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Liaki V, Rosas-Perez B, Guerra C. Unlocking the Genetic Secrets of Pancreatic Cancer: KRAS Allelic Imbalances in Tumor Evolution. Cancers (Basel) 2025; 17:1226. [PMID: 40227826 PMCID: PMC11987834 DOI: 10.3390/cancers17071226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 03/13/2025] [Accepted: 03/31/2025] [Indexed: 04/15/2025] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) belongs to the types of cancer with the highest lethality. It is also remarkably chemoresistant to the few available cytotoxic therapeutic options. PDAC is characterized by limited mutational heterogeneity of the known driver genes, KRAS, CDKN2A, TP53, and SMAD4, observed in both early-stage and advanced tumors. In this review, we summarize the two proposed models of genetic evolution of pancreatic cancer. The gradual or stepwise accumulated mutations model has been widely studied. On the contrary, less evidence exists on the more recent simultaneous model, according to which rapid tumor evolution is driven by the concurrent accumulation of genetic alterations. In both models, oncogenic KRAS mutations are the main initiating event. Here, we analyze the emerging topic of KRAS allelic imbalances and how it arises during tumor evolution, as it is often detected in advanced and metastatic PDAC. We also summarize recent evidence on how it affects tumor biology, metastasis, and response to therapy. To this extent, we highlight the necessity to include studies of KRAS allelic frequencies in the design of future therapeutic strategies against pancreatic cancer.
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Affiliation(s)
- Vasiliki Liaki
- Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain; (B.R.-P.); (C.G.)
| | - Blanca Rosas-Perez
- Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain; (B.R.-P.); (C.G.)
| | - Carmen Guerra
- Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain; (B.R.-P.); (C.G.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Vaezi MA, Nekoufar S, Robati AK, Salimi V, Tavakoli-Yaraki M. Therapeutic potential of β-hydroxybutyrate in the management of pancreatic neoplasms: exploring novel diagnostic and treatment strategies. Lipids Health Dis 2024; 23:376. [PMID: 39543582 PMCID: PMC11562866 DOI: 10.1186/s12944-024-02368-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/09/2024] [Indexed: 11/17/2024] Open
Abstract
Pancreatic neoplasm, a highly aggressive and often fatal cancer, poses challenges due to late detection and nonspecific symptoms. Therefore, both early diagnosis and appropriate therapeutic approaches are necessary to augment the condition of these patients. Cancer cells undergo metabolic deregulation, which enables their proliferation, survival, and invasion. As a result, it is crucial to focus on the metabolic pathways in prevalent cancers and explore treatment strategies that target these pathways to control tumor growth effectively. This is particularly relevant in cancers like pancreatic cancer, which undergo numerous metabolic alterations. The ketogenic regimen, characterized by low carbohydrate and protein contents and high-fat sources, does not involve caloric restriction. This allows for the induction of ketogenesis and an increase in ketone bodies, while insulin and glucose levels remain low even after meals. This unique metabolic state may influence the tumor microenvironment. Given the lack of unanimous agreement on the precise role and mechanism of the ketogenic diet, this review aims to clarify the diagnostic value and accuracy of ketone bodies in various types of pancreatic tumors and explore the potential anti-cancer effects of the ketogenic diet when used alone or in conjunction with chemotherapy, also to determine the potential of the ketogenic diet to be used as adjuvant therapy. The outcomes of this study are instrumental in enhancing our understanding of the benefits and drawbacks associated with employing this diet for the management and diagnosis of pancreatic cancer.
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Affiliation(s)
- Mohammad Amin Vaezi
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, P.O. Box: 1449614535, Tehran, Iran
| | - Samira Nekoufar
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, P.O. Box: 1449614535, Tehran, Iran
| | - Ali Karami Robati
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, P.O. Box: 1449614535, Tehran, Iran
| | - Vahid Salimi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Tavakoli-Yaraki
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, P.O. Box: 1449614535, Tehran, Iran.
- Finetech in Medicine Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Sharma B, Twelker K, Nguyen C, Ellis S, Bhatia ND, Kuschner Z, Agriantonis A, Agriantonis G, Arnold M, Dave J, Mestre J, Shafaee Z, Arora S, Ghanta H, Whittington J. Bile Acids in Pancreatic Carcinogenesis. Metabolites 2024; 14:348. [PMID: 39057671 PMCID: PMC11278541 DOI: 10.3390/metabo14070348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/10/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
Pancreatic cancer (PC) is a dangerous digestive tract tumor that is becoming increasingly common and fatal. The most common form of PC is pancreatic ductal adenocarcinoma (PDAC). Bile acids (BAs) are closely linked to the growth and progression of PC. They can change the intestinal flora, increasing intestinal permeability and allowing gut microbes to enter the bloodstream, leading to chronic inflammation. High dietary lipids can increase BA secretion into the duodenum and fecal BA levels. BAs can cause genetic mutations, mitochondrial dysfunction, abnormal activation of intracellular trypsin, cytoskeletal damage, activation of NF-κB, acute pancreatitis, cell injury, and cell necrosis. They can act on different types of pancreatic cells and receptors, altering Ca2+ and iron levels, and related signals. Elevated levels of Ca2+ and iron are associated with cell necrosis and ferroptosis. Bile reflux into the pancreatic ducts can speed up the kinetics of epithelial cells, promoting the development of pancreatic intraductal papillary carcinoma. BAs can cause the enormous secretion of Glucagon-like peptide-1 (GLP-1), leading to the proliferation of pancreatic β-cells. Using Glucagon-like peptide-1 receptor agonist (GLP-1RA) increases the risk of pancreatitis and PC. Therefore, our objective was to explore various studies and thoroughly examine the role of BAs in PC.
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Affiliation(s)
- Bharti Sharma
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Kate Twelker
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Cecilia Nguyen
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Scott Ellis
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Navin D. Bhatia
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Zachary Kuschner
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Andrew Agriantonis
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - George Agriantonis
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Monique Arnold
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Jasmine Dave
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Juan Mestre
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Zahra Shafaee
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Shalini Arora
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Hima Ghanta
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
| | - Jennifer Whittington
- Department of Surgery, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA; (K.T.); (C.N.); (S.E.); (N.D.B.); (Z.K.); (G.A.); (J.D.); (J.M.); (Z.S.); (S.A.); (H.G.); (J.W.)
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (A.A.); (M.A.)
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Liberda-Matyja D, Koziol-Bohatkiewicz P, Wrobel TP. Pancreatic intraepithelial neoplasia detection and duct pathology grading using FT-IR imaging and machine learning. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2024; 309:123756. [PMID: 38154304 DOI: 10.1016/j.saa.2023.123756] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 10/06/2023] [Accepted: 12/08/2023] [Indexed: 12/30/2023]
Abstract
Pancreatic intraepithelial neoplasia (PanIN) is manifested by noninvasive lesions in the epithelium of smaller pancreatic ducts. Generally, cancer development risk from low-grade PanIN is minor, whereas, invasive pancreatic ductal adenocarcinoma (PDAC) development is highly related to high-grade PanINs. Therefore, in the case of high-grade PanIN detection, additional surgical resection may be recommended. However, even the low-grade PanINs can indicate possible progression to PDAC. The definition of PanIN is constantly changing and there is a need for new tools to better characterize and understand its behavior. We have recently developed a comprehensive pancreatic cancer classification model with biopsies collected from over 600 biopsies from 250 patients. Here, we take the next step and employ Infrared (IR) spectroscopy to build the first classification model for PanINs detection. Furthermore, we created a Partial Least Squares Regression (PLSR) model to characterize ducts from benign to cancerous. This model was then used to predict and grade PanINs accordingly to their malignancy level.
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Affiliation(s)
- Danuta Liberda-Matyja
- Jagiellonian University, Doctoral School of Exact and Natural Sciences, Prof. St. Łojasiewicza 11, PL30348 Cracow, Poland; Solaris National Synchrotron Radiation Centre, Jagiellonian University, Czerwone Maki 98, 30-392 Krakow, Poland
| | - Paulina Koziol-Bohatkiewicz
- Solaris National Synchrotron Radiation Centre, Jagiellonian University, Czerwone Maki 98, 30-392 Krakow, Poland; Faculty of Physics, Astronomy and Applied Computer Science, Jagiellonian University, Lojasiewicza 11, 30-348 Krakow, Poland
| | - Tomasz P Wrobel
- Solaris National Synchrotron Radiation Centre, Jagiellonian University, Czerwone Maki 98, 30-392 Krakow, Poland.
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Rowell MC, Deschênes-Simard X, Lopes-Paciencia S, Le Calvé B, Kalegari P, Mignacca L, Fernandez-Ruiz A, Guillon J, Lessard F, Bourdeau V, Igelmann S, Duman AM, Stanom Y, Kottakis F, Deshpande V, Krizhanovsky V, Bardeesy N, Ferbeyre G. Targeting ribosome biogenesis reinforces ERK-dependent senescence in pancreatic cancer. Cell Cycle 2023; 22:2172-2193. [PMID: 37942963 PMCID: PMC10732607 DOI: 10.1080/15384101.2023.2278945] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/30/2023] [Indexed: 11/10/2023] Open
Abstract
Pancreatic adenocarcinomas (PDAC) often possess mutations in K-Ras that stimulate the ERK pathway. Aberrantly high ERK activation triggers oncogene-induced senescence, which halts tumor progression. Here we report that low-grade pancreatic intraepithelial neoplasia displays very high levels of phospho-ERK consistent with a senescence response. However, advanced lesions that have circumvented the senescence barrier exhibit lower phospho-ERK levels. Restoring ERK hyperactivation in PDAC using activated RAF leads to ERK-dependent growth arrest with senescence biomarkers. ERK-dependent senescence in PDAC was characterized by a nucleolar stress response including a selective depletion of nucleolar phosphoproteins and intranucleolar foci containing RNA polymerase I designated as senescence-associated nucleolar foci (SANF). Accordingly, combining ribosome biogenesis inhibitors with ERK hyperactivation reinforced the senescence response in PDAC cells. Notably, comparable mechanisms were observed upon treatment with the platinum-based chemotherapy regimen FOLFIRINOX, currently a first-line treatment option for PDAC. We thus suggest that drugs targeting ribosome biogenesis can improve the senescence anticancer response in pancreatic cancer.
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Affiliation(s)
- MC. Rowell
- Département de Biochimie et Médecine Moléculaire, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - X. Deschênes-Simard
- Département de Biochimie et Médecine Moléculaire, Maisonneuve-Rosemont Hospital, Université de Montréal, Montreal, QC, Canada
| | - S. Lopes-Paciencia
- Département de Biochimie et Médecine Moléculaire, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - B. Le Calvé
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, QC, Canada
| | - P. Kalegari
- Département de Biochimie et Médecine Moléculaire, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - L. Mignacca
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, QC, Canada
| | - A. Fernandez-Ruiz
- Département de Biochimie et Médecine Moléculaire, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - J. Guillon
- Département de Biochimie et Médecine Moléculaire, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - F. Lessard
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, QC, Canada
- Laboratory of Growth and Development, St-Patrick Research Group in Basic Oncology, Cancer Division of the Quebec University Research Centre, Canada, Present
| | - V. Bourdeau
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, QC, Canada
| | - S Igelmann
- Département de Biochimie et Médecine Moléculaire, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, QC, Canada
| | - AM. Duman
- Département de Biochimie et Médecine Moléculaire, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - Y. Stanom
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, QC, Canada
| | - F. Kottakis
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - V. Deshpande
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - V. Krizhanovsky
- Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel
| | - N. Bardeesy
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - G. Ferbeyre
- Département de Biochimie et Médecine Moléculaire, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, QC, Canada
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Huang X, Guo T, Zhang Z, Cai M, Guo X, Zhang J, Yu Y. Prediction of malignant intraductal papillary mucinous neoplasm: A nomogram based on clinical information and radiological outcomes. Cancer Med 2023; 12:16958-16971. [PMID: 37434479 PMCID: PMC10501290 DOI: 10.1002/cam4.6326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 05/02/2023] [Accepted: 06/28/2023] [Indexed: 07/13/2023] Open
Abstract
OBJECTIVE Clinical practitioners face a significant challenge in maintaining a healthy balance between overtreatment and missed diagnosis in the management of intraductal papillary mucinous neoplasm (IPMN). The current study aimed to identify significant risk factors of malignant IPMN from a series of clinical and radiological parameters that are widely available and noninvasive and develop a method to individually predict the risk of malignant IPMN to improve its management. METHODS We retrospectively investigated 168 patients who were pathologically diagnosed with IPMN after individualized pancreatic resection between June, 2012 and December, 2020. Independent predictors determined using both univariate and multivariate analyses to construct a predictive model. The discriminatory power of the nomogram was assessed using the area under the receiver operating characteristic curve (AUC). Decision curve analysis was performed to demonstrate the clinical usefulness of the nomogram. Internal cross validation was performed to assess the validity of the predictive model. RESULTS In the multivariate analysis, five significant independent risk factors were identified: increased serum CA19-9 level, low prognostic nutritional index (PNI), cyst size, enhancing mural nodule, and main pancreatic duct diameter. The nomogram based on the parameters mentioned above had outstanding performance in distinguishing malignancy, with an AUC of 0.907 (95% confidence interval: 0.859-0.956, p < 0.05), which remained 0.875 after internal cross-validation, and showed good clinical usefulness. CONCLUSION A novel nomogram for predicting malignant IPMN first introducing PNI was developed, which may aid in improving IPMN management. Nevertheless, external validation is required to confirm its efficacy.
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Affiliation(s)
- Xiaorui Huang
- Department of Biliopancreatic SurgeryTongji Hospital of Tongji Medical College of Huazhong University of Science and TechnologyWuhanChina
| | - Tong Guo
- Department of Biliopancreatic SurgeryTongji Hospital of Tongji Medical College of Huazhong University of Science and TechnologyWuhanChina
| | - Zhiwei Zhang
- Department of Biliopancreatic SurgeryTongji Hospital of Tongji Medical College of Huazhong University of Science and TechnologyWuhanChina
| | - Ming Cai
- Department of Biliopancreatic SurgeryTongji Hospital of Tongji Medical College of Huazhong University of Science and TechnologyWuhanChina
| | - Xinyi Guo
- Department of Biliopancreatic SurgeryTongji Hospital of Tongji Medical College of Huazhong University of Science and TechnologyWuhanChina
| | - Jingzhao Zhang
- Department of Biliopancreatic SurgeryTongji Hospital of Tongji Medical College of Huazhong University of Science and TechnologyWuhanChina
| | - Yahong Yu
- Department of Biliopancreatic SurgeryTongji Hospital of Tongji Medical College of Huazhong University of Science and TechnologyWuhanChina
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Suryadevara V, Roy A, Sahoo J, Kamalanathan S, Naik D, Mohan P, Kalayarasan R. Incretin based therapy and pancreatic cancer: Realising the reality. World J Gastroenterol 2022; 28:2881-2889. [PMID: 35978867 PMCID: PMC9280733 DOI: 10.3748/wjg.v28.i25.2881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/23/2022] [Accepted: 05/22/2022] [Indexed: 02/06/2023] Open
Abstract
Incretin-based therapies like glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors help maintain the glycaemic control in patients with type 2 diabetes mellitus with additional systemic benefits and little risk of hypoglycaemia. These medications are associated with low-grade chronic pancreatitis in animal models inconsistently. The incidence of acute pancreatitis was also reported in some human studies. This inflammation provides fertile ground for developing pancreatic carcinoma (PC). Although the data from clinical trials and population-based studies have established safety regarding PC, the pathophysiological possibility that low-grade chronic pancreatitis leads to PC remains. We review the existing literature and describe the relationship between incretin-based therapies and PC.
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Affiliation(s)
- Varun Suryadevara
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Ayan Roy
- Department of Endocrinology, All India Institute of Medical Sciences, Kalyani 741245, West Bengal, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Pazhanivel Mohan
- Department of Medical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Raja Kalayarasan
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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8
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Melzer MK, Breunig M, Arnold F, Wezel F, Azoitei A, Roger E, Krüger J, Merkle J, Schütte L, Resheq Y, Hänle M, Zehe V, Zengerling F, Azoitei N, Klein L, Penz F, Singh SK, Seufferlein T, Hohwieler M, Bolenz C, Günes C, Gout J, Kleger A. Organoids at the PUB: The Porcine Urinary Bladder Serves as a Pancreatic Niche for Advanced Cancer Modeling. Adv Healthc Mater 2022; 11:e2102345. [PMID: 35114730 PMCID: PMC11468201 DOI: 10.1002/adhm.202102345] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/17/2021] [Indexed: 12/17/2022]
Abstract
Despite intensive research and progress in personalized medicine, pancreatic ductal adenocarcinoma remains one of the deadliest cancer entities. Pancreatic duct-like organoids (PDLOs) derived from human pluripotent stem cells (PSCs) or pancreatic cancer patient-derived organoids (PDOs) provide unique tools to study early and late stage dysplasia and to foster personalized medicine. However, such advanced systems are neither rapidly nor easily accessible and require an in vivo niche to study tumor formation and interaction with the stroma. Here, the establishment of the porcine urinary bladder (PUB) is revealed as an advanced organ culture model for shaping an ex vivo pancreatic niche. This model allows pancreatic progenitor cells to enter the ductal and endocrine lineages, while PDLOs further mature into duct-like tissue. Accordingly, the PUB offers an ex vivo platform for earliest pancreatic dysplasia and cancer if PDLOs feature KRASG12D mutations. Finally, it is demonstrated that PDOs-on-PUB i) resemble primary pancreatic cancer, ii) preserve cancer subtypes, iii) enable the study of niche epithelial crosstalk by spiking in pancreatic stellate and immune cells into the grafts, and finally iv) allow drug testing. In summary, the PUB advances the existing pancreatic cancer models by adding feasibility, complexity, and customization at low cost and high flexibility.
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Affiliation(s)
- Michael Karl Melzer
- Department of UrologyUlm UniversityUlm89081Germany
- Department of Internal Medicine IUlm UniversityUlm89081Germany
| | - Markus Breunig
- Department of Internal Medicine IUlm UniversityUlm89081Germany
| | - Frank Arnold
- Department of Internal Medicine IUlm UniversityUlm89081Germany
| | - Felix Wezel
- Department of UrologyUlm UniversityUlm89081Germany
| | - Anca Azoitei
- Department of UrologyUlm UniversityUlm89081Germany
| | - Elodie Roger
- Department of Internal Medicine IUlm UniversityUlm89081Germany
| | - Jana Krüger
- Department of Internal Medicine IUlm UniversityUlm89081Germany
| | - Jessica Merkle
- Department of Internal Medicine IUlm UniversityUlm89081Germany
- Core Facility OrganoidsUlm UniversityUlm89081Germany
| | - Lena Schütte
- Department of Internal Medicine IUlm UniversityUlm89081Germany
| | - Yazid Resheq
- Department of Internal Medicine IUlm UniversityUlm89081Germany
| | - Mark Hänle
- Department of Internal Medicine IUlm UniversityUlm89081Germany
| | - Viktor Zehe
- Department of UrologyUlm UniversityUlm89081Germany
| | | | - Ninel Azoitei
- Department of Internal Medicine IUlm UniversityUlm89081Germany
| | - Lukas Klein
- Department of GastroenterologyGastrointestinal Oncology and EndocrinologyUniversity Medicine GoettingenGoettingen37075Germany
| | - Frederike Penz
- Department of GastroenterologyGastrointestinal Oncology and EndocrinologyUniversity Medicine GoettingenGoettingen37075Germany
| | - Shiv K. Singh
- Department of GastroenterologyGastrointestinal Oncology and EndocrinologyUniversity Medicine GoettingenGoettingen37075Germany
| | | | - Meike Hohwieler
- Department of Internal Medicine IUlm UniversityUlm89081Germany
| | | | | | - Johann Gout
- Department of Internal Medicine IUlm UniversityUlm89081Germany
| | - Alexander Kleger
- Department of Internal Medicine IUlm UniversityUlm89081Germany
- Core Facility OrganoidsUlm UniversityUlm89081Germany
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9
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Tsesmelis M, Tiwary K, Steiger K, Sperb N, Gerstenlauer M, Manfras U, Maier HJ, Hermann PC, Chan LK, Wirth T. Deletion of NEMO Inhibits EMT and Reduces Metastasis in KPC Mice. Cancers (Basel) 2021; 13:4541. [PMID: 34572768 PMCID: PMC8471477 DOI: 10.3390/cancers13184541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/04/2021] [Accepted: 09/08/2021] [Indexed: 11/23/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a largely incurable cancer type. Its high mortality is attributed to the lack of efficient biomarkers for early detection combined with its high metastatic properties. The aim of our study was to investigate the role of NF-κB signaling in the development and metastasis of PDAC. We used the well-established KPC mouse model, and, through genetic manipulation, we deleted NF-κB essential modulator (NEMO) in the pancreata of KPC mice. Interestingly, NEMO deletion altered the differentiation status of the primary tumor but did not significantly affect its development. However, in the absence of NEMO, the median survival of the mice was prolonged by 13.5 days (16%). In addition, examination of the liver demonstrated that, whereas KPC mice occasionally developed liver macro-metastasis, NEMO deletion completely abrogated this outcome. Further analysis of the tumor revealed that the expression of epithelial-mesenchymal transition (EMT) transcription factors was diminished in the absence of NEMO. Conclusively, our study provides evidence that NF-κB is dispensable for the progression of high-grade PanINs towards PDAC. In contrast, NF-κB signaling is essential for the development of metastasis by regulating the gene expression program of EMT.
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Affiliation(s)
- Miltiadis Tsesmelis
- Institute of Physiological Chemistry, University of Ulm, 89081 Ulm, Germany; (M.T.); (N.S.); (M.G.); (U.M.); (H.J.M.)
| | - Kanishka Tiwary
- Department of Internal Medicine I, University of Ulm, 89081 Ulm, Germany; (K.T.); (P.C.H.)
| | - Katja Steiger
- Department of Pathology, School of Medicine, Technical University of Munich, 81675 Munich, Germany;
| | - Nadine Sperb
- Institute of Physiological Chemistry, University of Ulm, 89081 Ulm, Germany; (M.T.); (N.S.); (M.G.); (U.M.); (H.J.M.)
| | - Melanie Gerstenlauer
- Institute of Physiological Chemistry, University of Ulm, 89081 Ulm, Germany; (M.T.); (N.S.); (M.G.); (U.M.); (H.J.M.)
| | - Uta Manfras
- Institute of Physiological Chemistry, University of Ulm, 89081 Ulm, Germany; (M.T.); (N.S.); (M.G.); (U.M.); (H.J.M.)
| | - Harald J. Maier
- Institute of Physiological Chemistry, University of Ulm, 89081 Ulm, Germany; (M.T.); (N.S.); (M.G.); (U.M.); (H.J.M.)
- Novartis Pharma AG, 4056 Basel, Switzerland
| | - Patrick C. Hermann
- Department of Internal Medicine I, University of Ulm, 89081 Ulm, Germany; (K.T.); (P.C.H.)
| | - Lap Kwan Chan
- Institute of Physiological Chemistry, University of Ulm, 89081 Ulm, Germany; (M.T.); (N.S.); (M.G.); (U.M.); (H.J.M.)
- Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland
- Department of Pathology and Molecular Pathology, University Hospital of Zurich, 8091 Zurich, Switzerland
| | - Thomas Wirth
- Institute of Physiological Chemistry, University of Ulm, 89081 Ulm, Germany; (M.T.); (N.S.); (M.G.); (U.M.); (H.J.M.)
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10
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Abstract
The latest WHO classification of tumors of the digestive system (2019) has introduced new concepts for the stratification of intraductal neoplasms of the pancreas, mostly based on molecular genetics and malignant potential. Among them, pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary mucinous neoplasms (IPMN) are both precursors of pancreatic ductal adenocarcinoma, whereas intraductal oncocytic papillary neoplasms (IOPN) and intraductal tubulopapillary neoplasms (ITPN) are usually associated with less aggressive subtypes of pancreatic cancer and therefore have a much better prognosis. Hence, it is of utmost importance to correctly classify these lesions and to distinguish them from each other as well as from other nonductal types of neoplasms, which can rarely display an intraductal growth, such as neuroendocrine tumors and acinar cell carcinomas. PanIN are microscopic lesions with limited clinical significance. In contrast, all other intraductal neoplasms can be identified as cystic processes and/or solid tumors by means of imaging, thereby setting an indication for a potential surgical resection. This review presents diagnostically relevant aspects of intraductal neoplasms of the pancreas, which are instrumental for the discussion within interdisciplinary tumor boards (resection vs. watch-and-wait strategies) as well as to determine the extent of resection intraoperatively.
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11
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Jiang Q, Sun J, Chen H, Ding C, Tang Z, Ruan Y, Liu F, Sun Y. Establishment of an Immune Cell Infiltration Score to Help Predict the Prognosis and Chemotherapy Responsiveness of Gastric Cancer Patients. Front Oncol 2021; 11:650673. [PMID: 34307129 PMCID: PMC8299334 DOI: 10.3389/fonc.2021.650673] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 06/22/2021] [Indexed: 12/24/2022] Open
Abstract
The immune microenvironment plays a critical role in tumor biology. The molecular profiles of immune components and related genes are of tremendous value for the study of primary resistance to immune checkpoint blockers (ICBs) for gastric cancer (GC) and serve as prognostic biomarkers to predict GC survival. Recent studies have revealed that tumor immune cell infiltration (ICI) is an indicator of the survival and responsiveness to chemotherapy in GC patients. Here, we describe the immune cell landscape based on the ESTIMATE and CIBERSORT algorithms to help separate GC into 3 ICI clusters using the unsupervised clustering method. Further in-depth analyses, such as differential expression gene (DEG) analysis and principal component analysis (PCA), help to establish an ICI scoring system. A low ICI score is characterized by an increased tumor mutation burden (TMB). The combination of the ICI score and TMB score better predicts the survival of GC patients. Analyses based on public and our own database revealed that the ICI scoring system could also help predict the survival and chemotherapy responsiveness of GC patients. The present study demonstrated that the ICI score may be an effective prognostic biomarker and predictive indicator for chemotherapy and immunotherapy.
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Affiliation(s)
- Quan Jiang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Human Phenome Institute, Fudan University, Shanghai, China
| | - Jie Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hao Chen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chen Ding
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhaoqing Tang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuanyuan Ruan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Fenglin Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yihong Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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12
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Intraductal Pancreatic Mucinous Neoplasms: A Tumor-Biology Based Approach for Risk Stratification. Int J Mol Sci 2020; 21:ijms21176386. [PMID: 32887490 PMCID: PMC7504137 DOI: 10.3390/ijms21176386] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 08/27/2020] [Accepted: 09/01/2020] [Indexed: 12/19/2022] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most lethal human cancers. Its precursor lesions include pancreatic intra-epithelial neoplasia, mucinous cystic neoplasm, and intraductal papillary mucinous neoplasm (IPMN). IPMNs usually present as an incidental finding at imaging in 2.6% of the population and, according to the degree of dysplasia, they are classified as low- or high-grade lesions. Since the risk of malignant transformation is not accurately predictable, the management of these lesions is based on morphological and clinical parameters, such as presence of mural nodule, main pancreatic duct dilation, presence of symptoms, or high-grade dysplasia. Although the main genetic alterations associated to IPMNs have been elucidated, they are still not helpful for disease risk stratification. The growing body of genomic and epigenomic studies along with the more recent development of organotypic cultures provide the opportunity to improve our understanding of the malignant transformation process, which will likely deliver biomarkers to help discriminate between low- and high-risk lesions. Recent insights on the topic are herein summarized.
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13
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Use of Biomarkers and Imaging for Early Detection of Pancreatic Cancer. Cancers (Basel) 2020; 12:cancers12071965. [PMID: 32707720 PMCID: PMC7409286 DOI: 10.3390/cancers12071965] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 07/04/2020] [Accepted: 07/09/2020] [Indexed: 12/19/2022] Open
Abstract
Pancreatic cancer remains one of the deadliest cancers worldwide, and it is typically diagnosed late, with a poor prognosis. Early detection is the most important underlying factor for improving the prognosis of pancreatic cancer patients. One of the most effective strategies for detecting cancers at an early stage is screening of the general population. However, because of the low incidence of pancreatic cancer in the general population, the stratification of subjects who need to undergo further examinations by invasive and expensive modalities is important. Therefore, minimally invasive modalities involving biomarkers and imaging techniques that would facilitate the early detection of pancreatic cancer are highly needed. Multiple types of new blood biomarkers have recently been developed, including unique post-translational modifications of circulating proteins, circulating exosomes, microRNAs, and circulating tumor DNA. We previously reported that circulating apolipoprotein A2 undergoes unique processing in the bloodstream of patients with pancreatic cancer and its precancerous lesions. Additionally, we recently demonstrated a new method for measuring pancreatic proton density in the fat fraction using a fat–water magnetic resonance imaging technique that reflects pancreatic steatosis. In this review, we describe recent developments in potential biomarkers and imaging modalities for the early detection and risk stratification of pancreatic cancer, and we discuss current strategies for implementing screening programs for pancreatic cancer.
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14
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Early Detection of Pancreatic Intraepithelial Neoplasias (PanINs) in Transgenic Mouse Model by Hyperpolarized 13C Metabolic Magnetic Resonance Spectroscopy. Int J Mol Sci 2020; 21:ijms21103722. [PMID: 32466260 PMCID: PMC7279395 DOI: 10.3390/ijms21103722] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/20/2020] [Accepted: 05/22/2020] [Indexed: 12/16/2022] Open
Abstract
While pancreatic cancer (PC) survival rates have recently shown modest improvement, the disease remains largely incurable. Early detection of pancreatic cancer may result in improved outcomes and therefore, methods for early detection of cancer, even premalignant lesions, may provide more favorable outcomes. Pancreatic intraepithelial neoplasias (PanINs) have been identified as premalignant precursor lesions to pancreatic cancer. However, conventional imaging methods used for screening high-risk populations do not have the sensitivity to detect PanINs. Here, we have employed hyperpolarized metabolic imaging in vivo and nuclear magnetic resonance (1H-NMR) metabolomics ex vivo to identify and understand metabolic changes, towards enabling detection of early PanINs and progression to advanced PanINs lesions that precede pancreatic cancer formation. Progression of disease from tissue containing predominantly low-grade PanINs to tissue with high-grade PanINs showed a decreasing alanine/lactate ratio from high-resolution NMR metabolomics ex vivo. Hyperpolarized magnetic resonance spectroscopy (HP-MRS) allows over 10,000-fold sensitivity enhancement relative to conventional magnetic resonance. Real-time HP-MRS was employed to measure non-invasively changes of alanine and lactate metabolites with disease progression and in control mice in vivo, following injection of hyperpolarized [1-13C] pyruvate. The alanine-to-lactate signal intensity ratio was found to decrease as the disease progressed from low-grade PanINs to high-grade PanINs. The biochemical changes of alanine transaminase (ALT) and lactate dehydrogenase (LDH) enzyme activity were assessed. These results demonstrate that there are significant alterations of ALT and LDH activities during the transformation from early to advanced PanINs lesions. Furthermore, we demonstrate that real-time conversion kinetic rate constants (kPA and kPL) can be used as metabolic imaging biomarkers of pancreatic premalignant lesions. Findings from this emerging HP-MRS technique can be translated to the clinic for detection of pancreatic premalignant lesion in high-risk populations.
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15
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De Jesus-Acosta A, Narang A, Mauro L, Herman J, Jaffee EM, Laheru DA. Carcinoma of the Pancreas. ABELOFF'S CLINICAL ONCOLOGY 2020:1342-1360.e7. [DOI: 10.1016/b978-0-323-47674-4.00078-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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16
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Fischer CG, Wood LD. From somatic mutation to early detection: insights from molecular characterization of pancreatic cancer precursor lesions. J Pathol 2019; 246:395-404. [PMID: 30105857 DOI: 10.1002/path.5154] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 08/02/2018] [Accepted: 08/09/2018] [Indexed: 12/21/2022]
Abstract
Pancreatic cancer arises from noninvasive precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN), which are curable if detected early enough. Recently, these types of precursor lesions have been extensively characterized at the molecular level, defining the timing of critical genetic alterations in tumorigenesis pathways. The results of these studies deepen our understanding of tumorigenesis in the pancreas, providing novel insights into tumor initiation and progression. Perhaps more importantly, they also provide a rational foundation for early detection approaches that could allow clinical intervention prior to malignant transformation. In this review, we summarize the results of comprehensive molecular characterization of PanINs, IPMNs, and MCNs and discuss the implications for cancer biology as well as early detection. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Catherine G Fischer
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Laura D Wood
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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17
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Swayden M, Iovanna J, Soubeyran P. Pancreatic cancer chemo-resistance is driven by tumor phenotype rather than tumor genotype. Heliyon 2018; 4:e01055. [PMID: 30582059 PMCID: PMC6299038 DOI: 10.1016/j.heliyon.2018.e01055] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 09/28/2018] [Accepted: 12/12/2018] [Indexed: 12/12/2022] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest forms of cancer. A major reason for this situation is the fact that these tumors are already resistant or become rapidly resistant to all conventional therapies. Like any transformation process, initiation and development of PDCA are driven by a well known panel of genetic alterations, few of them are shared with most cancers, but many mutations are specific to PDAC and are partially responsible for the great inter-tumor heterogeneity. Importantly, this knowledge has been inefficient in predicting response to anticancer therapy, or in establishing diagnosis and prognosis. Hence, the pre-existing or rapidly acquired resistance of pancreatic cancer cells to therapeutic drugs rely on other parameters and features developed by the cells and/or the micro-environment, that are independent of their genetic profiles. This review sheds light on all major phenotypic, non genetic, alterations known to play important roles in PDAC cells resistance to treatments and therapeutic escape.
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Affiliation(s)
| | | | - Philippe Soubeyran
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France
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18
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Matsuda Y, Esaka S, Suzuki A, Hamashima Y, Imaizumi M, Matsukawa M, Fujii Y, Aida J, Takubo K, Ishiwata T, Nishimura M, Arai T. Abnormal immunolabelling of SMAD4 in cell block specimens to distinguish malignant and benign pancreatic cells. Cytopathology 2018; 30:201-208. [PMID: 30421464 DOI: 10.1111/cyt.12653] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 10/15/2018] [Accepted: 10/31/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Accurate diagnosis of malignant and benign pancreatic lesions can be challenging, especially with endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) samples that are small and/or degraded. In the present study, we determined how to best evaluate abnormal SMAD4 expression by immunohistochemical staining on cell block specimens from EUS-FNA samples. RESULTS In surgically resected pancreas, when abnormal SMAD4 immunolabelling was evaluated as negative SMAD4 expression, the sensitivity was low (33%), but when it was evaluated as decreased SMAD4 expression, the sensitivity improved (53%). Specificity and positive predictive value were high for both evaluations. There were no false-positive cases. In cell block specimens, decreased SMAD4 expression showed 47% sensitivity and 72% specificity, while negative SMAD4 expression showed lower sensitivity (20%) and higher specificity (100%). Both evaluations in cell block specimens showed lower sensitivity and specificity compared to resected specimens. False-positive and -negative rates were higher for cell blocks than for resected specimens. CONCLUSIONS Decreased SMAD4 immunolabelling provided improved sensitivity as compared to negative SMAD4 immunolabelling; therefore, it is important to compare SMAD4 expression in a sample to its expression in normal cells. Abnormal SMAD4 labelling showed low sensitivity and high specificity; therefore, SMAD4 staining using EUS-FNA samples might be helpful to detect malignancies that possess SMAD4 gene abnormalities.
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Affiliation(s)
- Yoko Matsuda
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Itabashi-ku, Tokyo, Japan
| | - Shikine Esaka
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Itabashi-ku, Tokyo, Japan
| | - Akemi Suzuki
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Itabashi-ku, Tokyo, Japan
| | - Yuri Hamashima
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Itabashi-ku, Tokyo, Japan
| | - Masayuki Imaizumi
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Itabashi-ku, Tokyo, Japan
| | - Miho Matsukawa
- Department of Endoscopy, Tokyo Metropolitan Geriatric Hospital, Itabashi-ku, Tokyo, Japan
| | - Yuko Fujii
- Department of Endoscopy, Tokyo Metropolitan Geriatric Hospital, Itabashi-ku, Tokyo, Japan
| | - Junko Aida
- Research Team for Geriatric Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku, Tokyo, Japan
| | - Kaiyo Takubo
- Research Team for Geriatric Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku, Tokyo, Japan
| | - Toshiyuki Ishiwata
- Research Team for Geriatric Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi-ku, Tokyo, Japan
| | - Makoto Nishimura
- Department of Endoscopy, Tokyo Metropolitan Geriatric Hospital, Itabashi-ku, Tokyo, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Itabashi-ku, Tokyo, Japan
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19
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Kha ML, Hesse L, Deisinger F, Sipos B, Röcken C, Arlt A, Sebens S, Helm O, Schäfer H. The antioxidant transcription factor Nrf2 modulates the stress response and phenotype of malignant as well as premalignant pancreatic ductal epithelial cells by inducing expression of the ATF3 splicing variant ΔZip2. Oncogene 2018; 38:1461-1476. [PMID: 30302023 DOI: 10.1038/s41388-018-0518-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 08/27/2018] [Accepted: 09/06/2018] [Indexed: 12/21/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) exhibits one of the worst survival rates of all cancers. While death rates show declining trends in the majority of cancers, PDAC registers rising rates. Based on the recently described crosstalk between TGF-β1 and Nrf2 in the PDAC development, the involvement of ATF3 and its splice variant ΔZip2 in TGF-β1- and Nrf2-driven pancreatic tumorigenesis was investigated. As demonstrated here, PDAC (Panc1, T3M4) cells or premalignant H6c7 pancreatic ductal epithelial cells differentially express ΔZip2- and ATF3, relating to stronger Nrf2 activity seen in Panc1 cells and TGF-ß1 activity in T3M4 or H6c7 cells, respectively. Treatment with the electrophile/oxidative stress inducer tBHQ or the cytostatic drug gemcitabine strongly elevated ΔZip2 expression in a Nrf2-dependent fashion. The differential expression of ATF3 and ΔZip2 in response to Nrf2 and TGF-ß1 relates to differential ATF3-gene promoter usage, giving rise of distinct splice variants. Nrf2-dependent ΔZip2 expression confers resistance against gemcitabine-induced apoptosis, only partially relating to interference with ATF3 and its proapoptotic activity, e.g., through CHOP-expression. In fact, ΔZip2 autonomously activates expression of cIAP anti-apoptotic proteins. Moreover, ΔZip2 favors and ATF3 suppresses growth and clonal expansion of PDAC cells, again partially independent of each other. Using a Panc1 tumor xenograft model in SCID-beige mice, the opposite activities of ATF3 and ΔZip2 on tumor-growth and chemoresistance were verified in vivo. Immunohistochemical analyses confirmed ΔZip2 and Nrf2 coexpression in cancerous and PanIN structures of human PDAC and chronic pancreatitis tissues, respectively, which to some extent was reciprocal to ATF3 expression. It is concluded that depending on selective ATF3-gene promoter usage by Nrf2, the ΔZip2 expression is induced in response to electrophile/oxidative (here through tBHQ) and xenobiotic (here through gemcitabine) stress, providing apoptosis protection and growth advantages to pancreatic ductal epithelial cells. This condition may substantially add to pancreatic carcinogenesis driven by chronic inflammation.
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Affiliation(s)
- My-Lan Kha
- Laboratory of Molecular Gastroenterology & Tumor Biology, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany
| | - Lisa Hesse
- Laboratory of Molecular Gastroenterology & Tumor Biology, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany
| | - Florian Deisinger
- Laboratory of Molecular Gastroenterology & Tumor Biology, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany
| | - Bence Sipos
- Department of Pathology and Neuropathology, University Hospital Tübingen, Liebermeisterstr. 8, 72076, Tübingen, Germany
| | - Christoph Röcken
- Institute of Pathology, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 14, Arnold-Heller-Straße 3, 24105, Kiel, Germany.,Biomaterial Bank of the Comprehensive Cancer Center Kiel, UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany
| | - Alexander Arlt
- Laboratory of Gastrointestinal Signal Transduction, Department of Internal Medicine I, UKSH Campus Kiel, Bldg. 6, Arnold-Heller-Straße 3, 24105 Kiel, Germany
| | - Susanne Sebens
- Biomaterial Bank of the Comprehensive Cancer Center Kiel, UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany.,Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany
| | - Ole Helm
- Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany
| | - Heiner Schäfer
- Laboratory of Molecular Gastroenterology & Tumor Biology, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany.
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20
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Bartsch DK, Gercke N, Strauch K, Wieboldt R, Matthäi E, Wagner V, Rospleszcz S, Schäfer A, Franke FS, Mintziras I, Bauer C, Grote T, Figiel J, Di Fazio P, Burchert A, Reinartz S, Pogge von Strandmann E, Klöppel G, Slater EP. The Combination of MiRNA-196b, LCN2, and TIMP1 is a Potential Set of Circulating Biomarkers for Screening Individuals at Risk for Familial Pancreatic Cancer. J Clin Med 2018; 7:295. [PMID: 30241369 PMCID: PMC6210952 DOI: 10.3390/jcm7100295] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 09/14/2018] [Accepted: 09/18/2018] [Indexed: 02/07/2023] Open
Abstract
Individuals at risk (IAR) of familial pancreatic cancer (FPC) are good candidates for screening. Unfortunately, neither reliable imaging modalities nor biomarkers are available to detect high-grade precursor lesions or early cancer. Circulating levels of candidate biomarkers LCN2, TIMP1, Glypican-1, RNU2-1f, and miRNA-196b were analyzed in 218 individuals with sporadic pancreatic ductal adenocarcinoma (PDAC, n = 50), FPC (n = 20), chronic pancreatitis (n = 10), IAR with relevant precursor lesions (n = 11) or non-relevant lesions (n = 5), 20 controls, and IAR with (n = 51) or without (n = 51) lesions on pancreatic imaging. In addition, corresponding duodenal juice samples were analyzed for Glypican-1 (n = 144) enrichment and KRAS mutations (n = 123). The panel miR-196b/LCN2/TIMP1 could distinguish high-grade lesions and stage I PDAC from controls with absolute specificity and sensitivity. In contrast, Glypican-1 enrichment in serum exosomes and duodenal juice was not diagnostic. KRAS mutations in duodenal juice were detected in 9 of 12 patients with PDAC and only 4 of 9 IAR with relevant precursor lesions. IAR with lesions on imaging had elevated miR-196b/LCN2/TIMP1 levels (p = 0.0007) and KRAS mutations in duodenal juice (p = 0.0004) significantly more often than IAR without imaging lesions. The combination miR-196b/LCN2/TIMP1 might be a promising biomarker set for the detection of high-grade PDAC precursor lesions in IAR of FPC families.
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Affiliation(s)
- Detlef K Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Norman Gercke
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Konstantin Strauch
- Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Faculty of Medicine, Ludwig-Maximilians-Universität, Marchioninistr. 15, D-81377 Munich, Germany.
- Institute of Genetic Epidemiology, Helmholtz Zentrum München⁻German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
| | - Ronja Wieboldt
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Elvira Matthäi
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Vinona Wagner
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Susanne Rospleszcz
- Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Faculty of Medicine, Ludwig-Maximilians-Universität, Marchioninistr. 15, D-81377 Munich, Germany.
- Institute of Genetic Epidemiology, Helmholtz Zentrum München⁻German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.
| | - Agnes Schäfer
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Frederike S Franke
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Ioannis Mintziras
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Christian Bauer
- Department of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Tobias Grote
- Department of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Jens Figiel
- Department of Diagnostic and Interventional Radiology, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Andreas Burchert
- Department of Hematology, Oncology and Immunology, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
| | - Silke Reinartz
- Center for Tumor and Immune Biology, Philipps University Marburg, Hans-Meerwein-Str. 3, D-35043 Marburg, Germany.
| | - Elke Pogge von Strandmann
- Center for Tumor and Immune Biology, Philipps University Marburg, Hans-Meerwein-Str. 3, D-35043 Marburg, Germany.
| | - Günter Klöppel
- Department of Pathology, Technical University Munich, Trogerstr. 18, D-81675 Munich, Germany.
| | - Emily P Slater
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany.
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21
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Ibrahim IS, Wasser MN, Wu Y, Inderson A, de Vos Tot Nederveen Cappel WH, Morreau H, Hes FJ, Veenendaal RA, Putter H, Feshtali S, van Mil AM, Gruis NA, Tollenaar RA, Bergman W, Bonsing BA, Vasen HFA. High Growth Rate of Pancreatic Ductal Adenocarcinoma in CDKN2A-p16-Leiden Mutation Carriers. Cancer Prev Res (Phila) 2018; 11:551-556. [PMID: 29991580 DOI: 10.1158/1940-6207.capr-18-0035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 04/09/2018] [Accepted: 06/29/2018] [Indexed: 11/16/2022]
Abstract
CDKN2A-p16-Leiden mutation carriers have a 20% to 25% risk of developing pancreatic ductal adenocarcinoma (PDAC). Better understanding of the natural course of PDAC might allow the surveillance protocol to be improved. The aims of the study were to evaluate the role of cystic precursor lesions in the development of PDAC and to assess the growth rate. In 2000, a surveillance program was initiated, consisting of annual MRI in carriers of a CDKN2A-p16-Leiden mutation. The study cohort included 204 (42% male) patients. Cystic precursor lesions were found in 52 (25%) of 204 mutation carriers. Five (9.7%) of 52 mutation carriers with cystic lesions and 8 (7.0%) of 114 mutation carriers without cystic lesions developed PDAC (P = 0.56). Three of 6 patients with a cystic lesion of ≥10 mm developed PDAC. The median size of all incident PDAC detected between 9 and 12 months since the previous normal MRI was 15 mm, suggesting an annual growth rate of about 15 mm/year. In conclusion, our findings show that patients with and without a cystic lesions have a similar risk of PDAC. However, cystic precursor lesions between 10 and 20 mm increase the risk of PDAC substantially. In view of the large size of the screen-detected tumors, a shorter interval of screening might be recommended for all patients. Cancer Prev Res; 11(9); 551-6. ©2018 AACR.
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Affiliation(s)
- Isaura S Ibrahim
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands.
| | - Martin N Wasser
- Department of Radiology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Yinghui Wu
- Department of Radiology, West Suffolk Hospital, Bury St. Edmunds, United Kingdom
| | - Akin Inderson
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | | | - Hans Morreau
- Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Frederik J Hes
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands
| | - Roeland A Veenendaal
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Hein Putter
- Department of Medical Statistics, Leiden University Medical Centre, Leiden, the Netherlands
| | - Shirin Feshtali
- Department of Radiology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Anneke M van Mil
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands
| | - Nelleke A Gruis
- Department of Dermatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Rob A Tollenaar
- Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
| | - Wilma Bergman
- Department of Dermatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Bert A Bonsing
- Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
| | - Hans F A Vasen
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
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22
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Welinsky S, Lucas AL. Familial Pancreatic Cancer and the Future of Directed Screening. Gut Liver 2018; 11:761-770. [PMID: 28609837 PMCID: PMC5669591 DOI: 10.5009/gnl16414] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Revised: 11/01/2016] [Accepted: 11/01/2016] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer (PC) is the third most common cause of cancer-related death in the United States and the 12th most common worldwide. Mortality is high, largely due to late stage of presentation and suboptimal treatment regimens. Approximately 10% of PC cases have a familial basis. The major genetic defect has yet to be identified but may be inherited by an autosomal dominant pattern with reduced penetrance. Several known hereditary syndromes or genes are associated with an increased risk of developing PC and account for approximately 2% of PCs. These syndromes include the hereditary breast-ovarian cancer syndrome, Peutz-Jeghers syndrome, familial atypical multiple mole melanoma, Lynch syndrome, familial polyposis, ataxia-telangiectasia, and hereditary pancreatitis. Appropriate screening using methods such as biomarkers or imaging, with endoscopic ultrasound and magnetic resonance imaging, may assist in the early detection of neoplastic lesions in the high-risk population. If these lesions are detected and treated before the development of invasive carcinoma, PC disease morbidity and mortality may be improved. This review will focus on familial PC and other hereditary syndromes implicated in the increased risk of PC; it will also highlight current screening methods and the future of new screening modalities.
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Affiliation(s)
- Sara Welinsky
- Samuel F. Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Aimee L Lucas
- Samuel F. Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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23
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Balázs A, Balla Z, Kui B, Maléth J, Rakonczay Z, Duerr J, Zhou-Suckow Z, Schatterny J, Sendler M, Mayerle J, Kühn JP, Tiszlavicz L, Mall MA, Hegyi P. Ductal Mucus Obstruction and Reduced Fluid Secretion Are Early Defects in Chronic Pancreatitis. Front Physiol 2018; 9:632. [PMID: 29896115 PMCID: PMC5987707 DOI: 10.3389/fphys.2018.00632] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 05/11/2018] [Indexed: 12/22/2022] Open
Abstract
Objective: Defective mucus production in the pancreas may be an important factor in the initiation and progression of chronic pancreatitis (CP), therefore we aimed to (i) investigate the qualitative and quantitative changes of mucus both in human CP and in an experimental pancreatitis model and (ii) to correlate the mucus phenotype with epithelial ion transport function. Design: Utilizing human tissue samples and a murine model of cerulein induced CP we measured pancreatic ductal mucus content by morphometric analysis and the relative expression of different mucins in health and disease. Pancreatic fluid secretion in CP model was measured in vivo by magnetic resonance cholangiopancreatography (MRCP) and in vitro on cultured pancreatic ducts. Time-changes of ductal secretory function were correlated to those of the mucin production. Results: We demonstrate increased mucus content in the small pancreatic ducts in CP. Secretory mucins MUC6 and MUC5B were upregulated in human, Muc6 in mouse CP. In vivo and in vitro fluid secretion was decreased in cerulein-induced CP. Analysis of time-course changes showed that impaired ductal ion transport is paralleled by increased Muc6 expression. Conclusion: Mucus accumulation in the small ducts is a combined effect of mucus hypersecretion and epithelial fluid secretion defect, which may lead to ductal obstruction. These results suggest that imbalance of mucus homeostasis may have an important role in the early-phase development of CP, which may have novel diagnostic and therapeutic implications.
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Affiliation(s)
- Anita Balázs
- First Department of Medicine, University of Szeged, Szeged, Hungary
- Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany
| | - Zsolt Balla
- MTA-SZTE Momentum Epithel Cell Signalling and Secretion Research Group, Szeged, Hungary
| | - Balázs Kui
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - József Maléth
- First Department of Medicine, University of Szeged, Szeged, Hungary
- MTA-SZTE Momentum Epithel Cell Signalling and Secretion Research Group, Szeged, Hungary
| | - Zoltán Rakonczay
- Department of Pathophysiology, University of Szeged, Szeged, Hungary
| | - Julia Duerr
- Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany
- Department of Pediatric Pulmonology and Immunology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Zhe Zhou-Suckow
- Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany
| | - Jolanthe Schatterny
- Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany
| | - Matthias Sendler
- Department of Internal Medicine A, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Julia Mayerle
- Department of Internal Medicine A, Universitätsmedizin Greifswald, Greifswald, Germany
| | - Jens-P. Kühn
- Institute of Radiology, Universitätsmedizin Greifswald, Greifswald, Germany
| | | | - Marcus A. Mall
- Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany
- Department of Pediatric Pulmonology and Immunology, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
| | - Peter Hegyi
- First Department of Medicine, University of Szeged, Szeged, Hungary
- Institute for Translational Medicine, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
- MTA-SZTE Translational Gastroenterology Research Group, Szeged, Hungary
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24
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Abstract
Pancreatic cancers with poor prognosis are highly malignant, readily metastatic and of immune tolerance, mainly due to delayed detection. The metastatic progression and immune tolerance of pancreatic cancer is greatly attributed to the intercellular communication. However, exosomes are deemed to be the most important tool of intercellular communicators. Thus, we present a review of pancreatic cancer and exosomes in this article. We intensively summarize the progress of early pancreatic cancer and the relationship of the proliferation, progression and metastasis of pancreatic cancer and pancreatic cancer-derived exosomes, and propose new ideas of the study of pancreatic cancer.
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Affiliation(s)
- Chengfei Zhao
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350108, Fujian, China
- Department of Pharmacy, Pharmacy and Medical Technology School, Putian University, Putian 351100, Fujian, China
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350108, Fujian, China
| | - Feng Gao
- Department of Pathology, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350108, Fujian, China
| | - Shaohuang Weng
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, Fujian Medical University, Fuzhou 350108, Fujian, China
| | - Qicai Liu
- Department of Clinical Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China
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25
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Lin X, Zhan B, Wen S, Li Z, Huang H, Feng J. Metabonomic alterations from pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma facilitate the identification of biomarkers in serum for early diagnosis of pancreatic cancer. MOLECULAR BIOSYSTEMS 2017; 12:2883-92. [PMID: 27400832 DOI: 10.1039/c6mb00381h] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is a highly malignant disease with a poor prognosis and it is essential to diagnose and treat the disease at an early stage. The aim of this study was to understand the underlying biochemical mechanisms of pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) and to identify potential serum biomarkers for early detection of pancreatic cancer. 7,12-Dimethylbenz(a)anthracene (DMBA)-induced PanIN and PDAC rat models were established and the serum samples were collected. The serum samples were measured using (1)H nuclear magnetic resonance (NMR) spectroscopy and analyzed by chemometric methods including principal component analysis (PCA) and (orthogonal) partial least squares discriminant analysis ((O)PLS-DA). The related biochemical pathways were derived from KEGG analysis of the significantly different metabolites. As results, some serum metabolites demonstrated alarming metabolic changes in the precursor lesion of pancreatic cancer (PanIN-2 in this study). These changes involved elevated levels of ketone compounds including 3-hydroxybutyrate, acetoacetate, and acetone, some amino acids including asparagine, glutamate, threonine, and phenylalanine, glycoproteins and lipoproteins including N-acetylglycoprotein, LDL and VLDL, and some metabolites that have been shown to contribute to mutagenicity and cancer promotion such as deoxyguanosine and cytidine. More metabolites were shown to be significantly different between PanIN and PDAC, suggesting that a more complex set of changes occurs from noninvasive precursor lesion to invasive cancer. The serum metabonomic changes of rats with PanIN and PDAC may extend our understanding of pancreatic molecular pathogenesis, and the metabolic variations from PanIN to PDAC will be helpful to understand evolution processes of the pancreatic disease. NMR-based metabonomic analysis of animal models will be beneficial for the human study and will be helpful for the early detection of pancreatic cancer.
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Affiliation(s)
- Xianchao Lin
- General Surgery Department, Fujian Medical University Union Hospital, Fuzhou 350001, China.
| | - Bohan Zhan
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361005, China.
| | - Shi Wen
- General Surgery Department, Fujian Medical University Union Hospital, Fuzhou 350001, China.
| | - Zhishui Li
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361005, China.
| | - Heguang Huang
- General Surgery Department, Fujian Medical University Union Hospital, Fuzhou 350001, China.
| | - Jianghua Feng
- Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen 361005, China.
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26
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The Prevalence and Clinicopathological Characteristics of High-Grade Pancreatic Intraepithelial Neoplasia: Autopsy Study Evaluating the Entire Pancreatic Parenchyma. Pancreas 2017; 46:658-664. [PMID: 28196020 DOI: 10.1097/mpa.0000000000000786] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE We sought to identify clinicopathological characteristics of high-grade pancreatic intraepithelial neoplasia (PanIN)/carcinoma in situ to facilitate screening for pancreatic ductal adenocarcinoma. METHODS We evaluated PanIN lesions in 173 consecutive autopsy cases with no evidence of pancreatic ductal adenocarcinoma and/or intraductal papillary mucinous neoplasm (mean age, 80.5 years) by submitting the entire pancreas for microscopic examination. RESULTS PanIN-3 was found in 4% of examined cases, whereas PanIN-1 and PanIN-2 were present in 77% and 28%, respectively. PanIN-3 was more frequently identified in patients with diabetes mellitus and/or older age. PanIN-3 lesions were always multifocal, and the number of PanIN-3 foci was positively associated with those of PanIN-1 or PanIN-2. PanIN-3 was located more frequently in the pancreatic body and tail than in the head and predominantly involved small interlobular/intralobular ducts rather than the main duct. Notably, 71% of pancreata with PanIN-3 showed cystic changes in PanIN-3 and lower grade PanIN lesions. PanIN-3 was also accompanied by higher grade extralobular fibrosis. CONCLUSIONS We found that 4% of the examined pancreata harbored PanIN-3 lesions that were associated with several unique clinicopathological features. The cystic change along with fibrotic pancreatic parenchyma may be detected by imaging studies such as endoscopic ultrasound.
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27
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Flattet Y, Yamaguchi T, Andrejevic-Blant S, Halkic N. Pancreatic adenocarcinoma: the impact of preneoplastic lesion pattern on survival. Biosci Trends 2016; 9:402-6. [PMID: 26781798 DOI: 10.5582/bst.2015.01163] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Pancreatic adenocarcinoma is associated with a very poor prognosis, characterized with a 5-year survival rate of only 5%. Surgery is the only curative treatment for selected patients. Nevertheless, recurrence is very frequent. Identifying prognostic factors is thus warranted. Like numerous other tumors, adenocarcinomas are preceded by preneoplastic lesions. The role and the impact of these lesions remain unclear. This study aimed to assess the impact of the preneoplastic lesion pattern and histo-morphological features, on survival after pancreatic resection. Thirty-five patients who underwent pancreatic resection for pancreatic adenocarcinoma were identified from a prospective database of a single center, between 2003 and 2008. We considered demographics, tumor characteristics and type of treatment. The major outcome was survival. Analyzes were separated into two groups, according to the preneoplastic lesions: Pancreatic intraepithelial neoplasia (PanIN)-related carcinomas and intracanalar papillary mucinous neoplasia (IPMN)-related carcinomas. The former were more frequent, accounting for 63% (22/35). Moreover, they displayed more aggressive features, with a higher tumor stage (p = 0.01) and higher rate of positive lymph nodes (p = 0.019). Lymphatic (p = 0.009) and perinervous (p = 0.019) invasions were also more frequent. Survival was negatively influenced by PanIN preneoplastic lesions (p = 0.015), T3-4 tumor stage (p = 0.038), positive lymph nodes (p = 0.044), lymphatic (p = 0.019) and vascular (p = 0.029) invasions. Pancreatic adenocarcinoma displays different behavior according to its preneoplastic lesion. Indeed, PanIN-related adenocarcinoma showed more aggressive features and lower survival rate. Preneoplastic lesions may represent predictive factors for survival. Their role and predictive value should be investigated more thoroughly.
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Affiliation(s)
- Yves Flattet
- Department of Pathology, University Hospital CHUV
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28
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Banerjee J, Papu John AM, Al-Wadei MH, Schuller HM. Prevention of pancreatic cancer in a hamster model by cAMP decrease. Oncotarget 2016; 7:44430-44441. [PMID: 27281617 PMCID: PMC5190108 DOI: 10.18632/oncotarget.9790] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 05/22/2016] [Indexed: 02/06/2023] Open
Abstract
Smoking and alcoholism are risk factors for the development of pancreatitis-associated pancreatic ductal adenocarcinoma (PDAC). We have previously shown that these cancers overexpressed stress neurotransmitters and cyclic adenosine monophosphate (cAMP) while the inhibitory neurotransmitter γ-aminobutyric acid (GABA) was suppressed. Using a hamster model, the current study has tested the hypothesis that cAMP decrease by GABA supplementation in the drinking water prevents the development of pancreatitis-associated PDAC. Our data reveal strong preventive effects of GABA supplementation on the development of PDAC and pancreatic intraductal neoplasia (PanIN). ELISA assays and immunohistochemistry revealed significant decreases in the levels of cAMP and interleukin 6 accompanied by reductions in the expression of several cancer stem cell markers and phosphorylated signaling proteins, which stimulate cell proliferation, and migration in pancreatic exocrine cells of GABA treated animals. We conclude that cAMP decrease by GABA supplementation inhibits multiple cancer stimulating pathways in cancer stem cells, differentiated cancer cells and the immune system, identifying this approach as promising novel tool for the prevention of PDAC in individuals with a history of smoking and alcoholism.
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Affiliation(s)
- Jheelam Banerjee
- Experimental Oncology Laboratory, Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA
| | - Arokya M.S. Papu John
- Experimental Oncology Laboratory, Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA
| | - Mohammed H. Al-Wadei
- Experimental Oncology Laboratory, Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA
| | - Hildegard M. Schuller
- Experimental Oncology Laboratory, Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA
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29
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Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF, Maitra A, DePinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2016; 30:355-85. [PMID: 26883357 PMCID: PMC4762423 DOI: 10.1101/gad.275776.115] [Citation(s) in RCA: 391] [Impact Index Per Article: 43.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Ying et al. review pancreatic ductal adenocarcinoma (PDAC) genetics and biology, particularly altered cancer cell metabolism, the complexity of immune regulation in the tumor microenvironment, and impaired DNA repair processes. With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival.
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Affiliation(s)
- Haoqiang Ying
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Prasenjit Dey
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Wantong Yao
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Alec C Kimmelman
- Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
| | - Giulio F Draetta
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Anirban Maitra
- Department of Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; Sheikh Ahmed Pancreatic Cancer Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Ronald A DePinho
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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30
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Wen S, Li Z, Feng J, Bai J, Lin X, Huang H. Metabonomic changes from pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma in tissues from rats. Cancer Sci 2016; 107:836-45. [PMID: 27019331 PMCID: PMC4968602 DOI: 10.1111/cas.12939] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 03/24/2016] [Accepted: 03/25/2016] [Indexed: 01/12/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors and is difficult to diagnose in the early phase. This study was aimed at obtaining the metabolic profiles and characteristic metabolites of pancreatic intraepithelial neoplasia (PanIN) and PDAC tissues from Sprague-Dawley (SD) rats to establish metabonomic methods used in the early diagnosis of PDAC. In the present study, the animal models were established by embedding 7,12-dimethylbenzanthracene (DMBA) in the pancreas of SD rats to obtain PanIN and PDAC tissues. After the preprocessing of tissues, (1) H nuclear magnetic resonance (NMR) spectroscopy combined with multivariate and univariate statistical analysis was applied to identify the potential metabolic signatures and the corresponding metabolic pathways. Pattern recognition models were successfully established and differential metabolites, including glucose, amino acids, carboxylic acids and coenzymes, were screened out. Compared with the control, the trends in the variation of several metabolites were similar in both PanIN and PDAC. Kynurenate and methionine levels were elevated in PanIN but decreased in PDAC, thus, could served as biomarkers to distinguish PanIN from PDAC. Our results suggest that NMR-based techniques combined with multivariate statistical analysis can distinguish the metabolic differences among PanIN, PDAC and normal tissues, and, therefore, present a promising approach for physiopathologic metabolism investigations and early diagnoses of PDAC.
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Affiliation(s)
- Shi Wen
- Department of General SurgeryFujian Medical University Union HospitalFuzhouChina
| | - Zhishui Li
- Department of Electronic ScienceFujian Provincial Key Laboratory of Plasma and Magnetic ResonanceXiamen UniversityXiamenChina
| | - Jianghua Feng
- Department of Electronic ScienceFujian Provincial Key Laboratory of Plasma and Magnetic ResonanceXiamen UniversityXiamenChina
| | - Jianxi Bai
- Department of General SurgeryFujian Medical University Union HospitalFuzhouChina
| | - Xianchao Lin
- Department of General SurgeryFujian Medical University Union HospitalFuzhouChina
| | - Heguang Huang
- Department of General SurgeryFujian Medical University Union HospitalFuzhouChina
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Chen SJ, Chen YT, Zeng LJ, Zhang QB, Lian GD, Li JJ, Yang KG, Huang CM, Li YQ, Chu ZH, Huang KH. Bmi1 combines with oncogenic KRAS to induce malignant transformation of human pancreatic duct cells in vitro. Tumour Biol 2016; 37:11299-309. [PMID: 26951514 DOI: 10.1007/s13277-016-4840-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 01/11/2016] [Indexed: 12/30/2022] Open
Abstract
It is critical to understand the pathogenesis of preinvasive stages of pancreatic duct adenocarcinoma (PDAC) for developing novel potential diagnostic and therapeutic targets. The polycomb group family member B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi1) is overexpressed and involved in cancer progression in PDAC; however, its role in the multistep malignant transformation of human pancreatic duct cells has not been directly demonstrated. In this study, we stably expressed Bmi1 in a model of telomerase-immortalized human pancreatic duct-derived cells (HPNE) and showed that Bmi1 promoted HPNE cell proliferation, migration, and invasion but not malignant transformation. We then used mutant KRASG12D as a second oncogene to transform HPNE cells and showed that it further enhanced Bmi1-induced malignant potential. More importantly, coexpression of KRASG12D and Bmi1 caused anchorage-independent growth transformation in vitro but still failed to produce tumors in nude mice. Finally, we found that mutant KRASG12D induced HPNE-Bmi1 cells to undergo partial epithelial-mesenchymal transition (EMT) likely via upregulation of snail. Knockdown of KRASG12D significantly reduced the expression of snail and vimentin at both the messenger RNA (mRNA) and protein level and further impaired the anchorage-independent growth capability of invasive cells. In summary, our findings demonstrate that coexpression of Bmi1 and KRASG12D could lead to transformation of HPNE cells in vitro and suggest potential new targets for diagnosis and treatment of PDAC.
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Affiliation(s)
- Shao-Jie Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yin-Ting Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Lin-Juan Zeng
- Department of Oncology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China
| | - Qiu-Bo Zhang
- Department of Gastroenterology, Lihuili Hospital of Ningbo Medical Center, Ningbo, China
| | - Guo-da Lian
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jia-Jia Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ke-Ge Yang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chu-Mei Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ya-Qing Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhong-Hua Chu
- Department of Gastroenteropancreatic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China.
| | - Kai-Hong Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road No. 107, Guangzhou, 510120, People's Republic of China. .,Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
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Noor NM, Banim PJ, Luben RN, Khaw KT, Hart AR. Investigating Physical Activity in the Etiology of Pancreatic Cancer: The Age at Which This Is Measured Is Important and Is Independent of Body Mass Index. Pancreas 2016; 45:388-93. [PMID: 26390426 PMCID: PMC4743065 DOI: 10.1097/mpa.0000000000000494] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVES There are plausible biological mechanisms for how increased physical activity (PA) may prevent pancreatic cancer, although findings from epidemiological studies are inconsistent. We investigated whether the risk is dependent on the age at which PA is measured and if independent of body mass index (BMI). METHODS A total of 23,639 participants, aged 40 to 74 years, were recruited into the EPIC-Norfolk (European Prospective Investigation of Cancer) cohort study between 1993 and 1997 and completed validated questionnaires on PA. The cohort was monitored for pancreatic cancer development, and hazard ratios (HRs) were estimated and adjusted for covariates. RESULTS Within 17 years, 88 participants developed pancreatic cancer (55% female). There was no association between PA and risk in the cohort (HR trend, 1.06; 95% confidence interval [CI], 0.86-1.29). However, in participants younger than 60 years, higher PA was associated with decreased risk (highest vs lowest category HR, 0.27; 95% CI, 0.07-0.99). Higher PA was not inversely associated when older than 60 years (HR trend, 1.23; 95% CI, 0.96-1.57). Including BMI in all models produced similar estimates. CONCLUSIONS The reasons why PA in younger, but not older, people may prevent pancreatic cancer need to be investigated. Physical activity may operate through mechanisms independent of BMI. If this association is causal, 1 in 6 cases might be prevented by encouraging more PA.
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Affiliation(s)
- Nurulamin M. Noor
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Paul J.R. Banim
- Department of Gastroenterology, James Paget University Hospital, Great Yarmouth, United Kingdom
| | - Robert N. Luben
- Institute of Public Health, University of Cambridge, Cambridge, United Kingdom
| | - Kay-Tee Khaw
- Institute of Public Health, University of Cambridge, Cambridge, United Kingdom
| | - Andrew R. Hart
- Department of Medicine, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
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33
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Tseng CH. Sitagliptin and pancreatic cancer risk in patients with type 2 diabetes. Eur J Clin Invest 2016; 46:70-79. [PMID: 26584246 DOI: 10.1111/eci.12570] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 11/12/2015] [Indexed: 12/25/2022]
Abstract
BACKGROUND The risk of pancreatic cancer associated with incretin-based therapies is controversial. METHODS This study retrospectively analysed the National Health Insurance database including patients with newly diagnosed type 2 diabetes mellitus at an age ≥ 25 years between 1999 and 2010. A total of 71 137 ever users of sitagliptin and 933 046 never users were followed for pancreatic cancer until 31 December 2011. A time-dependent approach was used to calculate incidence and estimate hazard ratios adjusted for propensity score using Cox regression. RESULTS During follow-up, 83 ever users and 3658 never users developed pancreatic cancer, representing an incidence of 73·6 and 55·0 per 100 000 person-years, respectively. The adjusted hazard ratio (95% confidence intervals) for ever versus never users was 1·40 (1·13-1·75). The respective adjusted hazard ratio for the first, second and third tertile of cumulative dose < 14 700, 14 700-33 700 and > 33 700 mg was 1·83 (1·28-2·62), 1·97 (1·41-2·76) and 0·72 (0·45-1·15). For average daily dose of < 50, 50-99·9 and ≥ 100 mg, the respective hazard ratio was 3·10 (1·17-8·26), 1·01 (0·63-1·61) and 1·53 (1·18-1·97). CONCLUSIONS Sitagliptin is significantly associated with a higher risk of pancreatic cancer, especially when the cumulative dose is < 33 700 mg. The risk diminished in users with a higher cumulative dose. The daily dose of sitagliptin should better be kept < 100 mg, and its use should be reconsidered in patients who suffer from severe renal impairment and thus a daily dose of < 50 mg is always recommended. Future studies are required to confirm the findings with more appropriate adjustment for smoking.
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Affiliation(s)
- Chin-Hsiao Tseng
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Division of Environmental Health and Occupational Medicine of the National Health Research Institutes, Zhunan, Taiwan
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34
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Matsuda Y, Yoshimura H, Ishiwata T, Sumiyoshi H, Matsushita A, Nakamura Y, Aida J, Uchida E, Takubo K, Arai T. Mitotic index and multipolar mitosis in routine histologic sections as prognostic markers of pancreatic cancers: A clinicopathological study. Pancreatology 2015; 16:127-32. [PMID: 26585687 DOI: 10.1016/j.pan.2015.10.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 10/20/2015] [Accepted: 10/25/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Pancreatic cancer is characterized by genomic complexity and chromosomal instability, and atypical mitotic figures are morphological features of this phenotype. In the present study, we determined the frequency and the clinicopathological and prognostic significance of mitotic figures in pancreatic cancers. METHODS We surveyed the mitotic figures of the normal ductal epithelium, acinar cells, pancreatic intraepithelial neoplasias, and pancreatic cancers on hematoxylin-and-eosin-stained tissue specimens (n = 121). RESULTS Pancreatic cancer cells showed significantly higher mitotic indices as compared with the ductal cells, acinar cells, and pancreatic intraepithelial neoplasias. Both normal and atypical mitosis were significantly elevated only in pancreatic cancers. In pancreatic cancers, approximately 30% of total mitosis was atypical including multipolar, lag-type, ring and asymmetrical mitosis, and anaphase bridges. The Kaplan-Meier curves in pancreatic cancers showed significant correlations between total mitosis and disease free survival. Furthermore, the cases with multipolar mitosis showed poorer prognosis than those without. Lymph node metastasis and multipolar mitosis were independent prognostic factors for overall survival of patients with pancreatic cancer. In addition, lymph node metastasis and total mitosis were independent factors for disease free survival. CONCLUSION These findings suggest that routinely obtained pathological specimens, even small biopsy or cytological specimens, can provide valuable information concerning the prognosis of pancreatic cancers.
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Affiliation(s)
- Yoko Matsuda
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.
| | - Hisashi Yoshimura
- Division of Physiological Pathology, Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan
| | - Toshiyuki Ishiwata
- Department of Integrated Diagnostic Pathology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
| | - Hiroki Sumiyoshi
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
| | - Akira Matsushita
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
| | - Yoshiharu Nakamura
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
| | - Junko Aida
- Research Team for Geriatric Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
| | - Eiji Uchida
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
| | - Kaiyo Takubo
- Research Team for Geriatric Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan; Research Team for Geriatric Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
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35
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Sindhu RS, Parvathy G, Fysal K, Jacob MK, Geetha S, Krishna B, Natesh B, Rajan R. Clinical profile of PanIN lesions in tropical chronic pancreatitis. Indian J Gastroenterol 2015; 34:436-41. [PMID: 26586139 DOI: 10.1007/s12664-015-0609-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 11/03/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Chronic pancreatitis (CP) found in the tropical countries is known to have a higher risk for carcinoma of the pancreas. This study aimed to explore the clinical profile of pancreatic intraepithelial neoplasia (PanIN), one of the precursors of carcinoma of the pancreas, in tropical CP and to identify the possible clinical predictors of the same. METHODOLOGY A retrospective study was done enrolling patients who underwent either Frey's procedure or pancreatic resection for symptomatic CP, between January 2008 and December 2012. They were grouped into PanIN positive and PanIN negative based on histopathology. Their clinical and laboratory parameters were compared statistically to identify the predictors of the PanIN status. RESULTS Sixty-two tropical CP patients who had Frey's procedure or pancreatic resection were enrolled into this study; 38.7 % cases showed PanIN changes and 61.29 % had no PanIN changes. Majority of the clinical and laboratory parameters were found comparable between the two groups except obstructive jaundice and CA 19-9 value >137.5 which were there in 54.2 % of PanIN-positive cases. On histopathology, 54.83 % cases were benign CP and 45.16 % were malignant CP. Among the benign CP, 33.3 % were PanIN positive and among those with malignancy 66.7 % were PanIN positive. Low-grade PanINs were seen in 73 % cases of benign CP and in 26.1 % of malignancy whereas high-grade PanIN-3 lesions were seen exclusively in patients with malignancy. CONCLUSION High-grade PanIN-3 lesions showed significant association with pancreatic malignancy. Obstructive jaundice and CA 19-9 ≥ 137.5 could predict PanIN positivity.
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Affiliation(s)
- R S Sindhu
- Department of Surgical Gastroenterology, Government Medical College, Thiruvananthapuram, 695 011, India.
| | - G Parvathy
- Department of Pathology, Government Medical College, Thiruvananthapuram, 695 011, India
| | - K Fysal
- Department of Surgical Gastroenterology, Government Medical College, Thiruvananthapuram, 695 011, India
| | - M K Jacob
- Department of Surgical Gastroenterology, Government Medical College, Thiruvananthapuram, 695 011, India
| | - S Geetha
- Department of Pathology, Government Medical College, Thiruvananthapuram, 695 011, India
| | - B Krishna
- Department of Pathology, Government Medical College, Thiruvananthapuram, 695 011, India
| | - Bonny Natesh
- Department of Surgical Gastroenterology, Government Medical College, Thiruvananthapuram, 695 011, India
| | - Ramesh Rajan
- Department of Surgical Gastroenterology, Government Medical College, Thiruvananthapuram, 695 011, India
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36
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Pandharipande PV, Heberle C, Dowling EC, Kong CY, Tramontano A, Perzan KE, Brugge W, Hur C. Targeted screening of individuals at high risk for pancreatic cancer: results of a simulation model. Radiology 2015; 275:177-87. [PMID: 25393849 PMCID: PMC4372492 DOI: 10.1148/radiol.14141282] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE To identify when, from the standpoint of relative risk, magnetic resonance (MR) imaging-based screening may be effective in patients with a known or suspected genetic predisposition to pancreatic cancer. MATERIALS AND METHODS The authors developed a Markov model of pancreatic ductal adenocarcinoma (PDAC). The model was calibrated to National Cancer Institute Surveillance, Epidemiology, and End Results registry data and informed by the literature. A hypothetical screening strategy was evaluated in which all population individuals underwent one-time MR imaging screening at age 50 years. Screening outcomes for individuals with an average risk for PDAC ("base case") were compared with those for individuals at an increased risk to assess for differential benefits in populations with a known or suspected genetic predisposition. Effects of varying key inputs, including MR imaging performance, surgical mortality, and screening age, were evaluated with a sensitivity analysis. RESULTS In the base case, screening resulted in a small number of cancer deaths averted (39 of 100 000 men, 38 of 100 000 women) and a net decrease in life expectancy (-3 days for men, -4 days for women), which was driven by unnecessary pancreatic surgeries associated with false-positive results. Life expectancy gains were achieved if an individual's risk for PDAC exceeded 2.4 (men) or 2.7 (women) times that of the general population. When relative risk increased further, for example to 30 times that of the general population, averted cancer deaths and life expectancy gains increased substantially (1219 of 100 000 men, life expectancy gain: 65 days; 1204 of 100 000 women, life expectancy gain: 71 days). In addition, results were sensitive to MR imaging specificity and the surgical mortality rate. CONCLUSION Although PDAC screening with MR imaging for the entire population is not effective, individuals with even modestly increased risk may benefit.
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Affiliation(s)
- Pari V. Pandharipande
- From the Massachusetts General Hospital Institute for Technology
Assessment (P.V.P., C.H., E.C.D., C.Y.K., A.T., K.E.P., C.H.), Department of
Radiology (P.V.P., C.H., E.C.D., C.Y.K., A.T.), and Department of General Medicine,
Gastrointestinal Unit (K.E.P., W.B., C.H.), Massachusetts General Hospital, 101
Merrimac St, 10th Floor, Boston, MA 02114; and Harvard Medical School, Boston,
Mass
| | - Curtis Heberle
- From the Massachusetts General Hospital Institute for Technology
Assessment (P.V.P., C.H., E.C.D., C.Y.K., A.T., K.E.P., C.H.), Department of
Radiology (P.V.P., C.H., E.C.D., C.Y.K., A.T.), and Department of General Medicine,
Gastrointestinal Unit (K.E.P., W.B., C.H.), Massachusetts General Hospital, 101
Merrimac St, 10th Floor, Boston, MA 02114; and Harvard Medical School, Boston,
Mass
| | - Emily C. Dowling
- From the Massachusetts General Hospital Institute for Technology
Assessment (P.V.P., C.H., E.C.D., C.Y.K., A.T., K.E.P., C.H.), Department of
Radiology (P.V.P., C.H., E.C.D., C.Y.K., A.T.), and Department of General Medicine,
Gastrointestinal Unit (K.E.P., W.B., C.H.), Massachusetts General Hospital, 101
Merrimac St, 10th Floor, Boston, MA 02114; and Harvard Medical School, Boston,
Mass
| | - Chung Yin Kong
- From the Massachusetts General Hospital Institute for Technology
Assessment (P.V.P., C.H., E.C.D., C.Y.K., A.T., K.E.P., C.H.), Department of
Radiology (P.V.P., C.H., E.C.D., C.Y.K., A.T.), and Department of General Medicine,
Gastrointestinal Unit (K.E.P., W.B., C.H.), Massachusetts General Hospital, 101
Merrimac St, 10th Floor, Boston, MA 02114; and Harvard Medical School, Boston,
Mass
| | - Angela Tramontano
- From the Massachusetts General Hospital Institute for Technology
Assessment (P.V.P., C.H., E.C.D., C.Y.K., A.T., K.E.P., C.H.), Department of
Radiology (P.V.P., C.H., E.C.D., C.Y.K., A.T.), and Department of General Medicine,
Gastrointestinal Unit (K.E.P., W.B., C.H.), Massachusetts General Hospital, 101
Merrimac St, 10th Floor, Boston, MA 02114; and Harvard Medical School, Boston,
Mass
| | - Katherine E. Perzan
- From the Massachusetts General Hospital Institute for Technology
Assessment (P.V.P., C.H., E.C.D., C.Y.K., A.T., K.E.P., C.H.), Department of
Radiology (P.V.P., C.H., E.C.D., C.Y.K., A.T.), and Department of General Medicine,
Gastrointestinal Unit (K.E.P., W.B., C.H.), Massachusetts General Hospital, 101
Merrimac St, 10th Floor, Boston, MA 02114; and Harvard Medical School, Boston,
Mass
| | - William Brugge
- From the Massachusetts General Hospital Institute for Technology
Assessment (P.V.P., C.H., E.C.D., C.Y.K., A.T., K.E.P., C.H.), Department of
Radiology (P.V.P., C.H., E.C.D., C.Y.K., A.T.), and Department of General Medicine,
Gastrointestinal Unit (K.E.P., W.B., C.H.), Massachusetts General Hospital, 101
Merrimac St, 10th Floor, Boston, MA 02114; and Harvard Medical School, Boston,
Mass
| | - Chin Hur
- From the Massachusetts General Hospital Institute for Technology
Assessment (P.V.P., C.H., E.C.D., C.Y.K., A.T., K.E.P., C.H.), Department of
Radiology (P.V.P., C.H., E.C.D., C.Y.K., A.T.), and Department of General Medicine,
Gastrointestinal Unit (K.E.P., W.B., C.H.), Massachusetts General Hospital, 101
Merrimac St, 10th Floor, Boston, MA 02114; and Harvard Medical School, Boston,
Mass
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Matsuda Y, Ishiwata T, Izumiyama-Shimomura N, Hamayasu H, Fujiwara M, Tomita KI, Hiraishi N, Nakamura KI, Ishikawa N, Aida J, Takubo K, Arai T. Gradual telomere shortening and increasing chromosomal instability among PanIN grades and normal ductal epithelia with and without cancer in the pancreas. PLoS One 2015; 10:e0117575. [PMID: 25658358 PMCID: PMC4319908 DOI: 10.1371/journal.pone.0117575] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 12/28/2014] [Indexed: 12/15/2022] Open
Abstract
A large body of evidence supports a key role for telomere dysfunction in carcinogenesis due to the induction of chromosomal instability. To study telomere shortening in precancerous pancreatic lesions, we measured telomere lengths using quantitative fluorescence in situ hybridization in the normal pancreatic duct epithelium, pancreatic intraepithelial neoplasias (PanINs), and cancers. The materials employed included surgically resected pancreatic specimens without cancer (n = 33) and with invasive ductal carcinoma (n = 36), as well as control autopsy cases (n = 150). In comparison with normal ducts, telomere length was decreased in PanIN-1, −2 and −3 and cancer. Furthermore, telomeres were shorter in cancer than in PanIN-1 and −2. Telomere length in cancer was not associated with histological type, lesion location, or cancer stage. PanINs with or without cancer showed similar telomere lengths. The incidences of atypical mitosis and anaphase bridges, which are morphological characteristics of chromosomal instability, were negatively correlated with telomere length. The telomeres in normal duct epithelium became shorter with aging, and those in PanINs or cancers were shorter than in age-matched controls, suggesting that telomere shortening occurs even when histological changes are absent. Our data strongly suggest that telomere shortening occurs in the early stages of pancreatic carcinogenesis and progresses with precancerous development. Telomere shortening and chromosomal instability in the duct epithelium might be associated with carcinogenesis of the pancreas. Determination of telomere length in pancreatic ductal lesions may be valuable for accurate detection and risk assessment of pancreatic cancer.
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Affiliation(s)
- Yoko Matsuda
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
- * E-mail: (YM); (KT)
| | - Toshiyuki Ishiwata
- Department of Integrated Diagnostic Pathology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan
| | - Naotaka Izumiyama-Shimomura
- Research Team for Geriatric Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
| | - Hideki Hamayasu
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
| | - Mutsunori Fujiwara
- Department of Pathology, Japanese Red Cross Medical Center, 4-1-22 Hiroo, Shibuya-ku, Tokyo, 150-8935, Japan
| | - Ken-ichiro Tomita
- Department of Pathology, Japanese Red Cross Medical Center, 4-1-22 Hiroo, Shibuya-ku, Tokyo, 150-8935, Japan
| | - Naoki Hiraishi
- Department of Laboratory Medicine, Hadano Red Cross Hospital, Hadano, Kanagawa, 257-0017, Japan
| | - Ken-ichi Nakamura
- Research Team for Geriatric Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
| | - Naoshi Ishikawa
- Research Team for Geriatric Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
| | - Junko Aida
- Research Team for Geriatric Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
| | - Kaiyo Takubo
- Research Team for Geriatric Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
- * E-mail: (YM); (KT)
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
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38
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Klöppel G, Basturk O, Schlitter AM, Konukiewitz B, Esposito I. Intraductal neoplasms of the pancreas. Semin Diagn Pathol 2014; 31:452-466. [DOI: 10.1053/j.semdp.2014.08.005] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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39
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Saiki Y, Horii A. Molecular pathology of pancreatic cancer. Pathol Int 2014; 64:10-9. [PMID: 24471965 DOI: 10.1111/pin.12114] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Accepted: 10/28/2013] [Indexed: 12/14/2022]
Abstract
By genomic and epigenomic screening techniques, substantial progress has been made in our understanding of pancreatic cancer. The comprehensive studies of the pancreatic cancer genome have revealed that most genetic alterations are identified to be associated with specific core signaling pathways including high-frequency mutated genes such as KRAS, CDKN2A, TP53, and SMAD4 along with several low-frequency mutated genes. Three types of histological precursors of pancreatic cancer: pancreatic intraepithelial neoplasia, mucinous cystic neoplasm, and intraductal papillary mucinous neoplasm, had been recognized by morphological studies and the recent genomic screening techniques revealed that each of these precursor lesions were associated with specific molecular alterations. In the familial pancreatic cancer cases, several responsible genes were discovered. Epigenetic changes also play an important role in the progression of pancreatic cancer. Several tumor suppressor genes were silenced due to aberrant promoter CpG island hypermethylation. Several genetically engineered mouse models, based on the Kras mutation, were created, and provided reliable tools to identify the key molecules responsible for the development or progression of pancreatic cancer.
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Affiliation(s)
- Yuriko Saiki
- Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan
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Esposito I, Konukiewitz B, Schlitter AM, Klöppel G. Pathology of pancreatic ductal adenocarcinoma: Facts, challenges and future developments. World J Gastroenterol 2014; 20:13833-13841. [PMID: 25320520 PMCID: PMC4194566 DOI: 10.3748/wjg.v20.i38.13833] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 01/02/2014] [Accepted: 05/14/2014] [Indexed: 02/06/2023] Open
Abstract
Despite major improvements concerning its diagnosis and treatment, pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease with an extremely poor prognosis. Pathology, as interface discipline between basic and clinical medicine, has substantially contributed to the recent developments and has laid the basis for further progress. The definition and classification of precursor lesions of PDAC and their molecular characterization is a fundamental step for the potential identification of biomarkers and the development of imaging methods for early detection. In addition, by integrating findings in humans with the knowledge acquired through the investigation of transgenic mouse models for PDAC, a new model for pancreatic carcinogenesis has been proposed and partially validated in individuals with genetic predisposition for PDAC. The introduction and validation of a standardized system for pathology reporting based on the axial slicing technique has shown that most pancreatic cancer resections are R1 resections and that this is due to inherent anatomical and biological properties of PDAC. This standardized assessment of prognostic relevant parameters represents the basis for the successful conduction of multicentric studies and for the interpretation of their results. Finally, recent studies have shown that distinct molecular subtypes of PDAC exist and are associated with different prognosis and therapy response. The prospective validation of these results and the integration of molecular analyses in a comprehensive pathology report in the context of individualised cancer therapy represent a major challenge for the future.
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Expression and clinical significance of IMP3 in microdissected premalignant and malignant pancreatic lesions. Clin Transl Oncol 2014; 17:215-22. [PMID: 25183049 DOI: 10.1007/s12094-014-1216-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Accepted: 08/08/2014] [Indexed: 10/24/2022]
Abstract
INTRODUCTION Insulin-like growth factor 2 (IGF-2) mRNA-binding protein 3 (IMP3) is overexpressed in pancreatic cancer, while remaining undetectable in the normal pancreas, indicating its important role in pancreatic cancer pathogenesis. The role of IMP3 in pancreatic carcinogenesis has not been fully understood. The main goal of this study was to probe the expression profile of IMP3 in different stages of pancreatic ductal adenocarcinoma (PDAC) development, and evaluate their prognostic significance in PDAC patients. MATERIALS AND METHODS We used quantitative real-time RT-PCR combined manual microdissection to precisely detect IMP3 expression in 97 microdissected foci from 50 patients with PDAC. Nonparametric test, Log-rank test and Cox regression analysis were used to evaluate the clinical significance of DNMTs expression. RESULTS Expression of IMP3 increased from normal duct to pancreatic intraductal neoplasia and to PDAC. IMP3 mRNA expression statistically correlated with TNM staging. Univariate analysis showed that high level of IMP3 expression, tumor differentiation, TNM staging and alcohol consumption were statistically significant risk factors. Multivariate analysis showed that high level of IMP3 expression and tumor differentiation were statistically significant independent poor prognostic factors. CONCLUSIONS These results suggested that pancreatic carcinogenesis involves an increased IMP3 mRNA expression, and it may become valuable diagnostic and prognostic markers as well as potential therapeutic targets for pancreatic cancer.
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Lami G, Biagini MR, Galli A. Endoscopic ultrasonography for surveillance of individuals at high risk for pancreatic cancer. World J Gastrointest Endosc 2014; 6:272-85. [PMID: 25031786 PMCID: PMC4094985 DOI: 10.4253/wjge.v6.i7.272] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2014] [Revised: 06/10/2014] [Accepted: 06/20/2014] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer is a highly lethal disease with a genetic susceptibility and familial aggregation found in 3%-16% of patients. Early diagnosis remains the only hope for curative treatment and improvement of prognosis. This can be reached by the implementation of an intensive screening program, actually recommended for individuals at high-risk for pancreatic cancer development. The aim of this strategy is to identify pre-malignant precursors or asymptomatic pancreatic cancer lesions, curable by surgery. Endoscopic ultrasound (EUS) with or without fine needle aspiration (FNA) seems to be the most promising technique for early detection of pancreatic cancer. It has been described as a highly sensitive and accurate tool, especially for small and cystic lesions. Pancreatic intraepithelial neoplasia, a precursor lesion which is highly represented in high-risk individuals, seems to have characteristics chronic pancreatitis-like changes well detected by EUS. Many screening protocols have demonstrated high diagnostic yields for pancreatic pre-malignant lesions, allowing prophylactic pancreatectomies. However, it shows a high interobserver variety even among experienced endosonographers and a low sensitivity in case of chronic pancreatitis. Some new techniques such as contrast-enhanced harmonic EUS, computer-aided diagnostic techniques, confocal laser endomicroscopy miniprobe and the detection of DNA abnormalities or protein markers by FNA, promise improvement of the diagnostic yield of EUS. As the resolution of imaging improves and as our knowledge of precursor lesions grows, we believe that EUS could become the most suitable method to detect curable pancreatic neoplasms in correctly identified asymptomatic at-risk patients.
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Slater EP, Strauch K, Rospleszcz S, Ramaswamy A, Esposito I, Klöppel G, Matthäi E, Heeger K, Fendrich V, Langer P, Bartsch DK. MicroRNA-196a and -196b as Potential Biomarkers for the Early Detection of Familial Pancreatic Cancer. Transl Oncol 2014; 7:464-71. [PMID: 24956938 PMCID: PMC4202799 DOI: 10.1016/j.tranon.2014.05.007] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 05/12/2014] [Accepted: 05/21/2014] [Indexed: 02/07/2023] Open
Abstract
Screening programs are recommended for individuals at risk (IAR) from families with familial pancreatic cancer (FPC). However, reliable imaging methods or biomarkers for early diagnosis of pancreatic ductal adenocarcinoma (PC) or its precursor lesions are still lacking. The ability of circulating microRNAs (miRNAs) to discriminate multifocal high-grade precursor lesions or PC from normal was examined. The presence of miRNA-21, -155, -196a, -196b and -210 was analyzed in the serum of transgenic KPC mice to test their ability to distinguish mice with different grades of pancreatic intraepithelial neoplasia (mPanIN1–3) or PC from control mice. Serum levels of miR-196a and -196b were significantly higher in mice with PanIN2/3 lesions (n = 10) or PC (n = 8) as compared to control mice (n = 10) or mice with PanIN1 lesions (n = 10; P = .01). In humans, miR-196a and -196b were also diagnostic. Patients with PC, sporadic (n = 9) or hereditary (n = 10), and IAR with multifocal PanIN2/3 lesions (n = 5) had significantly higher serum levels than patients with neuroendocrine pancreatic tumors (n = 10) or chronic pancreatitis (n = 10), IAR with PanIN1 or no PanIN lesions (n = 5), and healthy controls (n = 10). The combination of both miR-196a and -196b reached a sensitivity of 1 and specificity of 0.9 (area under the curve = 0.99) to diagnose PC or high-grade PanIN lesions. In addition, preoperative elevated serum levels of miR-196a and -196b in patients with PC or multifocal PanIN2/3 lesions dropped to normal after potential curative resection. The combination of miR-196a and -196b may be a promising biomarker test for the screening of IAR for FPC.
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Affiliation(s)
- Emily P Slater
- Department of Surgery, Philipps University of Marburg, Marburg, Germany.
| | - Konstantin Strauch
- Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany; Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Susanne Rospleszcz
- Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany; Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Annette Ramaswamy
- Department of Pathology, Philipps University of Marburg, Marburg, Germany
| | - Irene Esposito
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Günter Klöppel
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Elvira Matthäi
- Department of Surgery, Philipps University of Marburg, Marburg, Germany
| | - Kristin Heeger
- Department of Surgery, Philipps University of Marburg, Marburg, Germany
| | - Volker Fendrich
- Department of Surgery, Philipps University of Marburg, Marburg, Germany
| | - Peter Langer
- Department of Surgery, Philipps University of Marburg, Marburg, Germany
| | - Detlef K Bartsch
- Department of Surgery, Philipps University of Marburg, Marburg, Germany
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Bergmann F, Aulmann S, Welsch T, Herpel E, Werner J, Schirmacher P, Bläker H. Molecular analysis of pancreatic acinar cell cystadenomas: Evidence of a non-neoplastic nature. Oncol Lett 2014; 8:852-858. [PMID: 25009661 PMCID: PMC4081433 DOI: 10.3892/ol.2014.2163] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 03/21/2014] [Indexed: 11/05/2022] Open
Abstract
The biology of pancreatic acinar cell cystadenomas has not been clearly defined. However, a non-neoplastic process, caused by a cell differentiation failure leading to a cystic transformation, has been discussed, as well as a benign neoplastic lesion. Pancreatic acinar cell cystadenomas usually consist of thin-walled unilocular or multilocular cysts, and mural nodules have been described in two cases of a recent series. In one of these nodules, chromosomal imbalances were detected, which provided preliminary evidence for a neoplastic process. The aim of the current study was to further characterize the lesions by molecular analyses. In four cases without mural nodules, the clonality was assessed by performing mutational analyses within the highly variable displacement-loop region of the mitochondrial DNA. As a result, no closer correlation was identified between different foci within the tumors than between the tumors and adjacent normal pancreatic acinar tissue, indicating polyclonality of these lesions. Further molecular analyses revealed no mutations of the β-catenin and K-ras genes. In addition, no immunohistochemical evidence was identified for mutations of Smad4 or p53. In conclusion, the results of the current study demonstrated that pancreatic acinar cell cystadenomas are non-neoplastic lesions, with the potential exception of those rare cases with mural nodules.
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Affiliation(s)
- Frank Bergmann
- Institute of Pathology, University of Heidelberg, Heidelberg D-69120, Germany
| | - Sebastian Aulmann
- Institute of Pathology, University of Heidelberg, Heidelberg D-69120, Germany
| | - Thilo Welsch
- Department of General Surgery, University of Heidelberg, Heidelberg D-69120, Germany ; Institute of Pathology, Charité Berlin, Campus Mitte, Berlin D-10117, Germany
| | - Esther Herpel
- Institute of Pathology, University of Heidelberg, Heidelberg D-69120, Germany
| | - Jens Werner
- Department of General Surgery, University of Heidelberg, Heidelberg D-69120, Germany
| | - Peter Schirmacher
- Institute of Pathology, University of Heidelberg, Heidelberg D-69120, Germany
| | - Hendrik Bläker
- Institute of Pathology, University of Heidelberg, Heidelberg D-69120, Germany ; Department of Surgery, University of Dresden, Dresden D-01307, Germany
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Jones HB, Reens J, Brocklehurst SR, Betts CJ, Bickerton S, Bigley AL, Jenkins RP, Whalley NM, Morgan D, Smith DM. Islets of Langerhans from prohormone convertase-2 knockout mice show α-cell hyperplasia and tumorigenesis with elevated α-cell neogenesis. Int J Exp Pathol 2014; 95:29-48. [PMID: 24456331 DOI: 10.1111/iep.12066] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 11/14/2013] [Indexed: 01/24/2023] Open
Abstract
Antagonism of the effects of glucagon as an adjunct therapy with other glucose-lowering drugs in the chronic treatment of diabetes has been suggested to aggressively control blood glucose levels. Antagonism of glucagon effects, by targeting glucagon secretion or disabling the glucagon receptor, is associated with α-cell hyperplasia. We evaluated the influence of total glucagon withdrawal on islets of Langerhans using prohormone convertase-2 knockout mice (PC2-ko), in which α-cell hyperplasia is present from a young age and persists throughout life, in order to understand whether or not sustained glucagon deficit would lead to islet tumorigenesis. PC2-ko and wild-type (WT) mice were maintained drug-free, and cohorts of these groups sampled at 3, 12 and 18 months for plasma biochemical and morphological (histological, immunohistochemical, electron microscopical and image analytical) assessments. WT mice showed no islet tumours up to termination of the study, but PC2-ko animals displayed marked changes in islet morphology from α-cell hypertrophy/hyperplasia/atypical hyperplasia, to adenomas and carcinomas, these latter being first encountered at 6-8 months. Islet hyperplasias and tumours primarily consisted of α-cells associated to varying degrees with other islet endocrine cell types. In addition to substantial increases in islet neoplasia, increased α-cell neogenesis associated primarily with pancreatic duct(ule)s was present. We conclude that absolute blockade of the glucagon signal results in tumorigenesis and that the PC2-ko mouse represents a valuable model for investigation of islet tumours and pancreatic ductal neogenesis.
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Affiliation(s)
- Huw B Jones
- Department of Pathological Sciences, AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, UK
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Celesti G, Di Caro G, Bianchi P, Grizzi F, Marchesi F, Basso G, Rahal D, Delconte G, Catalano M, Cappello P, Roncalli M, Zerbi A, Montorsi M, Novelli F, Mantovani A, Allavena P, Malesci A, Laghi L. Early expression of the fractalkine receptor CX3CR1 in pancreatic carcinogenesis. Br J Cancer 2013; 109:2424-2433. [PMID: 24084767 PMCID: PMC3817321 DOI: 10.1038/bjc.2013.565] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 07/09/2013] [Accepted: 08/22/2013] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND In pancreatic ductal adenocarcinoma (PDAC), fractalkine receptor CX3CR1 contributes to perineural invasion (PNI). We investigated whether CX3CR1 expression occurs early in PDAC and correlates with tumour features other than PNI. METHODS We studied CX3CR1 and CX3CL1 expression by immunohistochemistry in 104 human PDAC and coexisting Pancreatic Intraepithelial Neoplasia (PanIN), and in PdxCre/LSL-Kras(G12D) mouse model of PDAC. CX3CR1 expression in vitro was studied by a spheroid model, and in vivo by syngenic mouse graft of tumour cells. RESULTS In total, 56 (53.9%) PDAC expressed CX3CR1, 70 (67.3%) CX3CL1, and 45 (43.3%) both. CX3CR1 expression was independently associated with tumour glandular differentiation (P=0.005) and PNI (P=0.01). Pancreatic Intraepithelial Neoplasias were more frequently CX3CR1+ (80.3%, P<0.001) and CX3CL1+ (86.8%, P=0.002) than matched cancers. The survival of PDAC patients was better in those with CX3CR1+ tumour (P=0.05). Mouse PanINs were also CX3CR1(+) and -CL1(+). In vitro, cytokines significantly increased CX3CL1 but not CX3CR1 expression. Differently, CX3CR1 was upregulated in tumour spheroids, and in vivo only in well-differentiated tumours. CONCLUSION Tumour differentiation, rather than inflammatory signalling, modulates CX3CR1 expression in PanINs and PDAC. CX3CR1 expression pattern suggests its early involvement in PDAC progression, outlining a potential target for interfering with the PanIN transition to invasive cancer.
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Affiliation(s)
- G Celesti
- Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
| | - G Di Caro
- Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
- PhD Programs in Pathology and Neuropathology, University of Milan, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
| | - P Bianchi
- Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
| | - F Grizzi
- Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
| | - F Marchesi
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
| | - G Basso
- Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
- School of Molecular Medicine, University of Milan, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
| | - D Rahal
- Department of Surgical Pathology, Humanitas Clinical and Research Center, University of Milan, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
| | - G Delconte
- Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
| | - M Catalano
- Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
| | - P Cappello
- Centro Ricerche Medicina Sperimentale, Azienda Universitaria Ospedaliera San Giovanni Battista, University of Torino, Via Cherasco, 15, 10126 Torino, Italy
- Department of Medicine and Experimental Oncology, University of Torino, Via Cherasco, 15, 10126 Torino, Italy
| | - M Roncalli
- Department of Surgical Pathology, Humanitas Clinical and Research Center, University of Milan, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - A Zerbi
- Department of General Surgery, Humanitas Clinical and Research Center, University of Milan, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
| | - M Montorsi
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
- Department of General Surgery, Humanitas Clinical and Research Center, University of Milan, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
| | - F Novelli
- Centro Ricerche Medicina Sperimentale, Azienda Universitaria Ospedaliera San Giovanni Battista, University of Torino, Via Cherasco, 15, 10126 Torino, Italy
- Department of Medicine and Experimental Oncology, University of Torino, Via Cherasco, 15, 10126 Torino, Italy
| | - A Mantovani
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - P Allavena
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
| | - A Malesci
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
- Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
| | - L Laghi
- Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
- Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy
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Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, Hruban RH. Recent progress in pancreatic cancer. CA Cancer J Clin 2013; 63:318-48. [PMID: 23856911 PMCID: PMC3769458 DOI: 10.3322/caac.21190] [Citation(s) in RCA: 677] [Impact Index Per Article: 56.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Revised: 03/22/2013] [Accepted: 03/22/2013] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in the understanding of the fundamental genetics of pancreatic cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with pancreatic cancer.
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Affiliation(s)
- Christopher L. Wolfgang
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Joseph M. Herman
- Department of Radiation Oncology & Molecular Radiation Sciences, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Daniel A. Laheru
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Alison P. Klein
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Epidemiology, the Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Michael A. Erdek
- Department of Anesthesiology and Critical Care Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Elliot K. Fishman
- Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Ralph H. Hruban
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
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Bobrowski A, Spitzner M, Bethge S, Mueller-Graf F, Vollmar B, Zechner D. Risk factors for pancreatic ductal adenocarcinoma specifically stimulate pancreatic duct glands in mice. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 182:965-74. [PMID: 23438477 DOI: 10.1016/j.ajpath.2012.11.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Revised: 10/26/2012] [Accepted: 11/01/2012] [Indexed: 01/03/2023]
Abstract
Diabetes mellitus type 2 and chronic pancreatitis are regarded as risk factors for pancreatic cancer. Pancreatic duct glands (PDGs) were recently described as a new compartment of the major duct in humans and mice. To evaluate the influence of diabetes and chronic pancreatitis on PDGs, cerulein was injected i.p., repetitively over 10 weeks, in mice exhibiting obesity and a type 2 diabetes-like syndrome (B6.V-Lep(ob/ob)) and in lean littermates. By using 5-bromo-2'-deoxyuridine (BrdU), a label-retaining cell population was characterized in PDGs. Cerulein administration led to more BrdU(+) cells in PDGs of obese mice compared with lean mice. The observed increase was specific to PDGs, because BrdU incorporation in cells of the pancreatic duct was not increased. In addition, the expression of distinct tumor markers in PDGs was characterized by Muc5ac, S100P, regenerating islet-derived 3β, 14-3-3 σ, and prostate stem cell antigen immunochemistry. Type 2 diabetes-like syndrome, accompanied by chronic pancreatitis, enhanced nuclear localization of S100P. Both risk factors for pancreatic cancer also induced the production of Muc5ac and the nuclear localization of S100P [corrected]. These results demonstrate that diabetes and chronic pancreatitis jointly enhance BrdU incorporation and production of pancreatic cancer-specific proteins in PDGs. The observed alterations suggest that pancreatic tumors might originate from the newly discovered histomorphological structures, called PDGs, which could represent a target for future anticancer therapies.
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Affiliation(s)
- Alexej Bobrowski
- Institute for Experimental Surgery, University of Rostock, Rostock, Germany
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50
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Dutruel C, Bergmann F, Rooman I, Zucknick M, Weichenhan D, Geiselhart L, Kaffenberger T, Rachakonda PS, Bauer A, Giese N, Hong C, Xie H, Costello JF, Hoheisel J, Kumar R, Rehli M, Schirmacher P, Werner J, Plass C, Popanda O, Schmezer P. Early epigenetic downregulation of WNK2 kinase during pancreatic ductal adenocarcinoma development. Oncogene 2013; 33:3401-10. [PMID: 23912455 DOI: 10.1038/onc.2013.312] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Revised: 05/16/2013] [Accepted: 06/13/2013] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here, we determine the contribution of epigenetically silenced genes to the development of PDAC. We analyzed enriched, highly methylated DNAs from PDACs, chronic pancreatitis (CP) and normal tissues using CpG island microarrays and identified WNK2 as a prominent candidate tumor suppressor gene being downregulated early in PDAC development. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanIN), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression. Demethylation assays confirmed the link between methylation and expression. WNK2 hypermethylation was higher in tumor than in surrounding inflamed tissues and was observed in PanIN lesions as well as in a PDAC mouse model. WNK2 mRNA and protein expressions were lower in PDAC and CP compared with normal tissues both in patients and mouse models. Overexpression of WNK2 led to reduced cell growth, and WNK2 expression in tissues correlated negatively with pERK1/2 expression, a downstream target of WNK2 responsible for cell proliferation. Downregulation of WNK2 by promoter hypermethylation occurs early in PDAC pathogenesis and may support tumor cell growth via the ERK-MAPK pathway.
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Affiliation(s)
- C Dutruel
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - F Bergmann
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - I Rooman
- Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia
| | - M Zucknick
- Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - D Weichenhan
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - L Geiselhart
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - T Kaffenberger
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - P S Rachakonda
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - A Bauer
- Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - N Giese
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - C Hong
- Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
| | - H Xie
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - J F Costello
- Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
| | - J Hoheisel
- Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - R Kumar
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - M Rehli
- Department of Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany
| | - P Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - J Werner
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - C Plass
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - O Popanda
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - P Schmezer
- Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
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