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Frendi S, Chassac A, Veron K, Raffenne J, Nicolle R, Albuquerque M, Paradis V, Couvelard A, Cros J, Rebours V. Protective role of oleic acid against palmitic acid-induced pancreatic fibrosis. J Transl Med 2025; 23:416. [PMID: 40211240 PMCID: PMC11983757 DOI: 10.1186/s12967-025-06313-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 02/23/2025] [Indexed: 04/12/2025] Open
Abstract
BACKGROUND Obesity has been associated with several pancreatic disorders and is an important risk factor for pancreatic cancer. Nevertheless, the role of lipids in the early steps of carcinogenesis is unknown. Although we previously identified two types of pancreatic fatty infiltration with different lipid compositions that were associated with precancerous lesions and fibrosis, their mechanisms of action have not been clarified. METHODS We hypothesized that saturated palmitic acid and mono-unsaturated oleic acid (OA and PA) could play diverse roles in the activation of pancreatic stellate cells (PSCs) during the genesis of pancreatic fibrosis and the promotion of precancerous lesions. This study explored the lipotoxic effect of OA and PA on PSCs and exocrine pancreatic tissue (acinar cells). We also explored PA-induced pyroptosis in PSCs. A three-dimensional culture system of organotypic slices from human pancreatic tissues was used as well as a two-dimensional culture of hTERT immortalized PSCs. RESULTS The results show that PA could induce the secretion of collagens and inflammatory cytokines (IL18) in PSCs (p < 0.05). We defined a standardized protocol of precision-cut pancreas slices cultured from human non-tumoral pancreatic tissue (n = 9). Both OA and PA are involved in the initiation of acinar cell transformation into ductal cells. OA was found to have a protective effect against PA-induced fibrosis (p < 0.05). CONCLUSION These results highlight the antagonistic roles of oleic and palmitic acids in the initiation of pancreatic fibrosis and show that palmitic acid has a profibrotic role.
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Affiliation(s)
- Sonia Frendi
- Paris-Cité University, Inflammation Research Center (CRI), INSERM, U1149, F-75018, Paris, France
| | - Anaïs Chassac
- Pathology Department, Bichat and Beaujon Hospitals, AP-HP, FHU MOSAIC, Paris-Cité University, Paris, France
| | - Killian Veron
- Paris-Cité University, Inflammation Research Center (CRI), INSERM, U1149, F-75018, Paris, France
| | | | - Rémy Nicolle
- Paris-Cité University, Inflammation Research Center (CRI), INSERM, U1149,, CNRS, ERL 8252, F-75018, Paris, France
| | - Miguel Albuquerque
- Paris-Cité University, Inflammation Research Center (CRI), INSERM, U1149, F-75018, Paris, France
- Pathology Department, Bichat and Beaujon Hospitals, AP-HP, FHU MOSAIC, Paris-Cité University, Paris, France
| | - Valérie Paradis
- Paris-Cité University, Inflammation Research Center (CRI), INSERM, U1149, F-75018, Paris, France
- Pathology Department, Bichat and Beaujon Hospitals, AP-HP, FHU MOSAIC, Paris-Cité University, Paris, France
| | - Anne Couvelard
- Paris-Cité University, Inflammation Research Center (CRI), INSERM, U1149, F-75018, Paris, France
- Pathology Department, Bichat and Beaujon Hospitals, AP-HP, FHU MOSAIC, Paris-Cité University, Paris, France
| | - Jérôme Cros
- Paris-Cité University, Inflammation Research Center (CRI), INSERM, U1149, F-75018, Paris, France
- Pathology Department, Bichat and Beaujon Hospitals, AP-HP, FHU MOSAIC, Paris-Cité University, Paris, France
| | - Vinciane Rebours
- Paris-Cité University, Inflammation Research Center (CRI), INSERM, U1149, F-75018, Paris, France.
- Pancreatology and Digestive Oncology Department - DMU Digest, Beaujon Hospital, AP-HP, INSERM, UMR 1149, Paris-Cité University, Clichy, France.
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Poulsen VV, Hadi A, Werge MP, Karstensen JG, Novovic S. Circulating Biomarkers Involved in the Development of and Progression to Chronic Pancreatitis-A Literature Review. Biomolecules 2024; 14:239. [PMID: 38397476 PMCID: PMC10887223 DOI: 10.3390/biom14020239] [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: 12/29/2023] [Revised: 02/13/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
Chronic pancreatitis (CP) is the end-stage of continuous inflammation and fibrosis in the pancreas evolving from acute- to recurrent acute-, early, and, finally, end-stage CP. Currently, prevention is the only way to reduce disease burden. In this setting, early detection is of great importance. Due to the anatomy and risks associated with direct sampling from pancreatic tissue, most of our information on the human pancreas arises from circulating biomarkers thought to be involved in pancreatic pathophysiology or injury. The present review provides the status of circulating biomarkers involved in the development of and progression to CP.
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Affiliation(s)
- Valborg Vang Poulsen
- Pancreatitis Center East, Gastrounit, Copenhagen University Hospital—Amager and Hvidovre, 2000 Copenhagen, Denmark; (V.V.P.); (A.H.); (M.P.W.); (J.G.K.)
| | - Amer Hadi
- Pancreatitis Center East, Gastrounit, Copenhagen University Hospital—Amager and Hvidovre, 2000 Copenhagen, Denmark; (V.V.P.); (A.H.); (M.P.W.); (J.G.K.)
| | - Mikkel Parsberg Werge
- Pancreatitis Center East, Gastrounit, Copenhagen University Hospital—Amager and Hvidovre, 2000 Copenhagen, Denmark; (V.V.P.); (A.H.); (M.P.W.); (J.G.K.)
| | - John Gásdal Karstensen
- Pancreatitis Center East, Gastrounit, Copenhagen University Hospital—Amager and Hvidovre, 2000 Copenhagen, Denmark; (V.V.P.); (A.H.); (M.P.W.); (J.G.K.)
- Department of Clinical Medicine, University of Copenhagen, 2000 Copenhagen, Denmark
| | - Srdan Novovic
- Pancreatitis Center East, Gastrounit, Copenhagen University Hospital—Amager and Hvidovre, 2000 Copenhagen, Denmark; (V.V.P.); (A.H.); (M.P.W.); (J.G.K.)
- Department of Clinical Medicine, University of Copenhagen, 2000 Copenhagen, Denmark
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Zajkowska M, Mroczko B. The Role of Pentraxin 3 in Gastrointestinal Cancers. Cancers (Basel) 2023; 15:5832. [PMID: 38136377 PMCID: PMC10741769 DOI: 10.3390/cancers15245832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/06/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Gastrointestinal cancers have become a huge problem worldwide as the number of new cases continues to increase. Due to the growing need to explore new biomarkers and therapeutic targets for the detection and treatment of cancerous lesions, we sought to elucidate the role of Pentraxin-3 in the progression of cancerous lesions, as it is involved in the process of angiogenesis and inflammation. Statistically significant changes in the concentration of this parameter have emerged in many gastrointestinal cancer patients. Moreover, it is related to the advancement of cancer, as well as processes leading to the development of those changes. In the case of studies concerning tissue material, both increased and decreased tissue expression of the tested parameter were observed and were dependent on the type of cancer. In the case of cell lines, both human and animal, a significant increase in Pentraxin 3 gene expression was observed, which confirmed the changes observed at the protein level. In conclusion, it can be assumed that PTX3, both at the level of gene expression and protein concentrations, is highly useful in the detection of gastrointestinal cancers, and its use as a biomarker and/or therapeutic target may be useful in the future.
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Affiliation(s)
- Monika Zajkowska
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland;
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland;
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
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4
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Bogdan M, Meca AD, Turcu-Stiolica A, Oancea CN, Kostici R, Surlin MV, Florescu C. Insights into the Relationship between Pentraxin-3 and Cancer. Int J Mol Sci 2022; 23:15302. [PMID: 36499628 PMCID: PMC9739619 DOI: 10.3390/ijms232315302] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 11/21/2022] [Accepted: 11/29/2022] [Indexed: 12/11/2022] Open
Abstract
Although cancer can be cured if detected early and treated effectively, it is still a leading cause of death worldwide. Tumor development can be limited by an appropiate immune response, but it can be promoted by chronic extensive inflammation through metabolic dysregulation and angiogenesis. In the past decade, numerous efforts have been made in order to identify novel candidates with predictive values in cancer diagnostics. In line with this, researchers have investigated the involvement of pentraxin-3 (PTX-3) in cellular proliferation and immune escape in various types of cancers, although it has not been clearly elucidated. PTX-3 is a member of the long pentraxin subfamily which plays an important role in regulating inflammation, innate immunity response, angiogenesis, and tissue remodeling. Increased synthesis of inflammatory biomarkers and activation of different cellular mechanisms can induce PTX-3 expression in various types of cells (neutrophils, monocytes, lymphocytes, myeloid dendritic cells, fibroblasts, and epithelial cells). PTX-3 has both pro- and anti-tumor functions, thus dual functions in oncogenesis. This review elucidates the potential usefulness of PTX-3 as a serum biomarker in cancer. While future investigations are needed, PTX-3 is emerging as a promising tool for cancer's diagnosis and prognosis, and also treatment monitoring.
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Affiliation(s)
- Maria Bogdan
- Department of Pharmacology, Faculty of Pharmacy, University of Medicine and Pharmacy, 200349 Craiova, Romania
| | - Andreea-Daniela Meca
- Department of Pharmacology, Faculty of Pharmacy, University of Medicine and Pharmacy, 200349 Craiova, Romania
| | - Adina Turcu-Stiolica
- Department of Pharmacoeconomics, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Carmen Nicoleta Oancea
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Roxana Kostici
- Department of Toxicology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Marin Valeriu Surlin
- Department of General Surgery, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Cristina Florescu
- Department of Cardiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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Li L, Yu XJ, Gao L, Cheng L, Sun B, Wang G. Diabetic Ferroptosis and Pancreatic Cancer: Foe or Friend? Antioxid Redox Signal 2022; 37:1206-1221. [PMID: 35996983 DOI: 10.1089/ars.2022.0101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Significance: Pancreatic cancer and diabetes have a reciprocal causation relationship. As a potential risk factor, diabetes increases morbidity and promotes pancreatic cancer progression. The main mechanisms include islet dysfunction-induced systemic metabolic disorder, pancreatic stellate cell activation, and immunosuppression. Ferroptosis is regarded as regulated cell death, which participates in chemotherapy resistance and is refractory to radiation therapy and immunotherapy. Diabetes-induced ferroptosis causes many complications, but the underlying mechanism of diabetes-related ferroptosis in pancreatic cancer has not been discussed. Recent Advances: Ferroptosis alleviates pancreatic intraepithelial neoplasia (PanIN) progression by activating chronic inflammation. The specific drugs that cause ferroptosis achieve tumor suppression by inducing lipid peroxidation. Ferroptosis plays pro and con roles in cancer. Both the ferroptosis inhibitor and inducer exhibit antitumor effects through killing cancer cells or directly affecting tumor growth. Diabetes-induced ferroptosis contributes to tumor cell death by different components, including tumor cells, fibroblasts, immune cells, and adipocytes. A better understanding of its role in modulating the tumor microenvironment will reveal diabetes-associated ferroptotic features in cancer development, which can be used to figure out possible treatment strategies for cancer patients with hyperglycemia. Critical Issues: We demonstrate the potential roles of diabetes-related ferroptosis in pancreatic cancer progression and discuss ferroptosis-related antitumor effects and therapeutics for pancreatic cancer treatment. Future Directions: Further studies are required to highlight mechanisms of diabetes-mediated ferroptosis in pancreatic cancer tumorigenesis and progression. The antitumor effects of ferroptosis regulators combined with chemotherapy, targeted therapy, or immunotherapy in diabetic patients should be investigated. We hope that pancreatic cancer patients with diabetes will benefit from ferroptosis-related therapies. Antioxid. Redox Signal. 37, 1206-1221.
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Affiliation(s)
- Le Li
- Department of Pancreatic and Biliary Surgery and The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xing-Jia Yu
- Department of Centric Operating Room, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lei Gao
- Department of Pancreatic and Biliary Surgery and The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Long Cheng
- Department of Pancreatic and Biliary Surgery and The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery and The First Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Gang Wang
- Department of Pancreatic and Biliary Surgery and The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Sharma S, Pande G, Rai MK, Agarwal V. Indigenous Primary Culture Protocols for Human Adult Skin Fibroblast, Pancreatic Stellate Cells, and Peritoneal Fibroblasts. INDIAN JOURNAL OF RHEUMATOLOGY 2021; 16:298-303. [DOI: 10.4103/injr.injr_160_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
| | - Gaurav Pande
- Departments of Medical Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Mohit Kumar Rai
- Departments of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
- Both authors contributed equally to this work
| | - Vikas Agarwal
- Departments of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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7
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Pang TCY, Xu Z, Mekapogu AR, Pothula S, Becker T, Corley S, Wilkins MR, Goldstein D, Pirola R, Wilson J, Apte M. HGF/c-Met Inhibition as Adjuvant Therapy Improves Outcomes in an Orthotopic Mouse Model of Pancreatic Cancer. Cancers (Basel) 2021; 13:2763. [PMID: 34199452 PMCID: PMC8199621 DOI: 10.3390/cancers13112763] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/12/2021] [Accepted: 05/14/2021] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Inhibition of hepatocyte growth factor (HGF)/c-MET pathway, a major mediator of pancreatic stellate cell (PSC)-PC cell interactions, retards local and distant cancer progression. This study examines the use of this treatment in preventing PC progression after resection. We further investigate the postulated existence of circulating PSCs (cPSCs) as a mediator of metastatic PC. METHODS Two orthotopic PC mouse models, produced by implantation of a mixture of luciferase-tagged human pancreatic cancer cells (AsPC-1), and human PSCs were used. Model 1 mice underwent distal pancreatectomy 3-weeks post-implantation (n = 62). One-week post-resection, mice were randomised to four treatments of 8 weeks: (i) IgG, (ii) gemcitabine (G), (iii) HGF/c-MET inhibition (HiCi) and (iv) HiCi + G. Tumour burden was assessed longitudinally by bioluminescence. Circulating tumour cells and cPSCs were enriched by filtration. Tumours of Model 2 mice progressed for 8 weeks prior to the collection of primary tumour, metastases and blood for single-cell RNA-sequencing (scRNA-seq). RESULTS HiCi treatments: (1) reduced both the risk and rate of disease progression after resection; (2) demonstrated an anti-angiogenic effect on immunohistochemistry; (3) reduced cPSC counts. cPSCs were identified using immunocytochemistry (α-smooth muscle actin+, pan-cytokeratin-, CD45-), and by specific PSC markers. scRNA-seq confirmed the existence of cPSCs and identified potential genes associated with development into cPSCs. CONCLUSIONS This study is the first to demonstrate the efficacy of adjuvant HGF/c-Met inhibition for PC and provides the first confirmation of the existence of circulating PSCs.
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Affiliation(s)
- Tony C. Y. Pang
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, Ingham Institute for Applied Medical Research, University of New South Wales, Sydney, NSW 2170, Australia; (T.C.Y.P.); (Z.X.); (A.R.M.); (S.P.); (D.G.); (R.P.); (J.W.)
- Surgical Innovations Unit, Westmead Hospital, Westmead, NSW 2145, Australia
- Westmead Clinical School, University of Sydney, Westmead, NSW 2145, Australia
| | - Zhihong Xu
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, Ingham Institute for Applied Medical Research, University of New South Wales, Sydney, NSW 2170, Australia; (T.C.Y.P.); (Z.X.); (A.R.M.); (S.P.); (D.G.); (R.P.); (J.W.)
| | - Alpha Raj Mekapogu
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, Ingham Institute for Applied Medical Research, University of New South Wales, Sydney, NSW 2170, Australia; (T.C.Y.P.); (Z.X.); (A.R.M.); (S.P.); (D.G.); (R.P.); (J.W.)
| | - Srinivasa Pothula
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, Ingham Institute for Applied Medical Research, University of New South Wales, Sydney, NSW 2170, Australia; (T.C.Y.P.); (Z.X.); (A.R.M.); (S.P.); (D.G.); (R.P.); (J.W.)
| | - Therese Becker
- Centre for Circulating Tumour Cell Diagnostics and Research, Ingham Institute for Applied Medical Research, Sydney, NSW 2170, Australia;
| | - Susan Corley
- Ramaciotti Centre for Genomics, School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, NSW 2052, Australia; (S.C.); (M.R.W.)
| | - Marc R. Wilkins
- Ramaciotti Centre for Genomics, School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, NSW 2052, Australia; (S.C.); (M.R.W.)
| | - David Goldstein
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, Ingham Institute for Applied Medical Research, University of New South Wales, Sydney, NSW 2170, Australia; (T.C.Y.P.); (Z.X.); (A.R.M.); (S.P.); (D.G.); (R.P.); (J.W.)
| | - Romano Pirola
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, Ingham Institute for Applied Medical Research, University of New South Wales, Sydney, NSW 2170, Australia; (T.C.Y.P.); (Z.X.); (A.R.M.); (S.P.); (D.G.); (R.P.); (J.W.)
| | - Jeremy Wilson
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, Ingham Institute for Applied Medical Research, University of New South Wales, Sydney, NSW 2170, Australia; (T.C.Y.P.); (Z.X.); (A.R.M.); (S.P.); (D.G.); (R.P.); (J.W.)
| | - Minoti Apte
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, Ingham Institute for Applied Medical Research, University of New South Wales, Sydney, NSW 2170, Australia; (T.C.Y.P.); (Z.X.); (A.R.M.); (S.P.); (D.G.); (R.P.); (J.W.)
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Kang Z, Wang C, Tong Y, Li Y, Gao Y, Hou S, Hao M, Han X, Wang B, Wang Q, Zhang C. Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment. J Med Chem 2020; 64:629-643. [PMID: 33381963 DOI: 10.1021/acs.jmedchem.0c01197] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In a pancreatic tumor microenvironment, activated pancreatic stellate cells (PSCs) produce extracellular matrix (ECM) to form a barrier to drug penetration. Moreover, the interaction between cancer cells and activated PSCs promotes the tumor growth. Vitamin D receptor (VDR), as a key regulator to promote the recovery of PSCs to the resting state, is an attractive therapeutic target for pancreatic cancer. Herein, we reported the design and synthesis of 57 nonsecosteroidal VDR modulators based on the skeleton of phenyl-pyrrolyl pentane. Among them, compounds C4, I5, and I8 exhibited excellent VDR affinity and effective inhibition of the activation of PSCs, as well as potent suppression of the interaction between cancer cells and PSCs in vitro. In vivo, compound I5 combined with gemcitabine achieved efficacious antitumor activity without causing hypercalcemia. In conclusion, the compounds designed in our study can remodel the tumor microenvironment and are expected to be candidates for the treatment of pancreatic cancer.
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Affiliation(s)
- Zisheng Kang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Cong Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Yu Tong
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Yanyi Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Yi Gao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Siyuan Hou
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Meixi Hao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Xiaolin Han
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Bin Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Qianqian Wang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Can Zhang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, P.R. China
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Thomas D, Radhakrishnan P. Role of Tumor and Stroma-Derived IGF/IGFBPs in Pancreatic Cancer. Cancers (Basel) 2020; 12:E1228. [PMID: 32414222 PMCID: PMC7281733 DOI: 10.3390/cancers12051228] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/09/2020] [Accepted: 05/11/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is the utmost stroma-rich cancer, which is accompanied by fibrotic reactions that stimulate interactions between tumor cells and stroma to promote tumor progression. Considerable research evidence denotes that insulin-like growth factor (IGF)/IGF binding proteins (IGFBP) signaling axis facilitate tumor growth, metastasis, drug resistance, and thereby facilitate PC into an advanced stage. The six members of IGFBPs were initially considered as passive carriers of free IGFs; however, current evidence revealed their functions beyond the endocrine role in IGF transport. Though numerous efforts have been made in blocking IGF/IGFBPs, the targeted therapies remain unsuccessful due to the complexity of tumor-stromal interactions in the pancreas. In this review, we explore the emerging evidence of the various roles of the tumor as well as stroma derived IGF/IGFBPs and highlight as a novel therapeutic target against PC progression.
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Affiliation(s)
- Divya Thomas
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA;
| | - Prakash Radhakrishnan
- Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA;
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
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10
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Sun L, Qu L, Brigstock DR, Li H, Li Y, Gao R. Biological and Proteomic Characteristics of an Immortalized Human Pancreatic Stellate Cell Line. Int J Med Sci 2020; 17:137-144. [PMID: 31929747 PMCID: PMC6945563 DOI: 10.7150/ijms.36337] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 12/12/2019] [Indexed: 02/07/2023] Open
Abstract
Human pancreatic stellate cells (PSCs) play a critical role in fibrogenesis during chronic pancreatitis (CP). However, primary PSCs have a short lifespan in vitro, which seriously affects their use in various applications. We have established a stable immortalized human PSC line (HP-1) by RSV promoter/enhancer-driven SV40 T antigen expression in primary activated human PSCs. HP-1 cells express cytoskeleton proteins including glial fibrillary acidic protein (GFAP), α-smooth muscle actin (α-SMA), vimentin and desmin, and are typical of PSCs, which are high transfeciability and viable in 0.5% serum. The cells express receptors such as TGFβR2, PDGFR, TGF-β pseudoreceptor Bambi and PPRPγ that are commonly found in PSCs. HP-1 cells are similar to activated human PSCs in that they have enhanced expression of α-SMA, CTGF, Col1 and TIMP-2 mRNAs or proteins, as well as decreased expression of MMP-1/2 mRNAs or proteins in response to TGF-β1 stimulation. Comparative proteomics revealed 4,537 shared proteins between HP-1 cells and PSCs and no single protein in HP-1 cells versus PSCs. Statistical analysis reveals no significantly difference between HP-1 cells and PSCs in their expression of proteins associated with matrix and matrix remodeling. The similarity between HP-1 cell and PSC is further shown by the finding that only 9 proteins are differentially up-regulated > ± 2-fold in HP-1 cells and 13 proteins are up-regulated > ± 2-fold in PSCs and none of these proteins include ECM proteins, cytokines, growth factors or matrix remodeling regulatory proteins. Therefore, HP-1 cells can be used as an effective tool for the study of PSC-mediated pancreatic fibrosis.
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Affiliation(s)
- Li Sun
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, 130021, China
| | - Limei Qu
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, 130021, China
| | - David R Brigstock
- Research Institute at Nationwide Children's Hospital, Columbus, 43205, United States
| | - Hongyan Li
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, 130021, China
| | - Yanyan Li
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, 130021, China
| | - Runping Gao
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, 130021, China
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11
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Li W, Zhou Y, Wang X, Cai M, Gao F, Carlsson PO, Sun Z. A modified in vitro tool for isolation and characterization of rat quiescent islet stellate cells. Exp Cell Res 2019; 384:111617. [PMID: 31505166 DOI: 10.1016/j.yexcr.2019.111617] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 09/02/2019] [Accepted: 09/05/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Islet stellate cells (ISCs) play a critical role in islet fibrosis, contributing to the progression of pancreatic diseases. Previous studies have focused on fibrosis-associated activated ISCs obtained by standard islet explant techniques. However, in vitro models of quiescent ISCs (qISCs) are lacking. This study aims to develop a method to isolate qISCs and analyze their phenotype during activation. METHODS Immunofluorescence staining was applied to localize ISCs in normal human, rat, and mouse islets. qISCs were isolated from rat islets using density gradient centrifugation (DGC) method. qRT-PCR, immunoblotting, proliferation, and migration assays were employed for their characterization. RESULTS Desmin-positive ISCs were detected in normal human, rat, and mouse islets. Freshly isolated qISCs, obtained by density gradient centrifugation, displayed a polygonal appearance with refringent cytoplasmic lipid droplets and expressed transcriptional markers indicating a low activation/quiescent state. With increasing culture time, the marker expression pattern changed, reflecting ISC activation. qISCs contained more lipid droplets and exhibited lower proliferation and migration abilities compared to spindle-shaped ISCs obtained by traditional explant techniques. CONCLUSIONS This study describes a new method for efficient isolation of qISCs from rat islets, representing a useful in vitro tool to study the biology of ISCs in more physiological conditions.
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Affiliation(s)
- Wei Li
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Yunting Zhou
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Xiaohang Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Min Cai
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Feng Gao
- Graduate Innovation Platform of Southeast University, Nanjing, China
| | - Per-Ola Carlsson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Zilin Sun
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China.
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12
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Abstract
Primary cultures of pancreatic stellate cells (PSCs) remain an important basis for in vitro study. However, effective methods for isolating abundant PSCs are currently lacking. This purpose of this chapter is to report our novel approach to isolating PSCs from normal rat pancreas and human pancreatic ductal adenocarcinoma (PDAC) tissue. Normal PSCs were isolated with enzyme digestion and ladder centrifugation with Nycodenz solution. Isolated PSCs were cultured in DMEM/F12 containing 10% fetal bovine serum. Cancer-associated PSCs were obtained by an outgrow method from fresh human PDAC tissues. Isolated activated PSCs were cultured in DMEM/F12 containing 20% fetal bovine serum. With our modification, normal pancreas tissue yields an adequate number of PSCs (approximately 0.5-5 million/g pancreas) for in vitro studies, and the cell viability was about 90%. And a modified outgrowth method made tissue blocks attached more tightly and significantly shortened the outgrowth time of the activated cells. Our modification in PSC isolation methods significantly increased the isolation efficiency and shortened the culture period, thus facilitating future PSC-related research.
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13
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Mutgan AC, Besikcioglu HE, Wang S, Friess H, Ceyhan GO, Demir IE. Insulin/IGF-driven cancer cell-stroma crosstalk as a novel therapeutic target in pancreatic cancer. Mol Cancer 2018; 17:66. [PMID: 29475434 PMCID: PMC5824531 DOI: 10.1186/s12943-018-0806-0] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Accepted: 02/01/2018] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is unrivalled the deadliest gastrointestinal cancer in the western world. There is substantial evidence implying that insulin and insulin-like growth factor (IGF) signaling axis prompt PDAC into an advanced stage by enhancing tumor growth, metastasis and by driving therapy resistance. Numerous efforts have been made to block Insulin/IGF signaling pathway in cancer therapy. However, therapies that target the IGF1 receptor (IGF-1R) and IGF subtypes (IGF-1 and IGF-2) have been repeatedly unsuccessful. This failure may not only be due to the complexity and homology that is shared by Insulin and IGF receptors, but also due to the complex stroma-cancer interactions in the pancreas. Shedding light on the interactions between the endocrine/exocrine pancreas and the stroma in PDAC is likely to steer us toward the development of novel treatments. In this review, we highlight the stroma-derived IGF signaling and IGF-binding proteins as potential novel therapeutic targets in PDAC.
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Affiliation(s)
- Ayse Ceren Mutgan
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, München, Germany
| | - H Erdinc Besikcioglu
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, München, Germany.,Department of Histology and Embryology, Gazi University Institute of Health Sciences, Ankara, Turkey
| | - Shenghan Wang
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, München, Germany
| | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, München, Germany
| | - Güralp O Ceyhan
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, München, Germany
| | - Ihsan Ekin Demir
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, München, Germany.
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14
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D'Alessandro R, Refolo MG, Lippolis C, Carella N, Messa C, Cavallini A, Carr BI. Strong enhancement by IGF1-R antagonists of hepatocellular carcinoma cell migration inhibition by Sorafenib and/or vitamin K1. Cell Oncol (Dordr) 2018; 41:283-296. [PMID: 29470830 DOI: 10.1007/s13402-018-0370-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2018] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Emerging evidence indicates that combining Sorafenib with vitamin K1 (VK1) may result in a synergistic inhibition of hepatocellular carcinoma (HCC) cell migration and proliferation. Despite this synergy, its benefits may be limited due to drug resistance resulting from cross-talk with the tumor microenvironment. Insulin-like growth factor-1 (IGF1) signaling acts as an important modulator of HCC cell growth, motility and drug resistance. Therefore, we aimed to explore the effects of Sorafenib in combination with VK1 and/or IGF1-R antagonists on HCC cells. METHODS Scratch wound migration assays were performed to assess the motility of HCC-derived PLC/PRF/5, HLF and Hep3B cells. The synergistic, additive or antagonistic effects of Sorafenib, VK1 and IGF1-R antagonists on HCC cell motility were assessed using CompuSyn software. The effects mediated by these various compounds on HCC cytoskeleton organization were evaluated using DyLight 554 Phalloidin staining. Proliferation and migration-associated signaling pathways were analyzed in PLC/PRF/5 cells using Erk1/2 and Akt activation kits and Western blotting (Mek, JNK, Akt, Paxillin and p38), respectively. RESULTS The effects of the IGF1-R antagonists GSK1838705A and OSI-906 on HCC cell migration inhibition after Sorafenib and/or VK1 administration, individually or in combination, were evaluated. We found a synergistic effect in PLC/PRF/5, HLF and Hep3B cells for combinations of fixed doses of GSK1838705A or OSI-906 together with different doses of Sorafenib and/or VK1. The levels of synergy were found to be stronger at higher Sorafenib and/or VK1 concentrations and lower or absent at lower concentrations, with some variation among the different cell lines tested. In addition, we found that in PLC/PRF/5 and HLF cells IGF1-R blockage strongly enhanced the reduction and redistribution of F-actin induced by Sorafenib and/or VK1 through alterations in the phosphorylation levels of some of the principal proteins involved in the MAPK signaling cascade, which is essential for cell migration. CONCLUSIONS Our results indicate that modulation of the efficacy of Sorafenib through combinations with VK1 and/or IGF1-R antagonists results in synergistic inhibition of HCC cell migration.
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Affiliation(s)
- Rosalba D'Alessandro
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, National Institute of Gastroenterology, "S. De Bellis" Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Maria Grazia Refolo
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, National Institute of Gastroenterology, "S. De Bellis" Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Catia Lippolis
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, National Institute of Gastroenterology, "S. De Bellis" Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Nicola Carella
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, National Institute of Gastroenterology, "S. De Bellis" Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Caterina Messa
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, National Institute of Gastroenterology, "S. De Bellis" Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Aldo Cavallini
- Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, National Institute of Gastroenterology, "S. De Bellis" Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Brian Irving Carr
- Program for Targeted Experimental Therapeutics, Izmir Biomedicine and Genome Center, Dokuz Eylul University, Izmir, Turkey.
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15
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Suklabaidya S, Das B, Ali SA, Jain S, Swaminathan S, Mohanty AK, Panda SK, Dash P, Chakraborty S, Batra SK, Senapati S. Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia. Oncotarget 2018; 7:41825-41842. [PMID: 27259232 PMCID: PMC5173099 DOI: 10.18632/oncotarget.9729] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Accepted: 05/17/2016] [Indexed: 01/05/2023] Open
Abstract
Desmoplasia in human pancreatic cancer (PC) promotes cancer progression and hinders effective drug delivery. The objectives of this study were to characterize a homologous orthotopic model of PC in Syrian golden hamster and investigate the effect of anti-fibrotic (pirfenidone), antioxidant (N-acetyl cysteine, NAC) and anti-addiction (disulfiram, DSF) drugs on desmoplasia and tumor growth in this model. The HapT1 PC cells when implanted orthotopically into hamsters formed tumors with morphological, cellular and molecular similarities to human PC. Protein profiling of activated hamster pancreatic stellate cells (ha-PSCs) revealed expression of proteins involved in fibrosis, cancer cells growth and metastasis. Pirfenidone, suppressed growth of HapT1 cells and the desmoplastic response in vivo; these effects were enhanced by co-administration of NAC. Disulfiram alone or in combination with copper (Cu) was toxic to HapT1 cells and PSCs in vitro; but co-administration of DSF and Cu accelerated growth of HapT1 cells in vivo. Moreover, DSF had no effect on tumor-associated desmoplasia. Overall, this study identifies HapT1-derived orthotopic tumors as a useful model to study desmoplasia and tumor-directed therapeutics in PC. Pirfenidone in combination with NAC could be a novel combination therapy for PC and warrants investigation in human subjects.
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Affiliation(s)
- Sujit Suklabaidya
- Tumor Microenvironment and Animal Models Laboratory, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India.,Manipal University, Manipal, Karnataka, India
| | - Biswajit Das
- Tumor Microenvironment and Animal Models Laboratory, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India.,Manipal University, Manipal, Karnataka, India
| | - Syed Azmal Ali
- Proteomics and Structural Biology Laboratory, Animal Biotechnology Department, National Diary Research Institute, Haryana, India
| | - Sumeet Jain
- Tumor Microenvironment and Animal Models Laboratory, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India.,Manipal University, Manipal, Karnataka, India
| | - Sharada Swaminathan
- Department of Bioengineering, School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamil Nadu, India
| | - Ashok K Mohanty
- Proteomics and Structural Biology Laboratory, Animal Biotechnology Department, National Diary Research Institute, Haryana, India
| | - Susen K Panda
- Department of Veterinary Pathology, Odisha University of Agriculture and Technology, Bhubaneswar, Odisha, India
| | - Pujarini Dash
- Tumor Microenvironment and Animal Models Laboratory, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India
| | | | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, Buffett Cancer Center, Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA
| | - Shantibhusan Senapati
- Tumor Microenvironment and Animal Models Laboratory, Department of Translational Research, Institute of Life Sciences, Bhubaneswar, Odisha, India
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16
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Experimental models of pancreatic cancer desmoplasia. J Transl Med 2018; 98:27-40. [PMID: 29155423 DOI: 10.1038/labinvest.2017.127] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 10/12/2017] [Accepted: 10/12/2017] [Indexed: 01/18/2023] Open
Abstract
Desmoplasia is a fibro-inflammatory process and a well-established feature of pancreatic cancer. A key contributor to pancreatic cancer desmoplasia is the pancreatic stellate cell. Various in vitro and in vivo methods have emerged for the isolation, characterization, and use of pancreatic stellate cells in models of cancer-associated fibrosis. In addition to cell culture models, genetically engineered animal models have been established that spontaneously develop pancreatic cancer with desmoplasia. These animal models are currently being used for the study of pancreatic cancer pathogenesis and for evaluating therapeutics against pancreatic cancer. Here, we review various in vitro and in vivo models that are being used or have the potential to be used to study desmoplasia in pancreatic cancer.
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17
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Drifka CR, Loeffler AG, Esquibel CR, Weber SM, Eliceiri KW, Kao WJ. Human pancreatic stellate cells modulate 3D collagen alignment to promote the migration of pancreatic ductal adenocarcinoma cells. Biomed Microdevices 2017; 18:105. [PMID: 27819128 DOI: 10.1007/s10544-016-0128-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the ability for cancer cells to aggressively infiltrate and navigate through a dense stroma during the metastatic process. Key features of the PDAC stroma include an abundant population of activated pancreatic stellate cells (PSCs) and highly aligned collagen fibers; however, important questions remain regarding how collagen becomes aligned and what the biological manifestations are. To better understand how PSCs, aligned collagen, and PDAC cells might cooperate during the transition to invasion, we utilized a microchannel-based in vitro tumor model and advanced imaging technologies to recreate and examine in vivo-like heterotypic interactions. We found that PSCs participate in a collaborative process with cancer cells by orchestrating the alignment of collagen fibers that, in turn, are permissive to enhanced cell migration. Additionally, direct contact between PSCs, collagen, and PDAC cells is critical to invasion and co-migration of both cell types. This suggests PSCs may accompany and assist in navigating PDAC cells through the stromal terrain. Together, our data provides a new role for PSCs in stimulating the metastatic process and underscores the importance of collagen alignment in cancer progression.
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Affiliation(s)
- Cole R Drifka
- Department of Biomedical Engineering, University of Wisconsin, Madison, WI, USA.,Laboratory for Optical and Computational Instrumentation (LOCI), University of Wisconsin, Madison, WI, USA.,Morgridge Institute for Research, Madison, WI, USA
| | - Agnes G Loeffler
- Department of Surgical Pathology, University of Wisconsin, Madison, WI, USA.,University of Wisconsin Comprehensive Carbone Cancer Center, Madison, WI, USA
| | - Corinne R Esquibel
- Laboratory for Optical and Computational Instrumentation (LOCI), University of Wisconsin, Madison, WI, USA
| | - Sharon M Weber
- University of Wisconsin Comprehensive Carbone Cancer Center, Madison, WI, USA.,Department of Surgery, University of Wisconsin, Madison, WI, USA
| | - Kevin W Eliceiri
- Department of Biomedical Engineering, University of Wisconsin, Madison, WI, USA.,Laboratory for Optical and Computational Instrumentation (LOCI), University of Wisconsin, Madison, WI, USA.,Morgridge Institute for Research, Madison, WI, USA.,University of Wisconsin Comprehensive Carbone Cancer Center, Madison, WI, USA
| | - W John Kao
- Department of Biomedical Engineering, University of Wisconsin, Madison, WI, USA. .,University of Wisconsin Comprehensive Carbone Cancer Center, Madison, WI, USA. .,Department of Surgery, University of Wisconsin, Madison, WI, USA. .,Faculties of Medicine and Engineering, University of Hong Kong, Pokfulam Road, Pokfulam, Hong Kong.
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18
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Bynigeri RR, Jakkampudi A, Jangala R, Subramanyam C, Sasikala M, Rao GV, Reddy DN, Talukdar R. Pancreatic stellate cell: Pandora's box for pancreatic disease biology. World J Gastroenterol 2017; 23:382-405. [PMID: 28210075 PMCID: PMC5291844 DOI: 10.3748/wjg.v23.i3.382] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 11/09/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic stellate cells (PSCs) were identified in the early 1980s, but received much attention after 1998 when the methods to isolate and culture them from murine and human sources were developed. PSCs contribute to a small proportion of all pancreatic cells under physiological condition, but are essential for maintaining the normal pancreatic architecture. Quiescent PSCs are characterized by the presence of vitamin A laden lipid droplets. Upon PSC activation, these perinuclear lipid droplets disappear from the cytosol, attain a myofibroblast like phenotype and expresses the activation marker, alpha smooth muscle actin. PSCs maintain their activated phenotype via an autocrine loop involving different cytokines and contribute to progressive fibrosis in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Several pathways (e.g., JAK-STAT, Smad, Wnt signaling, Hedgehog etc.), transcription factors and miRNAs have been implicated in the inflammatory and profibrogenic function of PSCs. The role of PSCs goes much beyond fibrosis/desmoplasia in PDAC. It is now shown that PSCs are involved in significant crosstalk between the pancreatic cancer cells and the cancer stroma. These interactions result in tumour progression, metastasis, tumour hypoxia, immune evasion and drug resistance. This is the rationale for therapeutic preclinical and clinical trials that have targeted PSCs and the cancer stroma.
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19
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Insulin-like growth factor (IGF) axis in cancerogenesis. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2016; 772:78-104. [PMID: 28528692 DOI: 10.1016/j.mrrev.2016.08.007] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 08/27/2016] [Accepted: 08/31/2016] [Indexed: 12/21/2022]
Abstract
Determination of the role of insulin-like growth factor (IGF) family components in carcinogenesis of several human tumors is based on numerous epidemiological and pre-clinical studies, experiments in vivo and in vitro and on attempts at application of drugs affecting the IGF axis. Investigative hypotheses in original studies were based on biological functions manifested by the entire family of IGF (ligands, receptors, linking proteins, adaptor molecules). In the context of carcinogenesis the most important functions of IGF family involve intensification of proliferation and inhibition of cell apoptosis and effect on cell transformation through synthesis of several regulatory proteins. IGF axis controls survival and influences on metastases of cells. Interactions of IGF axis components may be of a direct or indirect nature. The direct effects are linked to activation of PI3K/Akt signaling pathway, in which the initiating role is first of all played by IGF-1 and IGF-1R. Activity of this signaling pathway leads to an increased mitogenesis, cell cycle progression, and protection against different apoptotic stresses. Indirect effects of the axis depend on interactions between IGF and other molecules important for cancer etiology (e.g. sex hormones, products of suppressor genes, viruses, and other GFs) and the style of life (nutrition, physical activity). From the clinical point of view, components of IGF system are first of all considered as diagnostic serous and/or tissue biomarkers of a given cancer, prognostic factors and attractive target of modern anti-tumor therapies. Several mechanisms in which IGF system components act in the process of carcinogenesis need to be clarified, mainly due to multifactorial etiology of the neoplasms. Pin-pointing of the role played in carcinogenesis by any single signaling pathway remains particularly difficult. The aim of this review is to summarize the current data of several epidemiological studies, experiments in vitro and on animal models, to increase our understanding of the complex role of IGF family components in the most common human cancers.
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20
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Abstract
Cancer is one of the major leading death causes of diseases. Prevention and treatment of cancer is an important way to decrease the incidence of tumorigenesis and prolong patients' lives. Subversive achievements on cancer immunotherapy have recently been paid much attention after many failures in basic and clinical researches. Based on deep analysis of genomics and proteomics of tumor antigens, a variety of cancer vaccines targeting tumor antigens have been tested in preclinical and human clinical trials. Many therapeutic cancer vaccines alone or combination with other conventional treatments for cancer obtained spectacular efficacy, indicating the tremendously potential application in clinic. With the illustration of underlying mechanisms of cancer immune regulation, valid, controllable, and persistent cancer vaccines will play important roles in cancer treatment, survival extension and relapse and cancer prevention. This chapter mainly summarizes the recent progresses and developments on cancer vaccine research and clinical application, thus exploring the existing obstacles in cancer vaccine research and promoting the efficacy of cancer vaccine.
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21
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Karnevi E, Rosendahl AH, Hilmersson KS, Saleem MA, Andersson R. Impact by pancreatic stellate cells on epithelial-mesenchymal transition and pancreatic cancer cell invasion: Adding a third dimension in vitro. Exp Cell Res 2016; 346:206-215. [PMID: 27443257 DOI: 10.1016/j.yexcr.2016.07.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 07/04/2016] [Accepted: 07/17/2016] [Indexed: 12/13/2022]
Abstract
Pancreatic cancer is associated with a highly abundant stroma and low-grade inflammation. In the local tumour microenvironment, elevated glucose levels, the presence of tumour-associated stellate cells and macrophages are hypothesised to promote the tumour progression and invasion. The present study investigated the influence by the microenvironment on pancreatic cancer cell invasion in vitro. After co-culture with tumour-associated pancreatic stellate cells (TPSCs), pancreatic cancer cells displayed up to 8-fold reduction in levels of epithelial-mesenchymal transition (EMT) markers E-cadherin and ZO-1, while β-catenin and vimentin levels were increased. A 3D organotypic model showed that TPSCs stimulated pancreatic cancer cell invasion, both as single cell (PANC-1) and cohort (MIAPaCa-2) invasion. The combined presence of TPSCs and M2-like macrophages induced invasion of the non-invasive BxPC-3 cells. High glucose conditions further enhanced changes in EMT markers as well as the cancer cell invasion. In summary, co-culture with TPSCs induced molecular changes associated with EMT in pancreatic cancer cells, regardless of differentiation status, and the organotypic model demonstrated the influence of microenvironmental factors, such as glucose, stellate cells and macrophages, on pancreatic cancer cell invasion.
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Affiliation(s)
- Emelie Karnevi
- Lund University and Skåne University Hospital, Department of Clinical Sciences Lund, Division of Surgery, Lund, Sweden; Lund University and Skåne University Hospital, Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund, Sweden.
| | - Ann H Rosendahl
- Lund University and Skåne University Hospital, Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund, Sweden.
| | - Katarzyna Said Hilmersson
- Lund University and Skåne University Hospital, Department of Clinical Sciences Lund, Division of Surgery, Lund, Sweden.
| | - Moin A Saleem
- University of Bristol, School of Clinical Sciences, Children's Renal Unit and Academic Renal Unit, Bristol, UK.
| | - Roland Andersson
- Lund University and Skåne University Hospital, Department of Clinical Sciences Lund, Division of Surgery, Lund, Sweden.
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22
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Zhao L, Cai B, Lu Z, Tian L, Guo S, Wu P, Qian D, Xu Q, Jiang K, Miao Y. Modified methods for isolation of pancreatic stellate cells from human and rodent pancreas. J Biomed Res 2016; 30:510-516. [PMID: 27924070 PMCID: PMC5138584 DOI: 10.7555/jbr.30.20160033] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 04/27/2016] [Accepted: 05/18/2016] [Indexed: 01/10/2023] Open
Abstract
Primary cultures of pancreatic stellate cells (PSCs) remain an important basis for in vitro study. However, effective methods for isolating abundant PSCs are currently lacking. We report on a novel approach to isolating PSCs from normal rat pancreases and human pancreatic ductal adenocarcinoma (PDAC) tissue. After anaesthesia and laparotomy of the rat, a blunt cannula was inserted into the pancreatic duct through the anti-mesentery side of the duodenum, and the pancreas was slowly infused with an enzyme solution until all lobules were fully dispersed. The pancreas was then pre-incubated, finely minced and incubated to procure a cell suspension. PSCs were obtained after the cell suspension was filtered, washed and subject to gradient centrifugation with Nycodenz solution. Fresh human PDAC tissue was finely minced into 1×1×1 mm3 cubes with sharp blades. Tissue blocks were placed at the bottom of a culture plate with fresh plasma (EDTA-anti-coagulated plasma from the same patient, mixed with CaCl2) sprinkled around the sample. After culture for 5–10 days under appropriate conditions, activated PSCs were harvested. An intraductal perfusion of an enzyme solution simplified the procedure of isolation of rat PSCs, as compared with the multiple injections technique, and a modified outgrowth method significantly shortened the outgrowth time of the activated cells. Our modification in PSC isolation methods significantly increased the isolation efficiency and shortened the culture period, thus facilitating future PSC-related research.
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Affiliation(s)
- Liangtao Zhao
- Pancreas Institute of Nanjing Medical University, Nanjing, Jiangsu 211166, China.,Lab for Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Baobao Cai
- Pancreas Institute of Nanjing Medical University, Nanjing, Jiangsu 211166, China.,Pancreas Center.,Lab for Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Zipeng Lu
- Pancreas Institute of Nanjing Medical University, Nanjing, Jiangsu 211166, China.,Pancreas Center.,Lab for Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Lei Tian
- Pancreas Institute of Nanjing Medical University, Nanjing, Jiangsu 211166, China.,Pancreas Center.,Lab for Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Song Guo
- Pancreas Institute of Nanjing Medical University, Nanjing, Jiangsu 211166, China.,Lab for Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Pengfei Wu
- Pancreas Institute of Nanjing Medical University, Nanjing, Jiangsu 211166, China.,Pancreas Center.,Lab for Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Dong Qian
- Pancreas Institute of Nanjing Medical University, Nanjing, Jiangsu 211166, China.,Lab for Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Qingcheng Xu
- Pancreas Institute of Nanjing Medical University, Nanjing, Jiangsu 211166, China.,Lab for Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Kuirong Jiang
- Pancreas Institute of Nanjing Medical University, Nanjing, Jiangsu 211166, China.,Pancreas Center.,Lab for Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yi Miao
- Pancreas Institute of Nanjing Medical University, Nanjing, Jiangsu 211166, China.,Pancreas Center.,Lab for Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China;
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23
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Abstract
PURPOSE OF REVIEW Ever since the first descriptions of methods to isolate pancreatic stellate cells (PSCs) from rodent and human pancreas 17 years ago, rapid advances have been made in our understanding of the biology of these cells and their functions in health and disease. This review updates recent literature in the field, which indicates an increasingly complex role for the cells in normal pancreas, pancreatitis and pancreatic cancer. RECENT FINDINGS Work reported over the past 12 months includes improved methods of PSC immortalization, a role for PSCs in islet fibrosis, novel factors causing PSC activation as well as those inducing quiescence, and translational research aimed at inhibiting the facilitatory effects of PSCs on disease progression in chronic pancreatitis as well as pancreatic cancer. SUMMARY Improved understanding of the role of PSCs in pancreatic pathophysiology has prompted a focus on translational studies aimed at developing novel approaches to modulate PSC function in a bid to improve clinical outcomes of two major fibrotic diseases of the pancreas: chronic pancreatitis and pancreatic cancer.
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Affiliation(s)
- Minote Apte
- Pancreatic Research Group, South Western Sydney Clinical School, University of New South Wales, and Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
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Sadowska A, Nynca A, Korzeniewska M, Piasecka-Srader J, Jablonska M, Orlowska K, Swigonska S, Ciereszko RE. Characterization of Porcine Granulosa Cell Line AVG-16. Folia Biol (Praha) 2015; 61:184-94. [PMID: 26667575 DOI: 10.14712/fb2015061050184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Commercially available, but not yet characterized, the AVG-16 granulosa cell line was established from granulosa cells of medium porcine follicles. To examine the suitability of the AVG-16 cell line for studying the molecular mechanism of action of various environmental oestrogens, we investigated: 1/ cell morphology (by standard haematoxylin and eosin (HE) staining); 2/ basal and follicle-stimulating hormone (FSH) or luteinizing hormone (LH)-stimulated steroid hormone (progesterone; P4 and 17β-oestradiol; E2) secretion (by radioimmunoassay) and 3/ expression of receptors involved in the regulation of granulosa cell function: FSH receptor (FSHR), LH receptor (LHR), oestrogen receptor α (ERα), oestrogen receptor β (ERβ) and aryl hydrocarbon receptor (AhR). mRNA and protein expression was determined by RT-PCR and fluorescence immunocytochemistry, respectively. The secretion of P4 and E2 by AVG-16 cells was in the range of steroid hormone secretion by porcine cultured primary granulosa cells. Neither FSH (100 ng/ml) nor LH (100 ng/ml) affected P4 and E2 secretion by AVG-16 cells. The presence of FSHR and LHR at both mRNA and protein level was not demonstrated in the cells. However, AVG-16 cells were found to express mRNA and protein of ERα, ERβ and AhR. The results of our study showed that AVG-16 cells possess the capability of steroid hormone production, and both oestrogen receptors and AhR are present in these cells. Therefore, AVG-16 cells may serve as an unlimited source of homogenous porcine granulosa cells useful for studying the effects of environmental oestrogens on ovarian physiology.
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Affiliation(s)
- A Sadowska
- Department of Animal Physiology, University of Warmia and Mazury, Olsztyn, Poland
| | - A Nynca
- Laboratory of Molecular Diagnostics, University of Warmia and Mazury, Olsztyn, Poland
| | - M Korzeniewska
- Department of Animal Physiology, University of Warmia and Mazury, Olsztyn, Poland
| | - J Piasecka-Srader
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | | | - K Orlowska
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - S Swigonska
- Laboratory of Molecular Diagnostics, University of Warmia and Mazury, Olsztyn, Poland
| | - R E Ciereszko
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
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