arrays identified that HuR regulates the secretion of signaling molecules involved in stromal activation and extracellular matrix organization [i.e. platelet-derived growth factor AA (PDGFAA) and pentraxin 3]. Ribonucleoprotein immunoprecipitation analysis and transcription inhibition studies validated PDGFA mRNA as a novel HuR target. These data suggest that tumor-intrinsic HuR supports extrinsic activation of the stroma to produce collagen and desmoplasia through regulating signaling molecules (e.g. PDGFAA). HuR-deficient PDAC in vivo tumors with an altered tumor microenvironment are more sensitive to the standard of care gemcitabine, as compared to HuR-proficient tumors. Taken together, we identified a novel role of tumor-intrinsic HuR in its ability to modify the surrounding tumor microenvironment and regulate PDGFAA.
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Affiliation(s)
- Grace A McCarthy
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
| | - Roberto Di Niro
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
| | - Jennifer M Finan
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
| | - Aditi Jain
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Yifei Guo
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
| | - Cory R Wyatt
- Department of Diagnostic Radiology, Oregon Health & Science University, Portland, OR 97239, USA
- Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR 97239, USA
| | - Alexander R Guimaraes
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
- Department of Diagnostic Radiology, Oregon Health & Science University, Portland, OR 97239, USA
- Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR 97239, USA
| | - Trent A Waugh
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
| | - Dove Keith
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
| | - Terry K Morgan
- Department of Pathology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Rosalie C Sears
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR 97201, USA
| | - Jonathan R Brody
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
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5
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TRPM7 Modulates Human Pancreatic Stellate Cell Activation. Cells 2022; 11:cells11142255. [PMID: 35883700 PMCID: PMC9316618 DOI: 10.3390/cells11142255] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/10/2022] [Accepted: 07/19/2022] [Indexed: 01/27/2023] Open
Abstract
Pancreatic diseases, such as pancreatitis or pancreatic ductal adenocarcinoma, are characterized by the presence of activated pancreatic stellate cells (PSCs). These cells represent key actors in the tumor stroma, as they actively participate in disease development and progression: reprograming these PSCs into a quiescent phenotype has even been proposed as a promising strategy for restoring the hallmarks of a healthy pancreas. Since TRPM7 channels have been shown to regulate hepatic stellate cells proliferation and survival, we aimed to study the role of these magnesium channels in PSC activation and proliferation. PS-1 cells (isolated from a healthy pancreas) were used as a model of healthy PSCs: quiescence or activation were induced using all-trans retinoic acid or conditioned media of pancreatic cancer cells, respectively. The role of TRPM7 was studied by RNA silencing or by pharmacological inhibition. TRPM7 expression was found to be correlated with the activation status of PS-1 cells. TRPM7 expression was able to regulate proliferation through modulation of cell cycle regulators and most importantly p53, via the PI3K/Akt pathway, in a magnesium-dependent manner. Finally, the analysis of TCGA database showed the overexpression of TRPM7 in cancer-associated fibroblasts. Taken together, we provide strong evidences that TRPM7 can be considered as a marker of activated PSCs.
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6
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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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7
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Lu T, Prakash J. Nanomedicine Strategies to Enhance Tumor Drug Penetration in Pancreatic Cancer. Int J Nanomedicine 2021; 16:6313-6328. [PMID: 34552327 PMCID: PMC8450289 DOI: 10.2147/ijn.s279192] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/30/2021] [Indexed: 12/24/2022] Open
Abstract
Pancreatic cancer is one of the most malignant tumors with one of the worst survival rates due to its insidious onset and resistance to therapies. Most therapeutics show a desired anticancer effect in vitro; however, very poor efficacy in vivo because of the limited drug delivery and penetration into pancreatic tumors attributed to the abundance of the tumor stroma, ie, the fibrotic tumor microenvironment surrounding the cancer cells. For a better understanding of the challenges posed by the pancreatic tumor stroma, we outline the key features of the tumor microenvironment. Then we highlight major strategies used to tackle the challenges to improve drug penetration into the tumor and achieve enhanced efficacy (pre)clinically. Furthermore, we describe nanomedicine strategies to modulate the tumor stroma, degrade the extracellular matrix, and co-deliver multi-functional drugs, to improve the chemotherapeutics delivery and penetration into pancreatic tumors.
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Affiliation(s)
- Tao Lu
- Engineered Therapeutics Group, Department of Biomaterials Science and Technology, University of Twente, Enschede, The Netherlands
| | - Jai Prakash
- Engineered Therapeutics Group, Department of Biomaterials Science and Technology, University of Twente, Enschede, The Netherlands
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8
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Li J, Chen B, Fellows GF, Goodyer CG, Wang R. Activation of Pancreatic Stellate Cells Is Beneficial for Exocrine but Not Endocrine Cell Differentiation in the Developing Human Pancreas. Front Cell Dev Biol 2021; 9:694276. [PMID: 34490247 PMCID: PMC8418189 DOI: 10.3389/fcell.2021.694276] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 06/14/2021] [Indexed: 02/04/2023] Open
Abstract
Pancreatic stellate cells (PaSCs) are non-endocrine, mesenchymal-like cells that reside within the peri-pancreatic tissue of the rodent and human pancreas. PaSCs regulate extracellular matrix (ECM) turnover in maintaining the integrity of pancreatic tissue architecture. Although there is evidence indicating that PaSCs are involved in islet cell survival and function, its role in islet cell differentiation during human pancreatic development remains unclear. The present study examines the expression pattern and functional role of PaSCs in islet cell differentiation of the developing human pancreas from late 1st to 2nd trimester of pregnancy. The presence of PaSCs in human pancreata (8–22 weeks of fetal age) was characterized by ultrastructural, immunohistological, quantitative RT-PCR and western blotting approaches. Using human fetal PaSCs derived from pancreata at 14–16 weeks, freshly isolated human fetal islet-epithelial cell clusters (hIECCs) were co-cultured with active or inactive PaSCs in vitro. Ultrastructural and immunofluorescence analysis demonstrated a population of PaSCs near ducts and newly formed islets that appeared to make complex cell-cell dendritic-like contacts. A small subset of PaSCs co-localized with pancreatic progenitor-associated transcription factors (PDX1, SOX9, and NKX6-1). PaSCs were highly proliferative, with significantly higher mRNA and protein levels of PaSC markers (desmin, αSMA) during the 1st trimester of pregnancy compared to the 2nd trimester. Isolated human fetal PaSCs were identified by expression of stellate cell markers and ECM. Suppression of PaSC activation, using all-trans retinoic acid (ATRA), resulted in reduced PaSC proliferation and ECM proteins. Co-culture of hIECCs, directly on PaSCs or indirectly using Millicell® Inserts or using PaSC-conditioned medium, resulted in a reduction the number of insulin+ cells but a significant increase in the number of amylase+ cells. Suppression of PaSC activation or Notch activity during the co-culture resulted in an increase in beta-cell differentiation. This study determined that PaSCs, abundant during the 1st trimester of pancreatic development but decreased in the 2nd trimester, are located near ductal and islet structures. Direct and indirect co-cultures of hIECCs with PaSCs suggest that activation of PaSCs has opposing effects on beta-cell and exocrine cell differentiation during human fetal pancreas development, and that these effects may be dependent on Notch signaling.
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Affiliation(s)
- Jinming Li
- Children's Health Research Institute, Western University, London, ON, Canada.,Departments of Physiology and Pharmacology, Western University, London, ON, Canada
| | - Bijun Chen
- Children's Health Research Institute, Western University, London, ON, Canada
| | - George F Fellows
- Department of Obstetrics and Gynecology, Western University, London, ON, Canada
| | | | - Rennian Wang
- Children's Health Research Institute, Western University, London, ON, Canada.,Departments of Physiology and Pharmacology, Western University, London, ON, Canada
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Cannon A, Thompson CM, Bhatia R, Armstrong KA, Solheim JC, Kumar S, Batra SK. Molecular mechanisms of pancreatic myofibroblast activation in chronic pancreatitis and pancreatic ductal adenocarcinoma. J Gastroenterol 2021; 56:689-703. [PMID: 34279724 PMCID: PMC9052363 DOI: 10.1007/s00535-021-01800-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/15/2021] [Indexed: 02/04/2023]
Abstract
Pancreatic fibrosis (PF) is an essential component of the pathobiology of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Activated pancreatic myofibroblasts (PMFs) are crucial for the deposition of the extracellular matrix, and fibrotic reaction in response to sustained signaling. Consequently, understanding of the molecular mechanisms of PMF activation is not only critical for understanding CP and PDAC biology but is also a fertile area of research for the development of novel therapeutic strategies for pancreatic pathologies. This review analyzes the key signaling events that drive PMF activation including, initiating signals from transforming growth factor-β1, platelet derived growth factor, as well as other microenvironmental cues, like hypoxia and extracellular matrix rigidity. Further, we discussed the intracellular signal events contributing to PMF activation, and crosstalk with different components of tumor microenvironment. Additionally, association of epidemiologically established risk factors for CP and PDAC, like alcohol intake, tobacco exposure, and metabolic factors with PMF activation, is discussed to comprehend the role of lifestyle factors on pancreatic pathologies. Overall, this analysis provides insight into the biology of PMF activation and highlights salient features of this process, which offer promising therapeutic targets.
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Affiliation(s)
- Andrew Cannon
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Christopher Michael Thompson
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Rakesh Bhatia
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | | | - Joyce Christopher Solheim
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder Kumar Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
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10
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Zhou Y, Wang H, Zhou J, Qiu S, Cai T, Li H, Shen Z, Hu Y, Ding B, Luo M, Huang R, Yan R, Xu W, He C, Zhang Y, Li F, Sun Z, Ma J. Vitamin A and Its Multi-Effects on Pancreas: Recent Advances and Prospects. Front Endocrinol (Lausanne) 2021; 12:620941. [PMID: 33679618 PMCID: PMC7930481 DOI: 10.3389/fendo.2021.620941] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 01/04/2021] [Indexed: 12/16/2022] Open
Abstract
Vitamin A (VA), which is stored in several forms in most tissues, is required to maintain metabolite homeostasis and other processes, including the visual cycle, energy balance, epithelial cell integrity, and infection resistance. In recent years, VA molecules, also known as retinoids, have been extensively explored and used in the treatment of skin disorders and immune-related tumors. To date, several observational and interventional studies have explored the relationship between VA status and the pathogenesis of diabetes. In particular, VA micronutrients have been shown to regulate pancreatic development, β-cell function, pancreatic innate immune responses, and pancreatic stellate cells phenotypes through multiple mechanisms. However, there are still many problems to be proven or resolved. In this review, we summarize and discuss recent and available evidence on VA biological metabolism in the pancreas. Analysis of the effects of VA on metabolism in the pancreas will contribute to our understanding of the supportive physiological roles of VA in pancreas protection.
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Affiliation(s)
- Yunting Zhou
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Huiying Wang
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Junming Zhou
- Department of Cadre Gastroenterology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Shanhu Qiu
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
- Department of Endocrinology, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Tingting Cai
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Huiqin Li
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Ziyang Shen
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yun Hu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Bo Ding
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Menghui Luo
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Rong Huang
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Rengna Yan
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Wei Xu
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Institute of Medical Sciences, Xuzhou Clinical School of Nanjing Medical University, Xuzhou, China
| | - Cong He
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Yumin Zhang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Fengfei Li
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Zilin Sun
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Jianhua Ma
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- *Correspondence: Jianhua Ma,
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11
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Han X, Xu Y, Geranpayehvaghei M, Anderson GJ, Li Y, Nie G. Emerging nanomedicines for anti-stromal therapy against desmoplastic tumors. Biomaterials 2020; 232:119745. [DOI: 10.1016/j.biomaterials.2019.119745] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 11/29/2019] [Accepted: 12/25/2019] [Indexed: 02/09/2023]
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12
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Brachi G, Bussolino F, Ciardelli G, Mattu C. Nanomedicine for Imaging and Therapy of Pancreatic Adenocarcinoma. Front Bioeng Biotechnol 2019; 7:307. [PMID: 31824928 PMCID: PMC6880757 DOI: 10.3389/fbioe.2019.00307] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 10/17/2019] [Indexed: 12/20/2022] Open
Abstract
Pancreatic adenocarcinoma has the worst outcome among all cancer types, with a 5-year survival rate as low as 10%. The lethal nature of this cancer is a result of its silent onset, resistance to therapies, and rapid spreading. As a result, most patients remain asymptomatic and present at diagnosis with an already infiltrating and incurable disease. The tumor microenvironment, composed of a dense stroma and of disorganized blood vessels, coupled with the dysfunctional signal pathways in tumor cells, creates a set of physical and biological barriers that make this tumor extremely hard-to-treat with traditional chemotherapy. Nanomedicine has great potential in pancreatic adenocarcinoma, because of the ability of nano-formulated drugs to overcome biological barriers and to enhance drug accumulation at the target site. Moreover, monitoring of disease progression can be achieved by combining drug delivery with imaging probes, resulting in early detection of metastatic patterns. This review describes the latest development of theranostic formulations designed to concomitantly treat and image pancreatic cancer, with a specific focus on their interaction with physical and biological barriers.
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Affiliation(s)
| | - Federico Bussolino
- Department of Oncology, University of Torino, Turin, Italy
- Candiolo Cancer Institute -IRCCS-FPO, Candiolo, Italy
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13
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Farran B, Nagaraju GP. The dynamic interactions between the stroma, pancreatic stellate cells and pancreatic tumor development: Novel therapeutic targets. Cytokine Growth Factor Rev 2019; 48:11-23. [PMID: 31331827 DOI: 10.1016/j.cytogfr.2019.07.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Revised: 07/09/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023]
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14
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Retinoids in Stellate Cells: Development, Repair, and Regeneration. J Dev Biol 2019; 7:jdb7020010. [PMID: 31137700 PMCID: PMC6630434 DOI: 10.3390/jdb7020010] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 05/15/2019] [Accepted: 05/17/2019] [Indexed: 01/17/2023] Open
Abstract
Stellate cells, either hepatic (HSCs) or pancreatic (PSCs), are a type of interstitial cells characterized by their ability to store retinoids in lipid vesicles. In pathological conditions both HSCs and PSCs lose their retinoid content and transform into fibroblast-like cells, contributing to the fibrogenic response. HSCs also participate in other functions including vasoregulation, drug detoxification, immunotolerance, and maintenance of the hepatocyte population. PSCs maintain pancreatic tissue architecture and regulate pancreatic exocrine function. Recently, PSCs have attracted the attention of researchers due to their interactions with pancreatic ductal adenocarcinoma cells. PSCs promote tumour growth and angiogenesis, and their fibrotic activity increases the resistance of pancreatic cancer to chemotherapy and radiation. We are reviewing the current literature concerning the role played by retinoids in the physiology and pathophysiology of the stellate cells, paying attention to their developmental aspects as well as the function of stellate cells in tissue repair and organ regeneration.
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15
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Ariza L, Rojas A, Muñoz-Chápuli R, Carmona R. The Wilms' tumor suppressor gene regulates pancreas homeostasis and repair. PLoS Genet 2019; 15:e1007971. [PMID: 30763305 PMCID: PMC6392337 DOI: 10.1371/journal.pgen.1007971] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 02/27/2019] [Accepted: 01/16/2019] [Indexed: 12/23/2022] Open
Abstract
The Wilms’ tumor suppressor gene (Wt1) encodes a zinc finger transcription factor that plays an essential role in the development of kidneys, gonads, spleen, adrenals and heart. Recent findings suggest that WT1 could also be playing physiological roles in adults. Systemic deletion of WT1 in mice provokes a severe deterioration of the exocrine pancreas, with mesothelial disruption, E-cadherin downregulation, disorganization of acinar architecture and accumulation of ascitic transudate. Despite this extensive damage, pancreatic stellate cells do not become activated and lose their canonical markers. We observed that pharmacological induction of pancreatitis in normal mice provokes de novo expression of WT1 in pancreatic stellate cells, concomitant with their activation. When pancreatitis was induced in mice after WT1 ablation, pancreatic stellate cells expressed WT1 and became activated, leading to a partial rescue of the acinar structure and the quiescent pancreatic stellate cell population after recovery from pancreatitis. We propose that WT1 modulates through the RALDH2/retinoic acid axis the restabilization of a part of the pancreatic stellate cell population and, indirectly, the repair of the pancreatic architecture, since quiescent pancreatic stellate cells are required for pancreas stability and repair. Thus, we suggest that WT1 plays novel and essential roles for the homeostasis of the adult pancreas and, through its upregulation in pancreatic stellate cells after a damage, for pancreatic regeneration. Due to the growing importance of the pancreatic stellate cells in physiological and pathophysiological conditions, these novel roles can be of translational relevance. The pancreas is largely composed by an exocrine tissue organized in acini, which secrete digestive enzymes. Pancreatic stellate cells (PSC) are arranged around the acini and they can become activated by a damage and contribute to pancreas repair. The pancreas is externally covered by a mesothelium characterized by the expression of the transcription factor WT1. Loss of WT1 function in adult mice provokes a rapid and severe deterioration of the pancreas, with disorganization of the acinar tissue. Despite the extensive damage, PSC do not become activated. We first showed that a pharmacologically induced acute pancreatitis led to expression of WT1 in PSC concomitant to their activation. Then, we induced pancreatitis in mice where WT1 had been previously deleted, and the upregulation of WT1 in PSC partially rescued the repairing phenotype of the PSC and reduced the disorganization of the acinar tissue. Thus, we suggest that WT1 function is necessary to maintain the integrity of the pancreatic mesothelium and, at the same time, it is required for activation of the repairing phenotype in PSC.
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Affiliation(s)
- Laura Ariza
- Department of Animal Biology, Faculty of Science, University of Málaga, Málaga, Spain
- Andalusian Center for Nanomedicine and Biotechnology (BIONAND), Málaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
| | - Anabel Rojas
- Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad Pablo de Olavide, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Ramón Muñoz-Chápuli
- Department of Animal Biology, Faculty of Science, University of Málaga, Málaga, Spain
- Andalusian Center for Nanomedicine and Biotechnology (BIONAND), Málaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
- * E-mail: (RMC); (RC)
| | - Rita Carmona
- Department of Animal Biology, Faculty of Science, University of Málaga, Málaga, Spain
- Andalusian Center for Nanomedicine and Biotechnology (BIONAND), Málaga, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
- * E-mail: (RMC); (RC)
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16
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Schnittert J, Bansal R, Prakash J. Targeting Pancreatic Stellate Cells in Cancer. Trends Cancer 2019; 5:128-142. [PMID: 30755305 DOI: 10.1016/j.trecan.2019.01.001] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/20/2018] [Accepted: 01/03/2019] [Indexed: 02/06/2023]
Abstract
Pancreatic stellate cells (PSCs) are the major contributor to the aggressive, metastatic, and resilient nature of pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis with a 5-year survival rate of 8%. PSCs constitute more than 50% of the tumor stroma in PDAC, where they induce extensive desmoplasia by secreting abundant extracellular matrix (ECM) proteins. In addition, they establish dynamic crosstalk with cancer cells and other stromal cells, which collectively supports tumor progression via various inter- and intracellular pathways. These cellular interactions and associated pathways may reveal novel therapeutic opportunities against this unmet clinical problem. In this review article, we discuss the role of PSCs in inducing tumor progression, their crosstalk with other cells, and therapeutic strategies to target PSCs.
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Affiliation(s)
- Jonas Schnittert
- Targeted Therapeutics, Department of Biomaterials Science and Technology, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - Ruchi Bansal
- Targeted Therapeutics, Department of Biomaterials Science and Technology, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands
| | - Jai Prakash
- Targeted Therapeutics, Department of Biomaterials Science and Technology, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands; ScarTec Therapeutics BV, Enschede, The Netherlands.
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17
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Lenggenhager D, Amrutkar M, Sántha P, Aasrum M, Löhr JM, Gladhaug IP, Verbeke CS. Commonly Used Pancreatic Stellate Cell Cultures Differ Phenotypically and in Their Interactions with Pancreatic Cancer Cells. Cells 2019; 8:cells8010023. [PMID: 30621293 PMCID: PMC6356867 DOI: 10.3390/cells8010023] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 12/24/2018] [Accepted: 12/28/2018] [Indexed: 02/07/2023] Open
Abstract
Activated pancreatic stellate cells (PSCs) play a central role in the tumor stroma of pancreatic ductal adenocarcinoma (PDAC). Given the limited availability of patient-derived PSCs from PDAC, immortalized PSC cell lines of murine and human origin have been established; however, it is not elucidated whether differences in species, organ disease status, donor age, and immortalization alter the PSC phenotype and behavior compared to that of patient-derived primary PSC cultures. Therefore, a panel of commonly used PSC cultures was examined for important phenotypical and functional features: three primary cultures from human PDAC, one primary from normal human pancreas, and three immortalized (one from human, two from murine pancreas). Growth rate was considerably lower in primary PSCs from human PDAC. Basal collagen synthesis varied between the PSC cultures, and TGF-β stimulation increased collagen synthesis only in non-immortalized cultures. Differences in secretome composition were observed along with a divergence in the DNA synthesis, migration, and response to gemcitabine of PDAC cell lines that were grown in conditioned medium from the various PSC cultures. The findings reveal considerable differences in features and functions that are key to PSCs and in the interactions with PDAC. These observations may be relevant to researchers when selecting the most appropriate PSC culture for their experiments.
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Affiliation(s)
- Daniela Lenggenhager
- Department of Pathology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway.
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway.
- Department of Pathology and Molecular Pathology, University Hospital Zürich, University of Zürich, Schmelzbergstrasse 12, 8091 Zürich, Switzerland.
| | - Manoj Amrutkar
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway.
- Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, P.O. Box 1171 Blindern, 0318 Oslo, Norway.
| | - Petra Sántha
- Department of Pathology, Oslo University Hospital Rikshospitalet, Nydalen, 0424 Oslo, Norway.
| | - Monica Aasrum
- Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway.
| | - Johannes-Matthias Löhr
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, K 53, 141 86 Stockholm, Sweden.
| | - Ivar P Gladhaug
- Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, P.O. Box 1171 Blindern, 0318 Oslo, Norway.
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital Rikshospitalet, Nydalen, 0424 Oslo, Norway.
| | - Caroline S Verbeke
- Department of Pathology, Institute of Clinical Medicine, University of Oslo, Blindern, 0316 Oslo, Norway.
- Department of Pathology, Oslo University Hospital Rikshospitalet, Nydalen, 0424 Oslo, Norway.
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18
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Han X, Li Y, Xu Y, Zhao X, Zhang Y, Yang X, Wang Y, Zhao R, Anderson GJ, Zhao Y, Nie G. Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem. Nat Commun 2018; 9:3390. [PMID: 30139933 PMCID: PMC6107580 DOI: 10.1038/s41467-018-05906-x] [Citation(s) in RCA: 240] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 07/26/2018] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma is characterised by a dense desmoplastic stroma composed of stromal cells and extracellular matrix (ECM). This barrier severely impairs drug delivery and penetration. Activated pancreatic stellate cells (PSCs) play a key role in establishing this unique pathological obstacle, but also offer a potential target for anti-tumour therapy. Here, we construct a tumour microenvironment-responsive nanosystem, based on PEGylated polyethylenimine-coated gold nanoparticles, and utilise it to co-deliver all-trans retinoic acid (ATRA, an inducer of PSC quiescence) and siRNA targeting heat shock protein 47 (HSP47, a collagen-specific molecular chaperone) to re-educate PSCs. The nanosystem simultaneously induces PSC quiescence and inhibits ECM hyperplasia, thereby promoting drug delivery to pancreatic tumours and significantly enhancing the anti-tumour efficacy of chemotherapeutics. Our combination strategy to restore homoeostatic stromal function by targeting activated PSCs represents a promising approach to improving the efficacy of chemotherapy and other therapeutic modalities in a wide range of stroma-rich tumours.
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Affiliation(s)
- Xuexiang Han
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
- Department of Chemistry, Tsinghua University, Beijing, 100084, P.R. China
| | - Yiye Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China.
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
| | - Ying Xu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Xiao Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Yinlong Zhang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Xiao Yang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Yongwei Wang
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, P.R. China
| | - Ruifang Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China
| | - Gregory J Anderson
- QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, QLD 4029, Australia
| | - Yuliang Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China.
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
| | - Guangjun Nie
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P.R. China.
- University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.
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19
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Kanat O, Ertas H. Shattering the castle walls: Anti-stromal therapy for pancreatic cancer. World J Gastrointest Oncol 2018; 10:202-210. [PMID: 30147846 PMCID: PMC6107476 DOI: 10.4251/wjgo.v10.i8.202] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 06/19/2018] [Accepted: 06/27/2018] [Indexed: 02/05/2023] Open
Abstract
Despite the availability of potent chemotherapy regimens, such as 5-fluorouracil, folinic acid, irinotecan, and oxaliplatin (FOLFIRINOX) and nab-paclitaxel plus gemcitabine, treatment outcomes in metastatic pancreatic cancer (PC) remain unsatisfactory. The presence of an abundant fibrous stroma in PC is considered a crucial factor for its unfavorable condition. Apparently, stroma acts as a physical barrier to restrict intratumoral cytotoxic drug penetration and creates a hypoxic environment that reduces the efficacy of radiotherapy. In addition, stroma plays a vital supportive role in the development and progression of PC, which has prompted researchers to assess the potential benefits of agents targeting several cellular (e.g., stellate cells) and acellular (e.g., hyaluronan) elements of the stroma. This study aims to briefly review the primary structural properties of PC stroma and its interaction with cancer cells and summarize the current status of anti-stromal therapies in the management of metastatic PC.
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Affiliation(s)
- Ozkan Kanat
- Department of Medical Oncology, Faculty of Medicine, Uludag University, Bursa 16059, Turkey
| | - Hulya Ertas
- Department of Medical Oncology, Faculty of Medicine, Uludag University, Bursa 16059, Turkey
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20
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Auci DL, Egilmez NK, Dryden GW. Anti-Fibrotic Potential of All Trans Retinoic Acid in Inflammatory Bowel Disease. ACTA ACUST UNITED AC 2018; 6. [PMID: 30740522 DOI: 10.15226/2374-815x/6/3/001126] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
| | - Nejat K Egilmez
- University of Louisville, Department of Microbiology and Immunology, Louisville, KY, USA
| | - Gerald W Dryden
- University of Louisville, Division of Gastroenterology, Hepatology, Nutrition Louisville, KY, USA
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21
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Pancreatic Stellate Cells Have Distinct Characteristics From Hepatic Stellate Cells and Are Not the Unique Origin of Collagen-Producing Cells in the Pancreas. Pancreas 2017; 46:1141-1151. [PMID: 28902784 DOI: 10.1097/mpa.0000000000000901] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVES The origin of collagen-producing myofibroblasts in pancreatic fibrosis is still controversial. Pancreatic stellate cells (PSCs), which have been recognized as the pancreatic counterparts of hepatic stellate cells (HSCs), are thought to play an important role in the development of pancreatic fibrosis. However, sources of myofibroblasts other than PSCs may exist because extensive studies of liver fibrosis have uncovered myofibroblasts that did not originate from HSCs. This study aimed to characterize myofibroblasts in an experimental pancreatic fibrosis model in mice. METHODS We used transgenic mice expressing green fluorescent protein via the collagen type I α1 promoter and induced pancreatic fibrosis with repetitive injections of cerulein. RESULTS Collagen-producing cells that are negative for glial fibrillary acidic protein (ie, not derived from PSCs) exist in the pancreas. Pancreatic stellate cells had different characteristics from those of HSCs in a very small possession of vitamin A using mass spectrometry and a low expression of lecithin retinol acyltransferase. The microstructure of PSCs was entirely different from that of HSCs using flow cytometry and electron microscopy. CONCLUSIONS Our study showed that characteristics of PSCs are different from those of HSCs, and myofibroblasts in the pancreas might be derived not only from PSCs but also from other fibrogenic cells.
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22
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Abstract
Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas. The currently available treatment of CP is aimed at controlling symptoms and managing complications. Unfortunately, no specific treatment is available to halt the progression of the disease process because the pathophysiological perturbations in CP are not well understood. In this review, we discuss various therapeutic targets and investigational agents acting on these targets. Among these, therapies modulating immune cells and those acting on pancreatic stellate cells appear promising and may translate into clinical benefit in near future. However, these experimental therapies are mostly in animal models and they do not recapitulate all aspects of human disease. Still they may be beneficial in developing effective therapeutic modalities to curb inflammation in chronic pancreatitis.
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23
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Kota J, Hancock J, Kwon J, Korc M. Pancreatic cancer: Stroma and its current and emerging targeted therapies. Cancer Lett 2017; 391:38-49. [PMID: 28093284 DOI: 10.1016/j.canlet.2016.12.035] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 12/22/2016] [Accepted: 12/23/2016] [Indexed: 12/20/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies with a 5-year survival rate of 8%. Dense, fibrotic stroma associated with pancreatic tumors is a major obstacle for drug delivery to the tumor bed and plays a crucial role in pancreatic cancer progression. Targeting stroma is considered as a potential therapeutic strategy to improve anti-cancer drug efficacy and patient survival. Although numerous stromal depletion therapies have reached the clinic, they add little to overall survival and are often associated with toxicity. Furthermore, increasing evidence suggests the anti-tumor properties of stroma. Its complete ablation enhanced tumor progression and reduced survival. Consequently, efforts are now focused on developing stromal-targeted therapies that normalize the reactive stroma and avoid the extremes: stromal abundance vs. complete depletion. In this review, we summarized the state of current and emerging anti-stromal targeted therapies, with major emphasis on the role of miRNAs in PDAC stroma and their potential use as novel therapeutic agents to modulate PDAC tumor-stromal interactions.
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Affiliation(s)
- Janaiah Kota
- Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA; The Melvin and Bren Simon Cancer Center, IUSM, Indianapolis, IN, USA; Center for Pancreatic Cancer Research, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN, USA.
| | - Julie Hancock
- Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA
| | - Jason Kwon
- Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA
| | - Murray Korc
- The Melvin and Bren Simon Cancer Center, IUSM, Indianapolis, IN, USA; Center for Pancreatic Cancer Research, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, IUSM, Indianapolis, IN, USA; Department of Medicine, IUSM, Indianapolis, IN, USA
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24
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Abstract
Retinoids (vitamin A and its natural and synthetic analogs) are required by most tissues for maintaining the normal health of the tissue. This is certainly true for the pancreas. The recent literature is convincing that retinoids are needed by the adult to assure normal pancreatic endocrine functions, especially those of the α- and β-cells. It is also well established that retinoids are required to insure normal pancreas development in utero, including the development of the endocrine pancreas. The actions of retinoids for maintaining normal pancreatic islet functions has drawn considerable research interest from investigators interested in understanding and treating metabolic disease. Pancreatic retinoids are also of interest to investigators studying the origins of pancreatic disease, including the development of pancreatic fibrosis and its sequelae. This research interest is focused on pancreatic stellate cells (PSCs) which store retinoids and possess the metabolic machinery needed to metabolize retinoids. The literature on pancreatic disease and retinoids suggests that there is an association between impairments in pancreatic retinoid storage and metabolism and the development of pancreatic disease. These topics will be considered in this review.
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Affiliation(s)
- Pierre-Jacques Brun
- 1 Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA ; 2 Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - Nuttaporn Wongsiriroj
- 1 Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA ; 2 Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
| | - William S Blaner
- 1 Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA ; 2 Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand
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25
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Witteck L, Jaster R. Trametinib and dactolisib but not regorafenib exert antiproliferative effects on rat pancreatic stellate cells. Hepatobiliary Pancreat Dis Int 2015; 14:642-50. [PMID: 26663013 DOI: 10.1016/s1499-3872(15)60032-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Modulation of the stroma response is considered a promising approach for the treatment of chronic pancreatitis and pancreatic cancer. The aim of this study was to evaluate the effects of three clinically available small molecule kinase inhibitors, regorafenib, trametinib and dactolisib, on effector functions of activated pancreatic stellate cells (PSCs), which play a key role in pancreatic fibrosis. METHODS Cultured rat PSCs were exposed to small molecule kinase inhibitors. Proliferation and cell death were assessed by measuring the incorporation of 5-bromo-2'-deoxyuridine and cytotoxicity, respectively. Levels of mRNA were determined by real-time PCR, while protein expression and phosphorylation were analyzed by immunoblotting. Interleukin-6 levels in culture supernatants were quantified by ELISA. Zymography assays were performed to monitor collagenase activity in culture supernatants. RESULTS The MEK inhibitor trametinib and the dual phosphatidylinositol 3-kinase/mTOR inhibitor dactolisib, but not the multi-kinase inhibitor regorafenib, efficiently inhibited PSC proliferation. Trametinib as well as regorafenib suppressed the expression of two autocrine mediators of PSC activation, interleukin-6 and transforming growth factor-beta1. Dactolisib-treated cells expressed less alpha1 type I collagen and lower levels of alpha-smooth muscle actin, a marker of the myofibroblastic PSC phenotype. Simultaneous application of dactolisib and trametinib displayed additive inhibitory effects on cell growth without statistically significant cytotoxicity. Activity of matrix metalloproteinase-2 was not affected by any of the drugs. CONCLUSION We suggest the combination of two drugs, that specifically target two key signaling pathways in PSC, Ras-Raf-MEK-ERK (trametinib) and phosphatidylinositol 3-kinase-AKT-mTOR (dactolisib), as a concept to modulate the activation state of the cells in the context of fibrosis.
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Affiliation(s)
- Laura Witteck
- Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, E.-Heydemann-Str. 6, 18057 Rostock, Germany.
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Xiao W, Jiang W, Shen J, Yin G, Fan Y, Wu D, Qiu L, Yu G, Xing M, Hu G, Wang X, Wan R. Retinoic Acid Ameliorates Pancreatic Fibrosis and Inhibits the Activation of Pancreatic Stellate Cells in Mice with Experimental Chronic Pancreatitis via Suppressing the Wnt/β-Catenin Signaling Pathway. PLoS One 2015; 10:e0141462. [PMID: 26556479 PMCID: PMC4640570 DOI: 10.1371/journal.pone.0141462] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 10/08/2015] [Indexed: 01/11/2023] Open
Abstract
Pancreatic fibrosis, a prominent feature of chronic pancreatitis (CP), induces persistent and permanent damage in the pancreas. Pancreatic stellate cells (PSCs) provide a major source of extracellular matrix (ECM) deposition during pancreatic injury, and persistent activation of PSCs plays a vital role in the progression of pancreatic fibrosis. Retinoic acid (RA), a retinoid, has a broad range of biological functions, including regulation of cell differentiation and proliferation, attenuating progressive fibrosis of multiple organs. In the present study, we investigated the effects of RA on fibrosis in experimental CP and cultured PSCs. CP was induced in mice by repetitive cerulein injection in vivo, and mouse PSCs were isolated and activated in vitro. Suppression of pancreatic fibrosis upon administration of RA was confirmed based on reduction of histological damage, α-smooth muscle actin (α-SMA) expression and mRNA levels of β-catenin, platelet-derived growth factor (PDGF)-Rβ transforming growth factor (TGF)-βRII and collagen 1α1 in vivo. Wnt 2 and β-catenin protein levels were markedly down-regulated, while Axin 2 expression level was up-regulated in the presence of RA, both in vivo and in vitro. Nuclear translation of β-catenin was significantly decreased following RA treatment, compared with cerulein-induced CP in mice and activated PSCs. Furthermore, RA induced significant PSC apoptosis, inhibited proliferation, suppressed TCF/LEF-dependent transcriptional activity and ECM production of PSC via down-regulation of TGFβRII, PDGFRβ and collagen 1α1 in vitro. These results indicate a critical role of the Wnt/β-catenin signaling pathway in RA-induced effects on CP and PSC regulation and support the potential of RA as a suppressor of pancreatic fibrosis in mice.
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MESH Headings
- Actins/biosynthesis
- Actins/genetics
- Active Transport, Cell Nucleus/drug effects
- Animals
- Apoptosis/drug effects
- Axin Protein/biosynthesis
- Axin Protein/genetics
- Cells, Cultured
- Ceruletide/toxicity
- Collagen Type I/biosynthesis
- Collagen Type I/genetics
- Disease Progression
- Drug Evaluation, Preclinical
- Fibrosis/prevention & control
- Gene Expression Regulation/drug effects
- Lipase/blood
- Male
- Mice
- Mice, Inbred BALB C
- Organ Size/drug effects
- Pancreas/drug effects
- Pancreas/pathology
- Pancreatic Stellate Cells/drug effects
- Pancreatic Stellate Cells/metabolism
- Pancreatic alpha-Amylases/blood
- Pancreatitis, Chronic/chemically induced
- Pancreatitis, Chronic/drug therapy
- Pancreatitis, Chronic/metabolism
- Pancreatitis, Chronic/pathology
- Proteoglycans/biosynthesis
- Proteoglycans/genetics
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- Random Allocation
- Receptor, Platelet-Derived Growth Factor beta/biosynthesis
- Receptor, Platelet-Derived Growth Factor beta/genetics
- Receptors, Transforming Growth Factor beta/biosynthesis
- Receptors, Transforming Growth Factor beta/genetics
- Tretinoin/pharmacology
- Tretinoin/therapeutic use
- Wnt Signaling Pathway/drug effects
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Affiliation(s)
- Wenqin Xiao
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Weiliang Jiang
- Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jie Shen
- Department of Gastroenterology, Shanghai Changzheng Hospital, Shanghai Second Military Medical University, Shanghai, China
| | - Guojian Yin
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuting Fan
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Deqing Wu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lei Qiu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ge Yu
- Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Miao Xing
- Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Guoyong Hu
- Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xingpeng Wang
- Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Rong Wan
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- * E-mail:
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Bläuer M, Sand J, Laukkarinen J. Physiological and clinically attainable concentrations of 1,25-dihydroxyvitamin D3 suppress proliferation and extracellular matrix protein expression in mouse pancreatic stellate cells. Pancreatology 2015; 15:366-71. [PMID: 26005021 DOI: 10.1016/j.pan.2015.05.044] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 04/30/2015] [Accepted: 05/05/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES Vitamin D is an antiproliferative and differentiation-promoting secosteroid hormone with pleiotropic homeostatic functions in bone and extraskeletal tissues. Signaling of vitamin D is mediated via its ubiquitously expressed nuclear receptor, the vitamin D receptor (VDR). Pancreatic stellate cells have recently been identified as targets of vitamin D action. Our aim was to elucidate the effectiveness of the most potent endogenous vitamin D metabolite, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on the proliferation and extracellular matrix (ECM) protein expression in pancreatic stellate cells (PSCs) using concentrations of the compound from the physiological and clinically attainable range in humans. METHODS Culture-activated mouse PSCs were exposed to 1,25(OH)2D3 concentrations ranging from 0.1 nM to 10 nM for 7 days and subjected to colorimetric crystal violet assay for cell growth assessment and to Western blot and immunohistochemical analyses of VDR, fibronectin and collagen I using protein-specific antibodies. Immunohistochemical localization of VDR was performed on mouse pancreatic tissue and on a set of human specimens obtained at pancreatic surgery. RESULTS A low basal level of VDR was detected in PSCs that was strongly induced in the presence of ligand. Cell growth was suppressed dose-dependently by 1,25(OH)2D3, the mean percentages of inhibition ranging from 24% at the physiological 0.1 nM concentration to around 60% at 10 nM. Significant 48% and 40% reductions in fibronectin expression were seen at 0.5 nM and 1 nM 1,25(OH)2D3. A minor decrease in collagen I expression was detected at 5 nM. VDR was predominantly localized in the islets of Langerhans in mouse and human tissues. In the latter VDR was expressed also in the exocrine tissue showing individual variation in its cellular distribution. CONCLUSIONS Mouse PSCs express VDR protein and are sensitive 1,25(OH)2D3 target cells with low levels of 1,25(OH)2D3 exerting antiproliferative and antifibrotic effects on activated PSCs in vitro.
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Affiliation(s)
- Merja Bläuer
- Tampere Pancreas Laboratory, Tampere University Hospital, Teiskontie 35, FIN-33521 Tampere, Finland
| | - Juhani Sand
- Tampere Pancreas Laboratory, Tampere University Hospital, Teiskontie 35, FIN-33521 Tampere, Finland; Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Teiskontie 35, FIN-33521 Tampere, Finland
| | - Johanna Laukkarinen
- Tampere Pancreas Laboratory, Tampere University Hospital, Teiskontie 35, FIN-33521 Tampere, Finland; Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Teiskontie 35, FIN-33521 Tampere, Finland.
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Haqq J, Howells LM, Garcea G, Metcalfe MS, Steward WP, Dennison AR. Pancreatic stellate cells and pancreas cancer: current perspectives and future strategies. Eur J Cancer 2014; 50:2570-82. [PMID: 25091797 DOI: 10.1016/j.ejca.2014.06.021] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 06/25/2014] [Accepted: 06/30/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis. To date patient outcomes have not improved principally due to the limited number of patients suitable for surgical resections and the radiation and chemotherapy resistance of these tumours. In the last decade, a failure of conventional therapies has forced researchers to re-examine the environment of PDAC. The tumour environment has been demonstrated to consist of an abundance of stroma containing many cells but predominantly pancreatic stellate cells (PSCs). Recent research has focused on understanding the interaction between PSCs and PDAC cells in vitro and in vivo. It is believed that the interaction between these cells is responsible for supporting tumour growth, invasion and metastasis and creating the barrier to delivery of chemotherapeutics. Novel approaches which focus on the interactions between PDAC and PSCs which sustain the tumour microenvironment may achieve significant patient benefits. This manuscript reviews the current evidence regarding PSCs, their interaction with PDAC cells and the potential implication this may have for future therapies. METHODS A PubMed search was carried out for the terms 'pancreas cancer' OR 'pancreatic cancer', AND 'pancreatic stellate cells', NOT 'hepatic stellate cells'. All studies were screened and assessed for their eligibility and manuscripts exploring the relationship between PSCs and PDAC were included. The studies were subdivided into in vitro and in vivo groups. RESULTS One hundred and sixty-six manuscripts were identified and reduced to seventy-three in vitro and in vivo studies for review. The manuscripts showed that PDAC cells and PSCs interact with each other to enhance proliferation, reduce apoptosis and increase migration and invasion of cancer cells. The pathways through which they facilitate these actions provide potential targets for future novel therapies. CONCLUSION There is accumulating evidence supporting the multiple roles of PSCs in establishing the tumour microenvironment and supporting the survival of PDAC. To further validate these findings there is a need for greater use of physiologically relevant models of pancreatic cancer in vitro such as three dimensional co-cultures and the use of orthotopic and genetically engineered murine (GEM) models in vivo.
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Affiliation(s)
- Jonathan Haqq
- Department of Hepatobiliary and Pancreatic Surgery & Cancer Studies and Molecular Medicine Group, University Hospitals of Leicester & University of Leicester, Leicester LE5 4PW, United Kingdom.
| | - Lynne M Howells
- Department of Hepatobiliary and Pancreatic Surgery & Cancer Studies and Molecular Medicine Group, University Hospitals of Leicester & University of Leicester, Leicester LE5 4PW, United Kingdom
| | - Giuseppe Garcea
- Department of Hepatobiliary and Pancreatic Surgery & Cancer Studies and Molecular Medicine Group, University Hospitals of Leicester & University of Leicester, Leicester LE5 4PW, United Kingdom
| | - Matthew S Metcalfe
- Department of Hepatobiliary and Pancreatic Surgery & Cancer Studies and Molecular Medicine Group, University Hospitals of Leicester & University of Leicester, Leicester LE5 4PW, United Kingdom
| | - Will P Steward
- Department of Hepatobiliary and Pancreatic Surgery & Cancer Studies and Molecular Medicine Group, University Hospitals of Leicester & University of Leicester, Leicester LE5 4PW, United Kingdom
| | - Ashley R Dennison
- Department of Hepatobiliary and Pancreatic Surgery & Cancer Studies and Molecular Medicine Group, University Hospitals of Leicester & University of Leicester, Leicester LE5 4PW, United Kingdom
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Elsner A, Lange F, Fitzner B, Heuschkel M, Krause BJ, Jaster R. Distinct antifibrogenic effects of erlotinib, sunitinib and sorafenib on rat pancreatic stellate cells. World J Gastroenterol 2014; 20:7914-7925. [PMID: 24976727 PMCID: PMC4069318 DOI: 10.3748/wjg.v20.i24.7914] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To study if three clinically available small molecule kinase inhibitors (SMI), erlotinib, sunitinib and sorafenib, exert antifibrogenic effects on pancreatic stellate cells (PSC) and analyze the basis of their action.
METHODS: Cultured rat PSC were exposed to SMI. Cell proliferation and viability were assessed employing 5-bromo-2’-deoxyuridine incorporation assay and flow cytometry, respectively. 2-Deoxy-2-[18F] fluoroglucose (18F-FDG) uptake was measured to study metabolic activity. Exhibition of the myofibroblastic PSC phenotype was monitored by immunofluorescence analysis of α-smooth muscle actin (α-SMA) expression. Levels of mRNA were determined by real-time PCR, while protein expression and phosphorylation were analyzed by immunoblotting. Transforming growth factor-β1 (TGF-β1) levels in culture supernatants were quantified by ELISA.
RESULTS: All three SMI inhibited cell proliferation and 18F-FDG uptake in a dose-dependent manner and without significant cytotoxic effects. Furthermore, additive effects of the drugs were observed. Immunoblot analysis showed that sorafenib and sunitib, but not erlotinib, efficiently blocked activation of the AKT pathway, while all three drugs displayed little effect on phosphorylation of ERK1/2. Cells treated with sorafenib or sunitinib expressed less interleukin-6 mRNA as well as less collagen type 1 mRNA and protein. Sorafenib was the only drug that also upregulated the expression of matrix metalloproteinase-2 and reduced the secretion of TGF-β1 protein. All three drugs showed insignificant or discordant effects on the mRNA and protein levels of α-SMA.
CONCLUSION: The tested SMI, especially sorafenib, exert inhibitory effects on activated PSC, which should be further evaluated in preclinical studies.
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Pomianowska E, Sandnes D, Grzyb K, Schjølberg AR, Aasrum M, Tveteraas IH, Tjomsland V, Christoffersen T, Gladhaug IP. Inhibitory effects of prostaglandin E2 on collagen synthesis and cell proliferation in human stellate cells from pancreatic head adenocarcinoma. BMC Cancer 2014; 14:413. [PMID: 24912820 PMCID: PMC4084579 DOI: 10.1186/1471-2407-14-413] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 05/20/2014] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Several studies have described an increased cyclooxygenase-2 (COX-2) expression in pancreatic cancer, but the role of COX-2 in tumour development and progression is not clear. The aim of the present study was to examine expression of COX-2 in cancer cells and stromal cells in pancreatic cancer specimens, and to explore the role of PGE2 in pancreatic stellate cell proliferation and collagen synthesis. METHODS Immunohistochemistry and immunofluorescence was performed on slides from whole sections of tissue blocks using antibodies against COX-2 and α-smooth muscle actin (αSMA). Pancreatic stellate cells (PSC) were isolated from surgically resected tumour tissue by the outgrowth method. Cells were used between passages 4 and 8. Collagen synthesis was determined by [(3)H]-proline incorporation, or by enzyme immunoassay measurement of collagen C-peptide. DNA synthesis was measured by incorporation of [(3)H]-thymidine in DNA. Cyclic AMP (cAMP) was determined by radioimmunoassay. Collagen 1A1 mRNA was determined by RT-qPCR. RESULTS Immunohistochemistry staining showed COX-2 in pancreatic carcinoma cells, but not in stromal cells. All tumours showed positive staining for αSMA in the fibrotic stroma. Cultured PSC expressed COX-2, which could be further induced by interleukin-1β (IL-1β), epidermal growth factor (EGF), thrombin, and PGE2, but not by transforming growth factor-β1 (TGFβ). Indirect coculture with the adenocarcinoma cell line BxPC-3, but not HPAFII or Panc-1, induced COX-2 expression in PSC. Treatment of PSC with PGE2 strongly stimulated cAMP accumulation, mediated by EP2 receptors, and also stimulated phosphorylation of extracellular signal-regulated kinase (ERK). Treatment of PSC with PGE2 or forskolin suppressed both TGFβ-stimulated collagen synthesis and PDGF-stimulated DNA synthesis. CONCLUSIONS The present results show that COX-2 is mainly produced in carcinoma cells and suggest that the cancer cells are the main source of PGE2 in pancreatic tumours. PGE2 exerts a suppressive effect on proliferation and fibrogenesis in pancreatic stellate cells. These effects of PGE2 are mediated by the cAMP pathway and suggest a role of EP2 receptors.
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Affiliation(s)
- Ewa Pomianowska
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Rikshospitalet, PO Box 4956, Nydalen 0424 Oslo, Norway
| | - Dagny Sandnes
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Krzysztof Grzyb
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Aasa R Schjølberg
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Monica Aasrum
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Ingun H Tveteraas
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Vegard Tjomsland
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Rikshospitalet, PO Box 4956, Nydalen 0424 Oslo, Norway
| | - Thoralf Christoffersen
- Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Ivar P Gladhaug
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Rikshospitalet, PO Box 4956, Nydalen 0424 Oslo, Norway
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Fitzner B, Lange A, Müller S, Jaster R. Cdkn1a is a key mediator of rat pancreatic stellate cell senescence. Pancreatology 2013; 13:254-62. [PMID: 23719597 DOI: 10.1016/j.pan.2013.03.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Revised: 02/27/2013] [Accepted: 03/08/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES Completion of pancreatic wound healing requires termination of pancreatic stellate cell (PSC) activation to prevent fibrosis. Besides induction of apoptosis and return to a quiescent phenotype, senescence of PSC followed by immune cell-mediated cytolysis represents a potential mechanism. Here, we have studied if the cell cycle inhibitor cyclin-dependent kinase inhibitor 1A (Cdkn1a, p21/Waf1), expression of which is increased in senescent rat PSC, plays a causative role in the senescence process. METHODS Senescence was induced by doxorubicin treatment. The functions of Cdkn1a were analyzed using two approaches, treatment of primary rat PSC with siRNA and tetracycline-regulated overexpression of Cdkn1a in immortalized rat cells. Expression of senescence-associated β-galactosidase (SA β-Gal) was used as a surrogate marker of senescence. RESULTS The knockdown of Cdkn1a significantly attenuated the growth-inhibitory effect of doxorubicin and strongly diminished the portion of SA β-Gal-positive cells. Overexpression of Cdkn1a enhanced both the antiproliferative effect of doxorubicin and induction of senescence. In primary PSC, doxorubicin treatment was associated with increased expression of interleukin-6 (IL-6) and matrix metalloproteinase (MMP)-9, while expression of the activation marker α-smooth muscle actin (α-SMA), p53, Cdk1 and Rad54 was diminished. The application of Cdkn1a siRNA specifically antagonized the effects of doxorubicin on the expression of p53, Cdk1 and Rad54 but not IL-6 and α-SMA, while MMP-9 expression and also activity were even enhanced. CONCLUSIONS Cdkn1a plays a direct role in the process of rat PSC senescence. Additional Cdkn1a-independent pathways may contribute to the partial maintenance of a gene expression profile typical of senescent PSC.
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Affiliation(s)
- Brit Fitzner
- Department of Medicine II, Division of Gastroenterology, University Medicine Rostock, E.-Heydemann-Strasse 6, Rostock, Germany
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Liu H, Ma Q, Xu Q, Lei J, Li X, Wang Z, Wu E. Therapeutic potential of perineural invasion, hypoxia and desmoplasia in pancreatic cancer. Curr Pharm Des 2012; 18:2395-403. [PMID: 22372500 DOI: 10.2174/13816128112092395] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 01/18/2012] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer is one of the most fatal human malignancies. Though a relatively rare malignancy, it remains one of the deadliest tumors, with an extremely high mortality rate. The prognosis of patients with pancreatic cancer remains poor; only patients with small tumors and complete resection have a chance of a complete cure. Pancreatic cancer responds poorly to conventional therapies, including chemotherapy and irradiation. Tumor-specific targeted therapy is a relatively recent addition to the arsenal of anti-cancer therapies. It is important to find novel targets to distinguish tumor cells from their normal counterparts in therapeutic approaches. In the past few decades, studies have revealed the molecular mechanisms of pancreatic tumorigenesis, growth, invasion and metastasis. The proteins that participate in the pathophysiological processes of pancreatic cancer might be potential targets for therapy. This review describes the main players in perineural invasion, hypoxia and desmoplasia and the molecular mechanisms of these pathophysiological processes.
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Affiliation(s)
- Han Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Imaging guided trials of the angiogenesis inhibitor sunitinib in mouse models predict efficacy in pancreatic neuroendocrine but not ductal carcinoma. Proc Natl Acad Sci U S A 2011; 108:E1275-84. [PMID: 22084065 DOI: 10.1073/pnas.1111079108] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Preclinical trials in mice represent a critical step in the evaluation of experimental therapeutics. Genetically engineered mouse models (GEMMs) represent a promising platform for the evaluation of drugs, particularly those targeting the tumor microenvironment. We evaluated sunitinib, an angiogenesis inhibitor that targets VEGF and PDGF receptor signaling, in two GEMMs of pancreatic cancer. Sunitinib did not reduce tumor burden in pancreatic ductal adenocarcinoma (PDAC), whereas tumor burden was reduced in the pancreatic neuroendocrine tumor (PNET) model, the latter results confirming and extending previous studies. To explore the basis for the lack of pathologic response in PDAC, we used noninvasive microbubble contrast-enhanced ultrasound imaging, which revealed that sunitinib reduced blood flow both in PDAC and in PNET, concomitant with a reduction in vessel density; nevertheless, PDAC tumors continued to grow, whereas PNET were growth impaired. These results parallel the response in humans, where sunitinib recently garnered FDA and European approval in PNET, whereas two antiangiogenic drugs failed to demonstrate efficacy in PDAC clinical trials. The demonstration of on-target activity but with discordant benefit in the PDAC and PNET GEMMs illustrates the potential value of linked preclinical and clinical trials.
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Froeling FEM, Feig C, Chelala C, Dobson R, Mein CE, Tuveson DA, Clevers H, Hart IR, Kocher HM. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-β-catenin signaling to slow tumor progression. Gastroenterology 2011; 141:1486-97, 1497.e1-14. [PMID: 21704588 DOI: 10.1053/j.gastro.2011.06.047] [Citation(s) in RCA: 333] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2010] [Revised: 06/01/2011] [Accepted: 06/13/2011] [Indexed: 01/03/2023]
Abstract
BACKGROUND & AIMS Patients with pancreatic ductal adenocarcinoma are deficient in vitamin A, resulting in activation of pancreatic stellate cells (PSCs). We investigated whether restoration of retinol to PSCs restores their quiescence and affects adjacent cancer cells. METHODS PSCs and cancer cell lines (AsPc1 and Capan1) were exposed to doses and isoforms of retinoic acid (RA) in 2-dimensional and 3-dimensional culture conditions (physiomimetic organotypic culture). The effects of all-trans retinoic acid (ATRA) were studied in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre mice, a model of human pancreatic ductal adenocarcinoma. RESULTS After incubation with ATRA, PSCs were quiescent and had altered expression of genes that regulate proliferation, morphology, and motility; genes that encode cytoskeletal proteins and cytokines; and genes that control other functions, irrespective of culture conditions or dosage. In the organotypic model, and in mice, ATRA induced quiescence of PSCs and thereby reduced cancer cell proliferation and translocation of β-catenin to the nucleus, increased cancer cell apoptosis, and altered tumor morphology. ATRA reduced the motility of PSCs, so these cells created a "wall" at the junction between the tumor and the matrix that prevented cancer cell invasion. Restoring secreted frizzled-related protein 4 (sFRP4) secretion to quiescent PSCs reduced Wnt-β-catenin signaling in cancer cells and their invasive ability. Human primary and metastatic pancreatic tumor tissues stained strongly for cancer cell nuclear β-catenin but had low levels of sFRP4 (in cancer cells and PSCs). CONCLUSIONS RA induces quiescence and reduces motility of PSCs, leading to reduced proliferation and increased apoptosis of surrounding pancreatic cancer cells. RA isoforms might be developed as therapeutic reagents for pancreatic cancer.
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Affiliation(s)
- Fieke E M Froeling
- Centre for Tumor Biology, Barts Cancer Institute-a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, London, England
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Ye Y, Dan Z. All-trans retinoic acid diminishes collagen production in a hepatic stellate cell line via suppression of active protein-1 and c-Jun N-terminal kinase signal. ACTA ACUST UNITED AC 2010; 30:726-33. [PMID: 21181362 DOI: 10.1007/s11596-010-0648-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Indexed: 12/16/2022]
Abstract
Following acute and chronic liver injury, hepatic stellate cells (HSCs) become activated to undergo a phenotypic transformation into myofibroblast-like cells and lose their retinol content, but the mechanisms of retinoid loss and its potential roles in HSCs activation and liver fibrosis are not understood. The influence of retinoids on HSCs and hepatic fibrosis remains controversial. The purpose of this study was to evaluate the effects of all-trans retinoid acid (ATRA) on cell proliferation, mRNA expression of collagen genes [procollagen α1 (I), procollagen α1 (III)], profibrogenic genes (TGF-β(1), CTGF, MMP-2, TIMP-1, TIMP-2, PAI-1), fibrolytic genes (MMP-3, MMP-13) and the upstream element (JNK and AP-1) in the rat hepatic stellate cell line (CFSC-2G). Cell proliferation was evaluated by measuring BrdU incorporation. The mRNA expression levels of collagen genes [procollagen α1 (I), procollagen α1 (III)], profibrogenic genes (TGF-β(1), CTGF, MMP-2, TIMP-1, TIMP-2, PAI-1), and fibrolytic genes (MMP-3, MMP-13) were quantitatively detected by using real-time PCR. The mRNA expression of JNK and AP-1 was quantified by RT-PCR. The results showed that ATRA inhibited HSCs proliferation and diminished the mRNA expression of collagen genes [procollagen α1 (I), procollagen α1 (III)] and profibrogenic genes (TGF-β(1), CTGF, MMP-2, TIMP-1, TIMP-2, PAI-1), and significantly stimulated the mRNA expression of MMP-3 and MMP-13 in HSCs by suppressing the mRNA expression of JNK and AP-1. These findings suggested that ATRA could inhibit proliferation and collagen production of HSCs via the suppression of active protein-1 and c-Jun N-terminal kinase signal, then decrease the mRNAs expression of profibrogenic genes (TGF-β(1), CTGF, MMP-2, TIMP-1, TIMP-2, PAI-1), and significantly induce the mRNA expression of MMP-3 and MMP-13.
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Affiliation(s)
- Yuan Ye
- Huazhong University of Science and Technology, Wuhan 430030, China.
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Corduk N, Koltuksuz U, Calli-Demirkan N, Rota S, Abban G, Sarioglu-Buke A. Effects of retinoic acid and zinc on the treatment of caustic esophageal burns. Pediatr Surg Int 2010; 26:619-24. [PMID: 20204651 DOI: 10.1007/s00383-010-2571-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/02/2010] [Indexed: 01/27/2023]
Abstract
PURPOSE An experimental study was carried out to investigate the efficacy of an anti-inflammatory and antiproliferative agent all-trans retinoic acid (ATRA) and an antioxidant agent zinc sulphate (ZnSO(4)) in the prevention of stricture after caustic esophageal burn in rats. METHODS Esophageal burn was induced using 50% NaOH. Rats were divided into four groups as follows: group A (sham; n = 8), group B (control; n = 8), group C (treated with ATRA; n = 8) and group D (treated with ZnSO(4); n = 8). All rats were killed on the 28th day and esophageal tissues were evaluated for histopathologic damage score, hydroxyproline (HP) content and TGF-beta1 expression. RESULTS Significant difference was detected in terms of histopathologic damage score between groups B and C (p = 0.002). Although mean HP levels of groups C and D were lower than group B, statistical comparison was not significant. TGF-beta1 expression in group C was significantly lower than group B. CONCLUSION Zinc has not been found effective in the prevention of stricture formation. The results indicate that ATRA has a preventive effect in the development of fibrosis in an experimental model of caustic esophageal burns in rats.
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Erkan M, Weis N, Pan Z, Schwager C, Samkharadze T, Jiang X, Wirkner U, Giese NA, Ansorge W, Debus J, Huber PE, Friess H, Abdollahi A, Kleeff J. Organ-, inflammation- and cancer specific transcriptional fingerprints of pancreatic and hepatic stellate cells. Mol Cancer 2010; 9:88. [PMID: 20416094 PMCID: PMC2876060 DOI: 10.1186/1476-4598-9-88] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2009] [Accepted: 04/23/2010] [Indexed: 12/12/2022] Open
Abstract
Background Tissue fibrosis is an integral component of chronic inflammatory (liver and pancreas) diseases and pancreatic cancer. Activated pancreatic- (PSC) and hepatic- (HSC) stellate cells play a key role in fibrogenesis. To identify organ- and disease-specific stellate cell transcriptional fingerprints, we employed genome-wide transcriptional analysis of primary human PSC and HSC isolated from patients with chronic inflammation or cancer. Methods Stellate cells were isolated from patients with pancreatic ductal adenocarcinoma (n = 5), chronic pancreatitis (n = 6), liver cirrhosis (n = 5) and liver metastasis of pancreatic ductal adenocarcinoma (n = 6). Genome-wide transcriptional profiles of stellate cells were generated using our 51K human cDNA microarray platform. The identified organ- and disease specific genes were validated by quantitative RT-PCR, immunoblot, ELISA, immunocytochemistry and immunohistochemistry. Results Expression profiling identified 160 organ- and 89 disease- specific stellate cell transcripts. Collagen type 11a1 (COL11A1) was discovered as a novel PSC specific marker with up to 65-fold higher expression levels in PSC compared to HSC (p < 0.0001). Likewise, the expression of the cytokine CCL2 and the cell adhesion molecule VCAM1 were confined to HSC. PBX1 expression levels tend to be increased in inflammatory- vs. tumor- stellate cells. Intriguingly, tyrosine kinase JAK2 and a member of cell contact-mediated communication CELSR3 were found to be selectively up-regulated in tumor stellate cells. Conclusions We identified and validated HSC and PSC specific markers. Moreover, novel target genes of tumor- and inflammation associated stellate cells were discovered. Our data may be instrumental in developing new tailored organ- or disease-specific targeted therapies and stellate cell biomarkers.
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Affiliation(s)
- Mert Erkan
- Department of General Surgery, Technische Universität München, Munich, Germany
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Abstract
The association between alcohol consumption and pancreatitis has been recognized for over 100 years. Despite the fact that this association is well recognized, the mechanisms by which alcohol abuse leads to pancreatic tissue damage are not entirely clear. Alcohol abuse is the major factor associated with pancreatitis in the Western world. Interestingly, although most cases of chronic pancreatitis and many cases of acute pancreatitis are associated with alcohol abuse, only a small percentage of individuals who abuse alcohol develop this disease. This situation is reminiscent of the association between alcohol abuse and the incidence of alcoholic liver disease. The liver and the pancreas are developmentally very closely related. Even though these two organs are quite different, they exhibit a number of general structural and functional similarities. Furthermore, the diseases mediated by alcohol abuse in these organs exhibit some striking similarities. The diseases in both organs are characterized by parenchymal cell damage, activation of stellate cells, aberrant wound healing, and fibrosis. Because of the similarities between the liver and the pancreas, and the alcohol-associated diseases of these organs, we may be able to apply much of the knowledge that we have gained regarding the effects of alcohol on the liver to the pancreas.
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Ding Z, Maubach G, Masamune A, Zhuo L. Glial fibrillary acidic protein promoter targets pancreatic stellate cells. Dig Liver Dis 2009; 41:229-36. [PMID: 18602878 DOI: 10.1016/j.dld.2008.05.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2008] [Revised: 04/25/2008] [Accepted: 05/05/2008] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic fibrosis is one of the clinical manifestations of chronic pancreatitis and pancreatic cancer. Pancreatic stellate cells (PSCs) have been recognised as principal effector cells in the development of pancreatic fibrosis. The ability to specifically address PSCs might offer a potential for developing a targeted therapy for pancreatic fibrosis. AIM Characterisation of the 2.2kb hGFAP (human glial fibrillary acidic protein) promoter for its usefulness to express reporter genes specifically in PSCs in vitro and in vivo. METHODS 2.2kb hGFAP-LacZ reporter expressions were examined in four immortalised PSC lines and two non-PSCs, meanwhile, GFAP-LacZ transgenic mice were used to detect LacZ reporter in pancreas tissue. Several kinase inhibitors, vitamin A and its metabolites were applied to study the regulation of 2.2kb hGFAP promoter in PSCs. RESULTS Our results showed that the 2.2kb hGFAP promoter is capable of regulating the expression of reporter genes exclusively in immortalised and primary PSCs, as well as in PSCs of transgenic GFAP-LacZ mice. When a PSC cell line transfected with the LacZ reporter (SAM-K/LacZ/C1) was treated with different anti-fibrotic agents and kinase inhibitors, the transgenic beta-galactosidase activity was found to be regulated by multiple signalling pathways known to be involved in the PSC activation. CONCLUSIONS This study provides the proof of concept for using the 2.2kb hGFAP promoter to specifically manipulate PSCs for the development of targeted gene and/or drug therapy in pancreatic fibrosis, and for the screening of anti-fibrotic agents.
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Affiliation(s)
- Z Ding
- Institute of Bioengineering and Nanotechnology, Singapore
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Shimizu K. Mechanisms of pancreatic fibrosis and applications to the treatment of chronic pancreatitis. J Gastroenterol 2009; 43:823-32. [PMID: 19012035 DOI: 10.1007/s00535-008-2249-7] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2008] [Accepted: 07/01/2008] [Indexed: 02/07/2023]
Abstract
Pancreatic stellate cells (PSCs) play a crucial role in pancreatic fibrogenesis in chronic pancreatitis and in the desmoplastic reaction of pancreatic cancer. When PSCs are stimulated by oxidative stress, ethanol and its metabolite acetaldehyde, and cytokines, the phenotype of quiescent fat-storing cells converts to myofibroblastlike activated PSCs, which then produce extracellular matrix, adhesion molecules, and various chemokines in response to cytokines and growth factors. Recent data suggest that PSCs have a phagocytic function. Plateletderived growth factor is a potent stimulator of PSC proliferation. Transforming growth factor beta, activin A, and connective tissue growth factor also play a role in PSC-mediated pancreatic fibrogenesis through autocrine and paracrine loops. Following pancreatic damage, pathophysiological processes that occur in the pancreas, including pancreas tissue pressure, hyperglycemia, intracellular reactive oxygen species production, activation of protease-activated receptor 2, induction of cyclooxygenase 2, and bacterial infection play a role in sustaining pancreatic fibrosis through increased PSC proliferation and collagen production by PSCs. Targeting PSCs might be an effective therapeutic approach in chronic pancreatitis. Various substances including vitamin A, vitamin E, polyphenols, peroxisome proliferator-activated receptor gamma ligands, and inhibitors of the renin-angiotensin system show great promise of being useful in the treatment of chronic pancreatitis.
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Affiliation(s)
- Kyoko Shimizu
- Department of Gastroenterology, Tokyo Women's Medical University, School of Medicine, 8-1 Kawada, Shinjuku-ku, Tokyo 162-8666, Japan
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Additive inhibitory effect of experimentally induced hepatic cirrhosis by agonists of peroxisome proliferator activator receptor gamma and retinoic acid receptor. Dig Dis Sci 2009; 54:292-9. [PMID: 18594976 DOI: 10.1007/s10620-008-0336-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2008] [Accepted: 05/06/2008] [Indexed: 01/09/2023]
Abstract
Peroxisome proliferator activator receptor (PPAR) ligands prevent liver fibrosis, while the role of all-trans retinoic acid (ATRA) and its metabolite 9-cis retinoic acid (9-cis RA) is less clear. We have investigated the ability of the combination of PPAR gamma ligand rosiglitazone (RSG) and of ATRA to prevent liver fibrosis. In vivo treatment with RSG or ATRA reduced fibrotic nodules, spleen weight, and hydroxyproline levels in rat model of thioacetamide-induced liver fibrosis. The combination of ATRA + RSG caused the strongest inhibition, accompanied by decreased expression of collagen I, alpha-smooth muscle actin, TGF beta 1, and TNFalpha. In vitro studies showed that PPAR gamma ligand 15-deoxy-Delta 12,14-prostaglandin J(2)[PJ(2)] and RXR ligand 9-cis RA or PJ(2) and ATRA inhibited proliferation of hepatic stellate cells HSC-T6. 9-cis RA inhibited c-jun levels and also inhibited expression of its receptor RXR alpha in HSC-T6 cells. The combination of PPAR-gamma and RAR agonists demonstrated an additive effect in the inhibition of TAA-induced hepatic fibrosis, due to inhibition of HSC proliferation and reduction of profibrotic TGF beta 1 and proinflammatory TNFalpha.
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Synergistic growth inhibitory effects of the dual endothelin-1 receptor antagonist bosentan on pancreatic stellate and cancer cells. Dig Dis Sci 2009; 54:309-20. [PMID: 18612819 DOI: 10.1007/s10620-008-0366-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2008] [Accepted: 06/03/2008] [Indexed: 12/11/2022]
Abstract
Pancreatic stellate cells (PSC) play a key role in pancreatic fibrosis. Activation of PSC occurs in response to pro-fibrogenic stimuli and is maintained by autocrine loops of mediators, such as endothelin (ET)-1. Here, we have evaluated effects of the dual ET receptor antagonist bosentan in models of pancreatic fibrogenesis and cancer. Cell culture studies revealed that PSC and DSL6A pancreatic cancer cells expressed both ET-1 and ET receptors. Bosentan efficiently inhibited proliferation of both cell types and collagen synthesis in PSC. Expression of the myofibroblastic marker alpha-smooth muscle actin, connective tissue growth factor, and ET-1 itself in PSC was reduced, while expression of matrix metalloproteinase-9 was enhanced. Like PSC, DSL6A cells secrete less ET-1 when cultured with bosentan. In a rat model of pancreatic fibrosis, chronic pancreatitis induced by dibutyltin dichloride, a tendency towards a diminished disease progression was observed in a subgroup of rats with less severe disease. Together, our results indicate that bosentan exerts antifibrotic and antitumor effects in vitro. Its efficiency in vivo warrants further investigation.
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Abstract
Chronic pancreatitis and pancreatic cancer are characterised by a progressive fibrosis. Accumulation of extracellular matrix not only accompanies both diseases but is directly involved in their progression, suggesting inhibition of fibrogenesis as a potential therapeutic strategy. Pancreatic stellate cells (PSC) are the main extracellular matrix-producing cell type in the diseased pancreas. In response to pro-fibrogenic mediators including cytokines and ethanol metabolites, PSC undergo phenotypic changes termed activation, resulting in the exhibition of a myofibroblast-like phenotype. In the perpetuation of PSC activation, autocrine loops of mediators such as transforming growth factor beta play an important role. Most recently signal transduction pathways in PSC that are associated with the process of activation were characterised, facilitating identification of potential intracellular targets for an anti-fibrotic therapy. While some putative inhibitors of fibrogenesis have been tested in animal models of pancreatic fibrosis for their in vivo efficiency, clinical studies still remain to be performed.
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Affiliation(s)
- Robert Jaster
- Department of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock, E.-Heydemann-Strasse 6, 18057 Rostock, Germany.
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Talukdar R, Tandon RK. Pancreatic stellate cells: new target in the treatment of chronic pancreatitis. J Gastroenterol Hepatol 2008; 23:34-41. [PMID: 17995943 DOI: 10.1111/j.1440-1746.2007.05206.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Chronic pancreatitis (CP) is characterized by progressive fibrosis, pain and/or loss of exocrine and endocrine functions. Recent in vitro and in vivo experiments have proven objectively the role of activated pancreatic stellate cells (PSC) in fibrogenesis in CP. Molecular mediators shown to regulate the pathogenesis include transforming growth factor beta (TGF-beta), platelet-derived growth factor (PDGF), and pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha. Furthermore, molecular pathways involving mitogen-activated protein kinases (MAPK), phosphatidyl inositol 3-kinase (PI3K), Ras superfamily G proteins, serine threonine protein kinase Raf-1 and peroxisome proliferator activated receptor gamma (PPAR-gamma) have been elucidated. Understanding of the pathogenesis has led to identification of novel molecular targets and development of potential newer therapeutic agents. Those found to retard the progression of experimental CP and fibrosis in animal models include interferon (IFN) beta and IFN-gamma; a Japanese herbal medicine called Saiko-keishi-to (TJ-10); curcumin; PPAR-gamma ligand (troglitazone); antioxidants (vitamin A, vitamin E, DA 9601 and epigallocatechin-3-gallate); a protease inhibitor (camostat mesilate) and hydroxymethylglutaryl-CoA inhibitor (lovastatin). This review summarizes the current literature addressing the role of different pharmacological agents aimed at reducing or preventing inflammation and the consequent fibrogenesis in CP.
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Affiliation(s)
- Rupjyoti Talukdar
- Department of Gastroenterology, Pushpawati Singhania Research Institute, New Delhi, India
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Bülow R, Fitzner B, Sparmann G, Emmrich J, Liebe S, Jaster R. Antifibrogenic effects of histone deacetylase inhibitors on pancreatic stellate cells. Biochem Pharmacol 2007; 74:1747-57. [PMID: 17889833 DOI: 10.1016/j.bcp.2007.08.023] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2007] [Revised: 08/16/2007] [Accepted: 08/16/2007] [Indexed: 12/11/2022]
Abstract
Pancreatic stellate cells (PSCs) are essentially involved in pancreatic fibrogenesis and considered as a target for antifibrotic therapies. Here, we have analyzed the effects of three histone deacetylase inhibitors (HDACIs), sodium butyrate, sodium valproate (VPA) and trichostatin A (TSA), on profibrogenic activities of PSC and elucidated molecular targets of HDACI action. Therefore, cultured PSCs were exposed to HDACI. Cell proliferation and viability were assessed by 5-bromo-2'-deoxyuridine (BrdU) incorporation and trypan blue staining assays. Exhibition of the myofibroblastic PSC phenotype was monitored by immunofluorescence analysis of alpha-smooth muscle actin (alpha-SMA) expression. [(3)H]-proline incorporation into acetic acid-soluble proteins was measured to quantify collagen synthesis. Levels of mRNA were determined by quantitative reverse transcriptase real-time PCR. Protein expression, phosphorylation and acetylation were analyzed by immunoblotting, and gel shift assays were performed to study DNA binding of nuclear proteins. HDACI enhanced histone H3 acetylation in a dose-dependent manner. In the same dose range, they strongly inhibited cell proliferation, alpha-SMA expression and collagen synthesis. A significantly increased rate of cell death was observed in response to TSA at 1 microM. While all three HDACI inhibited mRNA expression of endothelin-1, only VPA significantly reduced expression of transforming growth factor-beta1. Both mediators exert autocrine profibrogenic effects on PSC. Furthermore, HDACI-treated PSC displayed a diminished DNA binding of AP-1, a key transcription factor in profibrogenic signaling. Together, the results suggest that HDACI exert antifibrogenic effects on PSC. Interruption of AP-1 signaling and autocrine loops enhancing PSC activation might be key mechanisms of HDACI action.
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Affiliation(s)
- Robin Bülow
- Department of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock, E.-Heydemann-Str. 6, 18057 Rostock, Germany
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Baumert JT, Sparmann G, Emmrich J, Liebe S, Jaster R. Inhibitory effects of interferons on pancreatic stellate cell activation. World J Gastroenterol 2006; 12:896-901. [PMID: 16521217 PMCID: PMC4066154 DOI: 10.3748/wjg.v12.i6.896] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze and to compare the effects of interferon (IFN)-α, IFN-β, and IFN-γ on pancreatic stellate cell (PSC) activation in vitro and to elucidate the molecular basis of IFN action.
METHODS: PSCs were isolated from rat’s pancreatic tissue, cultured and stimulated with recombinant rat IFNs. Cell proliferation and collagen synthesis were assessed by measuring the incorporation of 5-bromo-2’-deoxyuridine (BrdU) into DNA and [3H]-proline into acetic acid-soluble proteins, respectively. Apoptotic cells were determined by FACS analysis (sub-G1 peak method). Exhibition of the myofibroblastic PSC phenotype was monitored by immunoblot analysis of α-smooth muscle actin (α-SMA) expression. To assess the activation of signal transducer and activator of transcription (STAT), Western blots using phospho-STAT-specific antibodies were performed. In studies on STAT1 function, expression of the protein was inhibited by siRNA.
RESULTS: IFN-β and IFN-γ, but not IFN-α significantly diminished PSC proliferation and collagen synthesis. IFN-γ was the only IFN that clearly inhibited α-SMA expression. Under the experimental conditions used, no enhanced rate of apoptotic cell death was observed in response to any IFN treatment. IFN-β and IFN-γ induced a strong increase of STAT1 and STAT3 tyrosine phosphorylation, while the effect of IFN-α was much weaker. Inhibition of STAT1 expression with siRNA was associated with a significantly reduced growth-inhibitory effect of IFN-γ.
CONCLUSION: IFN-β and particularly IFN-γ display inhibitory effects on PSC activation in vitro and should be tested regarding their in vitro efficiency. Growth inhibition by IFN-γ action requires STAT1.
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Affiliation(s)
- Jan-Tido Baumert
- Department of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock, 18057 Rostock, Germany
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Abstract
Fibrosis within the pancreas is a key feature of chronic pancreatitis and pancreatic cancer. It has now been well demonstrated that following injury to acinar cells, pancreatic stellate cell activation, migration and proliferation is the key mediator of this process. Many cytokines and growth factors have been studied, particularly TGF-beta, which appears to be the major stimulus to fibrinogenesis. There is current interest in the mechanisms of phenotypic change between the active and quiescent forms, apoptosis and the signalling pathways that may be involved. The pancreatic stellate cell is likely to play an important role in maintaining the normal extracellular matrix; we speculate that the dysregulation of this process is an important factor in chronic pancreatitis.
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Affiliation(s)
- M Patel
- Southampton University Hospitals NHS Trust, Southampton, UK
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Jaster R, Lichte P, Fitzner B, Brock P, Glass A, Karopka T, Gierl L, Koczan D, Thiesen HJ, Sparmann G, Emmrich J, Liebe S. Peroxisome proliferator-activated receptor gamma overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells. J Cell Mol Med 2005; 9:670-82. [PMID: 16202214 PMCID: PMC6741639 DOI: 10.1111/j.1582-4934.2005.tb00497.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Pancreatic stellate cells (PSCs) play a key role in the development of pancreatic fibrosis, a constant feature of chronic pancreatitis and pancreatic cancer. In response to pro-fibrogenic mediators, PSCs undergo an activation process that involves proliferation, enhanced production of extracellular matrix proteins and a phenotypic transition towards myofibroblasts. Ligands of the peroxisome proliferator-activated receptor gamma (PPARgamma), such as thiazolidinediones, are potent inhibitors of stellate cell activation and fibrogenesis in pancreas and liver. The effects of PPARgamma ligands, however, are at least in part mediated through PPARgamma-independent pathways. Here, we have chosen a different approach to study regulatory functions of PPARgamma in PSCs. Using immortalised rat PSCs, we have established a model of tetracycline (tet)-regulated PPARgamma overexpression. Induction of PPARgamma expression strongly inhibited proliferation and enhanced the rate of apoptotic cell death. Furthermore, PPARgamma-overexpressing cells synthesised less collagen than controls. To monitor effects of PPARgamma on PSC gene expression, we employed Affymetrix microarray technology. Using stringent selection criteria, we identified 21 up- and 19 down-regulated genes in PPARgamma-overexpressing cells. Most of the corresponding gene products are either involved in lipid metabolism, play a role in signal transduction, or are secreted molecules that regulate cell growth and differentiation. In conclusion, our data suggest an active role of PPARgamma in the induction of a quiescent PSC phenotype. PPARgamma-regulated genes in PSCs may serve as novel targets for the development of antifibrotic therapies.
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Affiliation(s)
- Robert Jaster
- Department of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock, Rostock, 18057, Germany.
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Jesnowski R, Fürst D, Ringel J, Chen Y, Schrödel A, Kleeff J, Kolb A, Schareck WD, Löhr M. Immortalization of pancreatic stellate cells as an in vitro model of pancreatic fibrosis: deactivation is induced by matrigel and N-acetylcysteine. J Transl Med 2005; 85:1276-91. [PMID: 16127427 DOI: 10.1038/labinvest.3700329] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Tissue fibrosis is one of the characteristics of chronic pancreatitis and pancreatic adenocarcinoma. Activated pancreatic stellate cells (PSC) play a central role in this process. However, analysis of the molecular mechanisms leading to PSC activation is hampered by the lack of an established human PSC line. To overcome this problem, we immortalized and characterized primary human PSC. The cells were isolated by the outgrowth method and were immortalized by transfection with SV40 large T antigen and human telomerase (hTERT). Primary human PSC served as controls. An immortalized line, RLT-PSC, was analyzed for the expression of stellate cell markers. Moreover, the effects of transforming growth factor beta 1(TGFbeta1) or platelet-derived growth factor stimulation and of cultivation on basement membrane components or N-acetylcysteine (NAC) treatment on gene and protein expression and proliferation were analyzed. Immortal RLT-PSC cells retained the phenotype of activated PSC proven by the expression of alpha-smooth muscle actin (alphaSMA), vimentin, desmin and glial fibrillary acidic protein (GFAP). TGFbeta1 treatment upregulated the expression of alphaSMA, collagen type I (Col I), fibronectin and TGFbeta1. Incubation of RLT-PSC cells and primary human activated PSC on Matrigel plus NAC treatment resulted in a deactivated phenotype as evidenced by a decrease of alphaSMA, connective tissue growth factor and Col I expression and by a decreased proliferation of the cells. Moreover, this treatment restored the ability of the cells to store vitamin A in cytoplasmic vesicles. In conclusion, we have established an immortal pancreatic stellate cell line, without changing the characteristic phenotype. Importantly, we were able to demonstrate that besides soluble factors, the matrix surrounding PSC plays a pivotal role in the maintenance of the activation process of PSC. Cultivation of activated PSC on a reconstituted basement membrane plus treatment with NAC was able to deactivate the cells, thus pointing to the possibility of an antifibrosis therapy in chronic pancreatitis.
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Affiliation(s)
- Ralf Jesnowski
- Clinical Cooperation Unit Molecular Gastroenterology, DKFZ, Heidelberg, Germany.
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Fuja TJ, Probst-Fuja MN, Titze IR. Transdifferentiation of vocal-fold stellate cells and all-trans retinol-induced deactivation. Cell Tissue Res 2005; 322:417-24. [PMID: 16047162 DOI: 10.1007/s00441-005-0028-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2005] [Accepted: 05/31/2005] [Indexed: 01/20/2023]
Abstract
The maculae flavae of the human vocal folds include dense extracellular matrices and compacted cells with a stellate morphology. These vocal-fold stellate cells are thought to participate in the metabolism of extracellular matrices essential in maintaining vocal-fold viscoelasticity required for phonation. We have isolated and cultured these new cells and have tested the hypothesis that they maintain a distinct cellular and biochemical phenotype. We have compared proliferation rates, changes on immunophenotype, and intracellular lipid and vitamin A storage. Vocal-fold stellate cells undergo culture-induced transdifferentiation to a myofibroblast-like phenotype with an altered phenotype resembling, but not identical to, activated hepatic and pancreatic stellate cells. Our results reveal that these cells are capable of responding to exogenous all-trans retinol in culture. Exposure to this synthetic co-factor causes deactivation characterized by decreased proliferation, loss of the activated stellate cell marker, alpha-smooth muscle actin, and restoration of intracellular lipid and vitamin A metabolite storage. These data establish a new and distinct cellular target for future investigations of the viscoelastic properties of the vocal-fold mucosa during normal phonation, aging, vocal-fold scarring, laryngeal fibrosis, and myofibroblastoma.
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Affiliation(s)
- Tannin J Fuja
- National Center for Voice and Speech, Department of Speech Pathology and Audiology, University of Iowa, 330 Wendell Johnson Speech and Hearing Center, IA 52242, Iowa City, USA.
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