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Mottini C, Auciello FR, Manni I, Pilarsky C, Caputo D, Caracciolo G, Rossetta A, Di Gennaro E, Budillon A, Blandino G, Roca MS, Piaggio G. The cross-talk between the macro and micro-environment in precursor lesions of pancreatic cancer leads to new and promising circulating biomarkers. J Exp Clin Cancer Res 2024; 43:198. [PMID: 39020414 PMCID: PMC11256648 DOI: 10.1186/s13046-024-03117-5] [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: 02/26/2024] [Accepted: 07/06/2024] [Indexed: 07/19/2024] Open
Abstract
Pancreatic cancer (PC) is a clinically challenging tumor to combat due to its advanced stage at diagnosis as well as its resistance to currently available therapies. The absence of early symptoms and known detectable biomarkers renders this disease incredibly difficult to detect/manage. Recent advances in the understanding of PC biology have highlighted the importance of cancer-immune cell interactions, not only in the tumor micro-environment but also in distant systemic sites, like the bone marrow, spleen and circulating immune cells, the so-called macro-environment. The response of the macro-environment is emerging as a determining factor in tumor development by contributing to the formation of an increasingly immunogenic micro-environment promoting tumor homeostasis and progression. We will summarize the key events associated with the feedback loop between the tumor immune micro-environment (TIME) and the tumor immune macroenvironment (TIMaE) in pancreatic precancerous lesions along with how it regulates disease development and progression. In addition, liquid biopsy biomarkers capable of diagnosing PC at an early stage of onset will also be discussed. A clearer understanding of the early crosstalk between micro-environment and macro-environment could contribute to identifying new molecular therapeutic targets and biomarkers, consequently improving early PC diagnosis and treatment.
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Affiliation(s)
- Carla Mottini
- Department of Research, Diagnosis and Innovative Technologies, UOSD SAFU, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Francesca Romana Auciello
- UOC Translational Oncology Research, IRCSS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Isabella Manni
- Department of Research, Diagnosis and Innovative Technologies, UOSD SAFU, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | | | | | - Giulio Caracciolo
- Dipartimento Di Medicina Molecolare Sapienza, Università Di Roma, Rome, Italy
| | | | - Elena Di Gennaro
- Experimental Pharmacology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via M. Semmola, 80131, Naples, Italy
| | - Alfredo Budillon
- Scientific Directorate, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy
| | - Giovanni Blandino
- UOC Translational Oncology Research, IRCSS Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Maria Serena Roca
- Experimental Pharmacology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via M. Semmola, 80131, Naples, Italy.
| | - Giulia Piaggio
- Department of Research, Diagnosis and Innovative Technologies, UOSD SAFU, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy
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Waldron RT, Lugea A, Chang HH, Su HY, Quiros C, Lewis MS, Che M, Ramanujan VK, Rozengurt E, Eibl G, Pandol SJ. Upregulated Matrisomal Proteins and Extracellular Matrix Mechanosignaling Underlie Obesity-Associated Promotion of Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2024; 16:1593. [PMID: 38672675 PMCID: PMC11048773 DOI: 10.3390/cancers16081593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/05/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
Diet-induced obesity (DIO) promotes pancreatic ductal adenocarcinoma (PDAC) in mice expressing KRasG12D in the pancreas (KC mice), but the precise mechanisms remain unclear. Here, we performed multiplex quantitative proteomic and phosphoproteomic analysis by liquid chromatography-tandem mass spectrometry and further bioinformatic and spatial analysis of pancreas tissues from control-fed versus DIO KC mice after 3, 6, and 9 months. Normal pancreatic parenchyma and associated proteins were steadily eliminated and the novel proteins, phosphoproteins, and signaling pathways associated with PDAC tumorigenesis increased until 6 months, when most males exhibited cancer, but females did not. Differentially expressed proteins and phosphoproteins induced by DIO revealed the crucial functional role of matrisomal proteins, which implies the roles of upstream regulation by TGFβ, extracellular matrix-receptor signaling to downstream PI3K-Akt-mTOR-, MAPK-, and Yap/Taz activation, and crucial effects in the tumor microenvironment such as metabolic alterations and signaling crosstalk between immune cells, cancer-associated fibroblasts (CAFs), and tumor cells. Staining tissues from KC mice localized the expression of several prognostic PDAC biomarkers and elucidated tumorigenic features, such as robust macrophage infiltration, acinar-ductal metaplasia, mucinous PanIN, distinct nonmucinous atypical flat lesions (AFLs) surrounded by smooth muscle actin-positive CAFs, invasive tumors with epithelial-mesenchymal transition arising close to AFLs, and expanding deserted areas by 9 months. We next used Nanostring GeoMX to characterize the early spatial distribution of specific immune cell subtypes in distinct normal, stromal, and PanIN areas. Taken together, these data richly contextualize DIO promotion of Kras-driven PDAC tumorigenesis and provide many novel insights into the signaling pathways and processes involved.
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Affiliation(s)
- Richard T. Waldron
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Aurelia Lugea
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Hui-Hua Chang
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Hsin-Yuan Su
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Crystal Quiros
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Michael S. Lewis
- Department of Medicine and Department of Pathology & Laboratory Medicine, VA Greater Los Angeles Health System, Cedars-Sinai Medical Center, Los Angeles, CA 90073, USA;
| | - Mingtian Che
- Biobank and Research Pathology Resource, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - V. Krishnan Ramanujan
- Biobank and Research Pathology Resource, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Stephen J. Pandol
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Saadh MJ, Baher H, Li Y, Chaitanya M, Arias-Gonzáles JL, Allela OQB, Mahdi MH, Carlos Cotrina-Aliaga J, Lakshmaiya N, Ahjel S, Amin AH, Gilmer Rosales Rojas G, Ameen F, Ahsan M, Akhavan-Sigari R. The bioengineered and multifunctional nanoparticles in pancreatic cancer therapy: Bioresponisive nanostructures, phototherapy and targeted drug delivery. ENVIRONMENTAL RESEARCH 2023; 233:116490. [PMID: 37354932 DOI: 10.1016/j.envres.2023.116490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/18/2023] [Accepted: 06/21/2023] [Indexed: 06/26/2023]
Abstract
The multidisciplinary approaches in treatment of cancer appear to be essential in term of bringing benefits of several disciplines and their coordination in tumor elimination. Because of the biological and malignant features of cancer cells, they have ability of developing resistance to conventional therapies such as chemo- and radio-therapy. Pancreatic cancer (PC) is a malignant disease of gastrointestinal tract in which chemotherapy and radiotherapy are main tools in its treatment, and recently, nanocarriers have been emerged as promising structures in its therapy. The bioresponsive nanocarriers are able to respond to pH and redox, among others, in targeted delivery of cargo for specific treatment of PC. The loading drugs on the nanoparticles that can be synthetic or natural compounds, can help in more reduction in progression of PC through enhancing their intracellular accumulation in cancer cells. The encapsulation of genes in the nanoparticles can protect against degradation and promotes intracellular accumulation in tumor suppression. A new kind of therapy for cancer is phototherapy in which nanoparticles can stimulate both photothermal therapy and photodynamic therapy through hyperthermia and ROS overgeneration to trigger cell death in PC. Therefore, synergistic therapy of phototherapy with chemotherapy is performed in accelerating tumor suppression. One of the important functions of nanotechnology is selective targeting of PC cells in reducing side effects on normal cells. The nanostructures are capable of being surface functionalized with aptamers, proteins and antibodies to specifically target PC cells in suppressing their progression. Therefore, a specific therapy for PC is provided and future implications for diagnosis of PC is suggested.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan; Applied Science Research Center. Applied Science Private University, Amman, Jordan
| | - Hala Baher
- Department of Radiology and Ultrasonography Techniques, College of Medical Techniques, Al-Farahidi University, Baghdad, Iraq
| | - Yuanji Li
- Institute of Electrical Engineering, Yanshan University, Qinhuangdao, 066004, China
| | - Mvnl Chaitanya
- Department of Pharmacognosy, School of Pharmacy, Lovely Professional University, Phagwara, Punjab, 144001, India
| | - José Luis Arias-Gonzáles
- Department of Social Sciences, Faculty of Social Studies, University of British Columbia, Vancouver, Canada
| | | | | | | | - Natrayan Lakshmaiya
- Department of Mechanical Engineering, Saveetha School of Engineering, SIMATS, Chennai, Tamil Nadu, India
| | - Salam Ahjel
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Ali H Amin
- Zoology Department, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt
| | | | - Fuad Ameen
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Muhammad Ahsan
- Department of Measurememts and Control Systems, Silesian University of Technology, Gliwice, 44-100, Poland.
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Germany; Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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Khairwa A, Kotru M, Dewan P, Narang S. Morphological markers of chromosomal instability in bone marrow aspiration and trephine biopsy of acute leukemia and myelodysplastic syndrome. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 2022; 63:418-422. [PMID: 36258637 DOI: 10.1002/em.22513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/09/2022] [Accepted: 10/17/2022] [Indexed: 06/16/2023]
Abstract
The role of chromosomal instability (CI) in oncogenesis is very well described in solid tumours, but there are a lack of studies on haematology malignancy, especially with multiple morphological markers. The study aims to analyze seven morphological markers of CI- chromatin bridges (CB), multipolar mitosis (MPM), nuclear budding (NB), micronuclei (MN), nuclear heterogeneity (NH), laggards, chromatin strings (CS) in bone marrow aspirate (BMA) and biopsy of acute leukaemia (AL), and myelodysplastic syndrome (MDS). It is a retrospective cross-sectional analytical study where BMA and biopsy were reviewed for CI markers. We compared CI markers in five categories. CI markers were further correlated with clinical manifestations and outcomes of patients. The study included 54 samples of 37 patients. Overall, the median (IQR) of markers were as follows: MN 3.5 (1,7), NB 5 (1,18), MPM 1 (0,4), CB 1(0,2), Laggards 0 (0,1), and CS 2.5 (0,6). NH was noted in 65.4% of samples. All CI markers except laggards were significantly increased in B-ALL, AML, and MDS compared to other categories. Many CI markers were significantly raised with a few clinical features. The MN, MPM, Laggard, and NH markers were significantly increased in the dead patients compared to those who survived. The study, one of the first to analyze multiple CI markers, revealed that the CI markers were significantly increased in AL and MDS patients and significantly associated with clinical manifestations and outcomes. Morphology markers of CI are valuable and cost-effective in diagnostic strategy, type of malignancies, and assessing prognosis.
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Affiliation(s)
- Anju Khairwa
- Department of Pathology, University College of Medical Sciences & GTB Hospital, Delhi, India
| | - Mrinalini Kotru
- Department of Pathology, University College of Medical Sciences & GTB Hospital, Delhi, India
| | - Pooja Dewan
- Department of Paediatrics, University College of Medical Sciences and GTB Hospital, Delhi, India
| | - Shiva Narang
- Department of Medicine, University College of Medical Sciences and GTB Hospital, Delhi, India
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Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects. Int J Mol Sci 2022; 23:ijms231710132. [PMID: 36077529 PMCID: PMC9456549 DOI: 10.3390/ijms231710132] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/01/2022] [Accepted: 09/01/2022] [Indexed: 02/06/2023] Open
Abstract
Although pancreatic cancer (PC) was considered in the past an orphan cancer type due to its low incidence, it may become in the future one of the leading causes of cancer death. Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of PC, being a highly aggressive malignancy and having a 5-year survival rate of less than 10%. Non-modifiable (family history, age, genetic susceptibility) and modifiable (smoking, alcohol, acute and chronic pancreatitis, diabetes mellitus, intestinal microbiota) risk factors are involved in PC pathogenesis. Chronic inflammation induced by various factors plays crucial roles in PC development from initiation to metastasis. In multiple malignant conditions such as PC, cytokines, chemokines, and growth factors activate the class I phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) (PI3K/AKT/mTOR) signaling pathway, which plays key roles in cell growth, survival, proliferation, metabolism, and motility. Currently, mTOR, AKT, and PI3K inhibitors are used in clinical studies. Moreover, PI3K/mTOR dual inhibitors are being tested in vitro and in vivo with promising results for PC patients. The main aim of this review is to present PC incidence, risk factors, tumor microenvironment development, and PI3K/AKT/mTOR dysregulation and inhibitors used in clinical, in vivo, and in vitro studies.
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Khanlarzadeh E, Nazari S, Ghobakhlou M, Ranjbar H, Nazari S. Epidemiologic and Pathologic Study of Pancreatic Cancer in Hamadan, Iran (2008 to 2018). J Gastrointest Cancer 2022; 53:725-729. [PMID: 34514515 DOI: 10.1007/s12029-021-00706-x] [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] [Accepted: 08/27/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE Pancreatic cancer is the seventh leading cause of cancer death in cases. The study was conducted to determine the epidemiologic and pathologic of pancreatic cancer METHODS: A case series study was conducted retrospectively at Beheshti Hospital in Hamadan, Iran. A total of 409 cases that had been diagnosed with pancreatic cancer from 2008 to 2018 were reviewed. The variables included age, gender, occupation, pathological type, location involved, early symptoms, metastasis status, prognosis, and treatments were extracted from the files and recorded in checklist. Data were analyzed by using SPSS/20 software. RESULTS Pancreatic cancer has been increasing trend in terms of time (2008-2018). Pancreatic cancer was most common age in the sixth decade of life and is more common in men than women. There was a significant relationship between aging and the incidence of pancreatic cancers (P < 0.05). Most of the subjects were urban (50.4%). The frequencies of smoking, alcohol, and drugs were 34.5, 15.6, and 14.0%, respectively. Also, there was no statistically significant relationship between smoking, alcohol, and drugs and pancreatic cancer (P > 0.05). The frequency of pancreatic cancers included adenocarcinomas (66.7%), unknown (25.2%), mucinous adenocarcinomas (4.2%), and carcinoma (3.9%), respectively. CONCLUSION Pancreatic cancer has been increasing trend in terms of time. Pancreatic cancer was most common age in the sixth decade of life and is more common in men than women. The most common type of pancreatic cancer was adenocarcinoma. Diagnosis usually occurs at higher stages. More preventive considerations were found to be beneficial among this population.
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Affiliation(s)
- Elham Khanlarzadeh
- Department of Community Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Saman Nazari
- Student Research Center, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Mehdi Ghobakhlou
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Hossein Ranjbar
- Department of Internal Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sasan Nazari
- Student Research Center, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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Truong E, Pandol S, Jeon C. Uniting epidemiology and experimental models: pancreatic steatosis and pancreatic cancer. EBioMedicine 2022; 79:103996. [PMID: 35405390 PMCID: PMC9010750 DOI: 10.1016/j.ebiom.2022.103996] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/07/2022] [Accepted: 03/28/2022] [Indexed: 02/07/2023] Open
Abstract
Research from epidemiologic studies and experimental animal models provide insights into the role of pancreatic steatosis in the development of pancreatic cancer. Epidemiologic data demonstrate that pancreatic steatosis is widely prevalent and significantly associated with both development and progression of pancreatic cancer. By focusing on current experimental models, this review elucidates potential cellular mechanisms underlying not only the pathophysiology of pancreatic steatosis itself, but also the pathogenesis behind pancreatic steatosis's role in changing the tumour microenvironment and accelerating the development of pancreatic cancer. This review further explores the impact of bariatric surgery on pancreatic steatosis and pancreatic cancer. Synthesizing knowledge from both epidemiologic studies and experimental animal models, this review identifies gaps in current knowledge regarding pancreatic steatosis and its role in carcinogenesis and proposes future research directions to elucidate the possible mechanisms underlying other obesity-associated cancers.
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Affiliation(s)
- Emily Truong
- Department of Medicine; Cedars-Sinai Medical Center, Los Angeles, California.
| | - Stephen Pandol
- Department of Medicine; Cedars-Sinai Medical Center, Los Angeles, California
| | - Christie Jeon
- Department of Medicine; Cedars-Sinai Medical Center, Los Angeles, California; UCLA Fielding School of Public Health, Los Angeles, CA
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Sequestration of Intestinal Acidic Toxins by Cationic Resin Attenuates Pancreatic Cancer Progression through Promoting Autophagic Flux for YAP Degradation. Cancers (Basel) 2022; 14:cancers14061407. [PMID: 35326559 PMCID: PMC8946475 DOI: 10.3390/cancers14061407] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/25/2022] [Accepted: 02/28/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Annually, more than 450,000 people are diagnosed with pancreatic cancer worldwide with over 430,000 mortalities. Pancreatic ductal carcinoma (PDAC) accounts for around 80% of pancreatic cancer cases with an extremely high mortality rate. Emerging research has demonstrated that gut dysbiosis is closely associated with pancreatic cancer, while the underlying mechanisms remain elusive. In this study, we found that elevated levels of endotoxin (LPS) and bile acids were associated with malignant progression in Kras-driven pancreatic cancer mice. Importantly, oral administration of cationic resins to sequestrate intestinal endotoxins and bile acids efficiently attenuated tumor progression. Thus, sequestration of intestinal acidic toxins by oral administration of cationic resins may have potential as an intervention strategy for pancreatic malignancy. Abstract Pancreatic cancer is driven by risk factors such as diabetes and chronic pancreatic injury, which are further associated with gut dysbiosis. Intestinal toxins such as bile acids and bacterial endotoxin (LPS), in excess and persistence, can provoke chronic inflammation and tumorigenesis. Of interest is that many intestinal toxins are negatively charged acidic components in essence, which prompted us to test whether oral administration of cationic resin can deplete intestinal toxins and ameliorate pancreatic cancer. Here, we found that increased plasma levels of endotoxin and bile acids in Pdx1-Cre: LSL-KrasG12D/+ mice were associated with the transformation of the pancreatic ductal carcinoma (PDAC) state. Common bile-duct-ligation or LPS injection impeded autolysosomal flux, leading to Yap accumulation and malignant transformation. Conversely, oral administration of cholestyramine to sequestrate intestinal endotoxin and bile acids resumed autolysosomal flux for Yap degradation and attenuated metastatic incidence. Conversely, chloroquine treatment impaired autolysosomal flux and exacerbated malignance, showing jeopardization of p62/ Sqxtm1 turnover, leading to Yap accumulation, which is also consistent with overexpression of cystatin A (CSTA) in situ with pancreatic cancer cells and metastatic tumor. At cellular levels, chenodeoxycholic acid or LPS treatment activated the ligand–receptor-mediated AKT-mTOR pathway, resulting in autophagy-lysosomal stress for YAP accumulation and cellular dissemination. Thus, this work indicates a potential new strategy for intervention of pancreatic metastasis through sequestration of intestinal acidic toxins by oral administration of cationic resins.
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Muller M, Haghnejad V, Schaefer M, Gauchotte G, Caron B, Peyrin-Biroulet L, Bronowicki JP, Neuzillet C, Lopez A. The Immune Landscape of Human Pancreatic Ductal Carcinoma: Key Players, Clinical Implications, and Challenges. Cancers (Basel) 2022; 14:cancers14040995. [PMID: 35205742 PMCID: PMC8870260 DOI: 10.3390/cancers14040995] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 02/04/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest cancer worldwide with an overall survival rate, all stages combined, of still <10% at 5 years. The poor prognosis is attributed to challenges in early detection, a low opportunity for radical resection, limited response to chemotherapy, radiotherapy, and resistance to immune therapy. Moreover, pancreatic tumoral cells are surrounded by an abundant desmoplastic stroma, which is responsible for creating a mechanical barrier, preventing appropriate vascularization and leading to poor immune cell infiltration. Accumulated evidence suggests that PDAC is impaired with multiple “immune defects”, including a lack of high-quality effector cells (CD4, CD8 T cells, dendritic cells), barriers to effector cell infiltration due to that desmoplastic reaction, and a dominance of immune cells such as regulatory T cells, myeloid-derived suppressor cells, and M2 macrophages, resulting in an immunosuppressive tumor microenvironment (TME). Although recent studies have brought new insights into PDAC immune TME, its understanding remains not fully elucidated. Further studies are required for a better understanding of human PDAC immune TME, which might help to develop potent new therapeutic strategies by correcting these immune defects with the hope to unlock the resistance to (immune) therapy. In this review, we describe the main effector immune cells and immunosuppressive actors involved in human PDAC TME, as well as their implications as potential biomarkers and therapeutic targets.
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Affiliation(s)
- Marie Muller
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
- Correspondence:
| | - Vincent Haghnejad
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
| | - Marion Schaefer
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
| | - Guillaume Gauchotte
- Department of Pathology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France;
- INSERM U1256, NGERE, Faculty of Medicine, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France
| | - Bénédicte Caron
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
- INSERM U1256, NGERE, Faculty of Medicine, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France
| | - Jean-Pierre Bronowicki
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
- INSERM U1256, NGERE, Faculty of Medicine, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France
| | - Cindy Neuzillet
- Medical Oncology Department, Curie Institute, Versailles Saint-Quentin University (UVQ), Paris Saclay University, 92064 Saint-Cloud, France;
| | - Anthony Lopez
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54500 Vandœuvre-lès-Nancy, France; (V.H.); (M.S.); (B.C.); (L.P.-B.); (J.-P.B.); (A.L.)
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Hrabák P, Kalousová M, Krechler T, Zima T. Pancreatic stellate cells - rising stars in pancreatic pathologies. Physiol Res 2021. [DOI: 10.33549//physiolres.934783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Pluripotent pancreatic stellate cells (PSCs) receive growing interest in past decades. Two types of PSCs are recognized –vitamin A accumulating quiescent PSCs and activated PSCs- the main producents of extracellular matrix in pancreatic tissue. PSCs plays important role in pathogenesis of pancreatic fibrosis in pancreatic cancer and chronic pancreatitis. PSCs are intensively studied as potential therapeutical target because of their important role in developing desmoplastic stroma in pancreatic cancer. There also exists evidence that PSC are involved in other pathologies like type-2 diabetes mellitus. This article brings brief characteristics of PSCs and recent advances in research of these cells.
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Affiliation(s)
| | - M Kalousová
- 2Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic.
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Maneshi P, Mason J, Dongre M, Öhlund D. Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits. Front Cell Dev Biol 2021; 9:787485. [PMID: 34901028 PMCID: PMC8656238 DOI: 10.3389/fcell.2021.787485] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/01/2021] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the worst outcomes among cancers with a 5-years survival rate of below 10%. This is a result of late diagnosis and the lack of effective treatments. The tumor is characterized by a highly fibrotic stroma containing distinct cellular components, embedded within an extracellular matrix (ECM). This ECM-abundant tumor microenvironment (TME) in PDAC plays a pivotal role in tumor progression and resistance to treatment. Cancer-associated fibroblasts (CAFs), being a dominant cell type of the stroma, are in fact functionally heterogeneous populations of cells within the TME. Certain subtypes of CAFs are the main producer of the ECM components of the stroma, with the most abundant one being the collagen family of proteins. Collagens are large macromolecules that upon deposition into the ECM form supramolecular fibrillar structures which provide a mechanical framework to the TME. They not only bring structure to the tissue by being the main structural proteins but also contain binding domains that interact with surface receptors on the cancer cells. These interactions can induce various responses in the cancer cells and activate signaling pathways leading to epithelial-to-mesenchymal transition (EMT) and ultimately metastasis. In addition, collagens are one of the main contributors to building up mechanical forces in the tumor. These forces influence the signaling pathways that are involved in cell motility and tumor progression and affect tumor microstructure and tissue stiffness by exerting solid stress and interstitial fluid pressure on the cells. Taken together, the TME is subjected to various types of mechanical forces and interactions that affect tumor progression, metastasis, and drug response. In this review article, we aim to summarize and contextualize the recent knowledge of components of the PDAC stroma, especially the role of different collagens and mechanical traits on tumor progression. We furthermore discuss different experimental models available for studying tumor-stromal interactions and finally discuss potential therapeutic targets within the stroma.
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Affiliation(s)
- Parniyan Maneshi
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - James Mason
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Mitesh Dongre
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Daniel Öhlund
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
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12
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Senavirathna L, Ma C, Chen R, Pan S. Proteomic Investigation of Glyceraldehyde-Derived Intracellular AGEs and Their Potential Influence on Pancreatic Ductal Cells. Cells 2021; 10:cells10051005. [PMID: 33923186 PMCID: PMC8145644 DOI: 10.3390/cells10051005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/14/2021] [Accepted: 04/23/2021] [Indexed: 02/07/2023] Open
Abstract
Glyceraldehyde-derived advanced glycation end products (AGEs) play an important role in the pathogenesis of many diseases including cancer. Accumulation of intracellular AGEs could stimulate cancer induction and facilitate cancer progression. We evaluated the toxic effect of glyceraldehyde-derived intracellular AGEs on normal and malignant pancreatic ductal cells by assessing the cell viability, toxicity, and oxidative stress, followed by proteomic analysis. Our functional studies showed that pancreatic cancer cells (PANC-1 and MIA PaCa-2) were more resistant to glyceraldehyde treatment compared to normal pancreatic ductal epithelial cells (HPDE), while cytotoxicity effects were observed in all cell types. Furthermore, using 13C isotopic labeled glyceraldehyde, the proteomic data revealed a dose-dependent increment of the number of glycation adducts in both these cell types. HPDE cells showed a higher number of intracellular AGEs compared to cancer cells. At a molecular level, the glycations in the lysine residues of proteins showed a concurrent increase with the concentration of the glyceraldehyde treatment, while the arginine glycations appeared to be less affected by the glyceraldehyde doses. Further pathway analysis of these glycated proteins suggested that the glycated proteins participate in important biological processes that are major hallmarks of cancer initiation and progression, including metabolic processes, immune response, oxidative stress, apoptosis, and S100 protein binding.
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Affiliation(s)
- Lakmini Senavirathna
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.S.); (C.M.)
| | - Cheng Ma
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.S.); (C.M.)
| | - Ru Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Sheng Pan
- The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.S.); (C.M.)
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Correspondence:
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13
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Koltai T, Reshkin SJ, Carvalho TMA, Cardone RA. Targeting the Stromal Pro-Tumoral Hyaluronan-CD44 Pathway in Pancreatic Cancer. Int J Mol Sci 2021; 22:3953. [PMID: 33921242 PMCID: PMC8069142 DOI: 10.3390/ijms22083953] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/01/2021] [Accepted: 04/08/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Present-day treatments have not shown real improvements in reducing the high mortality rate and the short survival of the disease. The average survival is less than 5% after 5 years. New innovative treatments are necessary to curtail the situation. The very dense pancreatic cancer stroma is a barrier that impedes the access of chemotherapeutic drugs and at the same time establishes a pro-proliferative symbiosis with the tumor, thus targeting the stroma has been suggested by many authors. No ideal drug or drug combination for this targeting has been found as yet. With this goal in mind, here we have explored a different complementary treatment based on abundant previous publications on repurposed drugs. The cell surface protein CD44 is the main receptor for hyaluronan binding. Many malignant tumors show over-expression/over-activity of both. This is particularly significant in pancreatic cancer. The independent inhibition of hyaluronan-producing cells, hyaluronan synthesis, and/or CD44 expression, has been found to decrease the tumor cell's proliferation, motility, invasion, and metastatic abilities. Targeting the hyaluronan-CD44 pathway seems to have been bypassed by conventional mainstream oncological practice. There are existing drugs that decrease the activity/expression of hyaluronan and CD44: 4-methylumbelliferone and bromelain respectively. Some drugs inhibit hyaluronan-producing cells such as pirfenidone. The association of these three drugs has never been tested either in the laboratory or in the clinical setting. We present a hypothesis, sustained by hard experimental evidence, suggesting that the simultaneous use of these nontoxic drugs can achieve synergistic or added effects in reducing invasion and metastatic potential, in PDAC. A non-toxic, low-cost scheme for inhibiting this pathway may offer an additional weapon for treating pancreatic cancer.
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Affiliation(s)
| | - Stephan Joel Reshkin
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (R.A.C.)
| | - Tiago M. A. Carvalho
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (R.A.C.)
| | - Rosa A. Cardone
- Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (T.M.A.C.); (R.A.C.)
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14
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Jin Y, Zhang Z, Zou S, Li F, Chen H, Peng C, Deng X, Wen C, Shen B, Zhan Q. A Novel c-MET-Targeting Antibody-Drug Conjugate for Pancreatic Cancer. Front Oncol 2021; 11:634881. [PMID: 33816276 PMCID: PMC8010262 DOI: 10.3389/fonc.2021.634881] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 02/22/2021] [Indexed: 12/20/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated death in the United States and has a 5-year survival rate of <4%. Although much effort has been invested in the research and development of pancreatic cancer drugs over the past 30 years, due to the lack of effective targetable carcinogenic drivers, no new targeted therapies that can improve patient prognosis have been approved for clinical use. SHR-A1403 is a new c-mesenchymal-epithelial transition factor (c-MET) antibody-drug conjugate that can be used for the targeted treatment of PDAC with high c-MET expression. This study reports for the first time the application prospects of SHR-A1403 in preclinical models of PDAC. SHR-A1403 significantly inhibited the proliferation, migration, and invasion of pancreatic cancer cells and induced cell cycle arrest and apoptosis. These changes were caused by inhibition of intracellular cholesterol biosynthesis by SHR-A1403. Therefore, targeting c-MET through SHR-A1403 showed strong preclinical anti-tumour efficacy in pancreatic cancer. Our work suggests the potential application of c-MET-targeted antibody-drug conjugate treatment for PDAC in clinical practise.
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Affiliation(s)
- Yangbing Jin
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zehui Zhang
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Siyi Zou
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fanlu Li
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Chen
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chenghong Peng
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaxing Deng
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chenlei Wen
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Baiyong Shen
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qian Zhan
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, China
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15
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Li C, Peng Z, Wang Y, Lam G, Nissen N, Tang J, Yuan X, Lewis M, Greene MI, Pandol SJ, Wang Q. Epithelial cell transforming 2 is regulated by Yes-associated protein 1 and mediates pancreatic cancer progression and metastasis. Am J Physiol Gastrointest Liver Physiol 2021; 320:G380-G395. [PMID: 33501895 PMCID: PMC8202240 DOI: 10.1152/ajpgi.00185.2020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and represents one of the deadliest forms of human cancers. Previous studies showed that activation of Yes-associated protein 1 (YAP1) plays a key role in malignant transformation in the pancreas. In this study, we found that YAP1 regulates the expression of epithelial cell transforming 2 (ECT2), a guanine nucleotide exchange factor for Rho-like GTPases. By immunohistochemistry analysis of human tissues, we show that ECT2 is highly expressed in primary PDAC and liver metastasis but not in normal pancreas. These correlations were also observed in a mouse model of PDAC, where pancreatic transformation is driven by mutants of Kras and Trp53. Notably, nuclear ECT2 is upregulated in the transition from preneoplastic lesions to PDAC. High levels of YAP1 or ECT2 expression correlates with the poor overall survival rate of patients with PDAC. We further demonstrate that ECT2 is required for pancreatic cancer cell proliferation and migration in vitro. Finally, using a syngeneic orthotopic xenograft mouse model for pancreatic cancer, we found that ablation of ECT2 expression reduces pancreatic cancer growth and dissemination to the liver. These findings highlight the critical role of ECT2 in promoting pancreatic cancer growth and metastasis and provides insights into the development of novel methods for early detection and treatment.NEW & NOTEWORTHY Pancreatic ductal adenocarcinoma is one of the deadliest forms of human cancers. In this study, we identified a novel signaling mechanism involved in PDAC progression and metastasis. Yes-associated protein 1 mediates the expression of epithelial cell transforming 2, which is elevated in PDAC and correlates with poor survival. Epithelial cell transforming 2 is required for PDAC growth and metastasis. This study provides insights into the development of novel methods for early detection and treatment of PDAC.
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Affiliation(s)
- Ce Li
- 1Department of Medical Oncology, First Hospital of China Medical University, Shenyang, China,2Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Zhenzi Peng
- 2Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California,3Central South University, Changsha, China
| | - Yizhou Wang
- 4Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Gloria Lam
- 2Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Nicholas Nissen
- 5Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Jie Tang
- 4Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
| | - Xiaopu Yuan
- 6Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Michael Lewis
- 7Department of Pathology, Veterans Affairs Greater Los Angeles Health Care System, Los Angeles, California
| | - Mark I. Greene
- 8Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Stephen J. Pandol
- 2Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Qiang Wang
- 2Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
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16
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Zhang Z, Song J, Xie C, Pan J, Lu W, Liu M. Pancreatic Cancer: Recent Progress of Drugs in Clinical Trials. AAPS JOURNAL 2021; 23:29. [PMID: 33580411 DOI: 10.1208/s12248-021-00556-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 01/06/2021] [Indexed: 12/18/2022]
Abstract
Pancreatic cancer is a highly malignant tumor and one of the primary causes of cancer-related death. Because pancreatic cancer is difficult to diagnose in the early course of the disease, most patients present with advanced lesions at the time of diagnosis, and only 20% of patients are eligible for surgery. Consequently, drug treatment has become extremely important. At present, the main treatment regimens for pancreatic cancer are gemcitabine and the FORFIRINOX and MPACT regimens. However, none of these regimens substantially improves the prognosis of patients with pancreatic cancer. Extensive efforts have been dedicated to the study of pancreatic cancer in recent years. With the development and clinical application of biological targeted drugs, the biological targeted treatment of tumors has been widely accepted. Therefore, this article used relevant clinical trial data to summarize the research progress of traditional chemotherapy drugs and biological targeted drugs for the treatment of pancreatic cancer.
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Affiliation(s)
- Zhiyi Zhang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People's Republic of China
| | - Jie Song
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People's Republic of China
| | - Cao Xie
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People's Republic of China
| | - Jun Pan
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People's Republic of China
| | - Weiyue Lu
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People's Republic of China
| | - Min Liu
- Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People's Republic of China.
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17
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Yamakawa K, Ye J, Nakano-Narusawa Y, Matsuda Y. Pathological Changes in Pancreatic Carcinogenesis: A Review. Cancers (Basel) 2021; 13:cancers13040686. [PMID: 33567676 PMCID: PMC7914468 DOI: 10.3390/cancers13040686] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 02/04/2021] [Accepted: 02/05/2021] [Indexed: 12/11/2022] Open
Abstract
Despite advances in diagnostics and therapeutics, the prognosis of pancreatic cancer remains dismal. Because of a lack of early diagnostic methods, aggressive local progression, and high incidence of distant metastasis, most pancreatic cancers are inoperable; therefore, the characteristics of early pancreatic cancer have not been well understood. Autopsy studies revealed the characteristics of prediagnostic pancreatic malignancies, including precancerous lesions, early stage pancreatic cancer, and pancreatic cancer without clinical symptoms (occult cancers). Animal models using hamsters and genetically engineered mice have focused on mechanisms of carcinogenesis, thereby providing insights into risk factors and prevention and serving as a preclinical test for the development of novel diagnostic and treatment modalities. In this review, we have summarized pathological changes in the pancreas of humans and experimental animals during carcinogenesis.
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Affiliation(s)
| | | | | | - Yoko Matsuda
- Correspondence: ; Tel.: +81-87-891-2109; Fax: +81-87-891-2112
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18
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Abstract
PURPOSE Pancreatic cancer is the seventh cause of death in men in the world and also is one of the most common malignancies worldwide with poor prognosis. Due to the lack of epidemiological aspects of pancreatic cancer in Iran, this study aimed to investigate the epidemiological aspects of pancreatic cancer in Iran. METHODS In February 2019, A search was conducted with the keywords "Pancreatic Neoplasm," "Pancreas Neoplasms," "Cancer of Pancreas," "Pancreas Cancer," "Pancreatic Cancer," "Cancer of the Pancreas," and "Iran" in their title or abstract and MeSH. The databases of Medline, Web of Science, Scopus, SID, IranMedex, and Google Scholar were searched. The title and abstract of the papers were reviewed, and articles that addressed the epidemiological aspects of pancreatic cancer were included; in total, 20 full papers were reviewed. RESULTS According to studies, the incidence and mortality rate of pancreatic cancer is steadily increasing with age. Actually, men are more likely to develop this carcinoma than women. Smoking, aging, and lifestyle changes are the most important risk factors for pancreatic cancer in Iran. Due to the lack of initial symptoms or a specific marker for early diagnosis of pancreatic cancer, this cancer is detected lately and therefore low survival rate is observed. CONCLUSION Mortality and incidence of pancreatic cancer is increasing in Iran. Pancreatic cancer is more common in men than women. Based on the results of this study, pancreatic cancer depends largely on the lifestyle. Survival of pancreatic cancer is low in untreated patients.
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Affiliation(s)
| | - Hamid Salehiniya
- Social Determinants of Health Research Center, Birjand University of Medical Sciences, Birjand, Iran.
- Department of Epidemiology and Biostatistics, Tehran University of medical sciences, Tehran, Iran.
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19
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Principe DR, Rana A. Updated risk factors to inform early pancreatic cancer screening and identify high risk patients. Cancer Lett 2020; 485:56-65. [PMID: 32389710 DOI: 10.1016/j.canlet.2020.04.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/06/2020] [Accepted: 04/23/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic adenocarcinoma (PDAC) is associated with poor clinical outcomes and incomplete responses to conventional therapy. Therefore, there is an unmet clinical need to better understand the predisposing factors for pancreatic cancer in hopes of providing early screening to high-risk patients. While select risk factors such as age, race, and family history, or predisposing syndromes are unavoidable, there are several new and established risk factors that allow for intervention, namely by counseling patients to make the appropriate lifestyle modifications. Here, we discuss the best-studied risk factors for PDAC such as tobacco use and chronic pancreatitis, as well as newly emerging risk factors including select nutritional deficits, bacterial infections, and psychosocial factors. As several of these risk factors appear to be additive or synergistic, by understanding their relationships and offering coordinated, multidisciplinary care to high-risk patients, it may be possible to reduce pancreatic cancer incidence and improve clinical outcomes through early detection.
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Affiliation(s)
- Daniel R Principe
- Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL, USA; Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, USA.
| | - Ajay Rana
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown VA Medical Center, Chicago, IL, USA.
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20
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Pothula SP, Pirola RC, Wilson JS, Apte MV. Pancreatic stellate cells: Aiding and abetting pancreatic cancer progression. Pancreatology 2020; 20:409-418. [PMID: 31928917 DOI: 10.1016/j.pan.2020.01.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 12/09/2019] [Accepted: 01/06/2020] [Indexed: 12/11/2022]
Abstract
Tumour-stromal interactions have now been acknowledged to play a major role in pancreatic cancer (PC) progression. The abundant collagenous stroma is produced by a specific cell type in the pancreas-the pancreatic stellate cell (PSC). Pancreatic stellate cells (PSCs) are a unique resident cell type of pancreas and with a critical role in both healthy and diseased pancreas. Accumulating evidence indicates that PSCs interact closely with cancer cells as well as with other cell types of the stroma such as immune cells, endothelial cells and neuronal cells, to set up a growth permissive microenvironment for pancreatic tumours, which facilitates local tumour growth as well as distant metastasis. Consequently, recent work in the field has focused on the development of novel therapeutic approaches targeting the stroma to inhibit PC progression. Such a multi-pronged approach targeting both tumour and stromal elements of PC has been successfully applied in pre-clinical settings. The challenge now is to translate the pre-clinical findings into the clinical setting to achieve better outcomes for pancreatic cancer patients.
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Affiliation(s)
- Srinivasa P Pothula
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, and the Ingham Institute for Applied Medical Research, Liverpool, Australia
| | - Romano C Pirola
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, and the Ingham Institute for Applied Medical Research, Liverpool, Australia
| | - Jeremy S Wilson
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, and the Ingham Institute for Applied Medical Research, Liverpool, Australia
| | - Minoti V Apte
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, The University of New South Wales, Sydney, and the Ingham Institute for Applied Medical Research, Liverpool, Australia.
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21
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Powell-Brett S, de Liguori Carino N, Roberts K. Understanding pancreatic exocrine insufficiency and replacement therapy in pancreatic cancer. Eur J Surg Oncol 2020; 47:539-544. [PMID: 32178962 DOI: 10.1016/j.ejso.2020.03.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 03/06/2020] [Indexed: 02/08/2023] Open
Abstract
Pancreatic exocrine insufficiency (PEI) is highly prevalent in patients with pancreatic cancer, and has substantial implications for quality of life and survival. Post resection, PEI is associated with increased post-operative complications, longer hospital stays and higher costs. Treatment with pancreatic enzyme replacement therapy (PERT) improves quality of life and confers significant survival advantages. Despite this many patients with pancreatic cancer do not currently receive PERT. The nutritional consequences of PEI are extensive and even more relevant in the elderly owing to age related gastrointestinal tract and pancreatic changes that predispose to malnutrition.
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Affiliation(s)
- S Powell-Brett
- Department of Hepatopancreatobiliary Surgery and Liver Transplantation, University Hospital Birmingham, Birmingham, UK.
| | - N de Liguori Carino
- Department of Hepatobiliary and Pancreatic Surgery, Manchester Royal Infirmary, Manchester University Hospitals Foundation Trust, UK
| | - K Roberts
- Department of Hepatopancreatobiliary Surgery and Liver Transplantation, University Hospital Birmingham, Birmingham, UK
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22
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Low Incidence of High-Grade Pancreatic Intraepithelial Neoplasia Lesions in a Crmp4 Gene-Deficient Mouse Model of Pancreatic Cancer. Transl Oncol 2020; 13:100746. [PMID: 32105991 PMCID: PMC7044544 DOI: 10.1016/j.tranon.2020.100746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 01/30/2020] [Accepted: 01/30/2020] [Indexed: 12/24/2022] Open
Abstract
Pancreatic intraepithelial neoplasia (PanIN), the most common premalignant lesion of the pancreas, is a histologically well-defined precursor to invasive pancreatic ductal adenocarcinoma (PDAC). However, the molecular mechanisms underlying the progression of PanINs have not been fully elucidated. Previously, we demonstrated that the expression of collapsin response mediator protein 4 (CRMP4) in PDAC was associated with poor prognosis. The expression of CRMP4 was also augmented in a pancreatitis mouse model. However, the role of CRMP4 in the progression of PanIN lesions remains uncertain. In the present study, we examined the relationship between CRMP4 expression and progression of PanIN lesions using genetically engineered mouse models. PanIN lesions were induced by peritoneal injection of the cholecystokinin analog caerulein in LSL-KRASG12D; Pdx1-Cre (KC-Crmp4 wild-type, WT) mice and LSL-KRASG12D; Pdx1-Cre; Crmp4−/− (KC-Crmp4 knockout, KO) mice. We analyzed pancreatic tissue sections from these mice and evaluated PanIN grade by hematoxylin and eosin staining. CRMP4 expression was examined and the cellular components assessed by immunohistochemistry using antibodies against CRMP4, CD3, and α-smooth muscle actin (SMA). The incidence of high-grade PanIN in KC-Crmp4 WT mice was higher than that in KC-Crmp4 KO animals. CRMP4 was expressed not only in epithelial cells but also in αSMA-positive cells in stromal areas of PanIN lesions. The CRMP4 expression in stromal areas correlated with PanIN grade in WT mice. These results suggested that the expression of CRMP4 in stromal cells may underlie the incidence or progression of PanIN.
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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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Abstract
Despite extensive research in the pathogenesis, early detection, and therapeutic approaches of pancreatic ductal adenocarcinoma (PDAC), it remains a devastating and incurable disease. As the global incidence and prevalence of PDAC continue to rise, there is a pressing need to place strong emphasis on its prevention. Although it is widely recognized that cigarette smoking, a potentially modifiable risk factor, has been linked to PDAC development, its contribution to prognosis is still uncertain. Moreover, the mechanistic pathways of PDAC progression secondary to smoking are various and lack a summative narration. Herein, we update and summarize the direct and indirect roles cigarette smoking plays on PDAC development, review literature to conclude the impact cigarette smoking has on prognosis, and postulate a comprehensive mechanism for cigarette smoking-induced PDAC.
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Correlation between mouse age and human age in anti-tumor research: Significance and method establishment. Life Sci 2019; 242:117242. [PMID: 31891723 DOI: 10.1016/j.lfs.2019.117242] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 12/22/2019] [Accepted: 12/27/2019] [Indexed: 12/24/2022]
Abstract
Age is closely related with the occurrence and development of tumors, and with treatment outcomes. To improve the accuracy and rigor of preclinical studies, and to enhance consistency between the preclinical research and the clinical reality, the age of experimental animals used in preclinical studies is important. The mouse genome is 99% identical to the human genome, and mice have similar patterns with respect to organs and systemic physiology. Thus, mice have been the most widely used animals in anti-tumor research. However, most mice used in such studies are 6 to 8 weeks old, ignoring the fact that different tumors may often occur in various periods, with a particular tendency to occur in later stages of life. The great difference in age limits the success rate of clinical transformation. Therefore, it is very important to choose mice of suitable age for preclinical studies and to correlate ages of human and mice. Only a few related studies have been reported and there is a lack of consistency in the findings. This review points out that age is one of the important factors in anti-tumor research, and establishes a new method for calculating the age correlation between humans and mice. The equations obtained from the method can help researchers conveniently determine suitable aged mouse for their research, which will improve the rigor of their experimental results. Furthermore, this method can be used beyond anti-tumor research, in studies on other diseases that use mouse as an animal model.
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Kobia F, Gitaka J, Makokha F, Kamita M, Kibera J, Mwenda C, Mucee G, Kilingo B. The state of cancer in Meru, Kenya: a retrospective study. AAS Open Res 2019. [DOI: 10.12688/aasopenres.13027.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: It is projected that by 2030, 70% of all cancer related deaths will occur in low-middle income countries. However, data on the state of cancer in most African countries is scanty. Cancer estimates for Kenya are based on the Nairobi and Eldoret cancer registries, leaving most parts of the country unrepresented. Lacking national coverage, these data do not accurately reflect Kenya’s cancer burden. The paucity of reliable data impedes formulation of effective cancer control strategies and cancer research prioritization. Here, we report the findings of a retrospective study of the cancer state in Meru County, Kenya. Methods: A retrospective analysis of patient files at Meru hospice was carried out. 2349 cancer cases seen at the Meru hospice between 2003 and 2018 were analyzed. Data abstracted from the records included patient age, gender and cancer type. The abstracted data was analyzed by descriptive statistics. Results: Our results indicate that cancer is almost evenly distributed across genders, with men accounting for 49% and women 51%. Stomach cancer rates are strikingly elevated and equal to those in countries with the highest stomach cancer rates globally – making it the commonest cancer in this region (14%). Among men, the most common cancers affect the prostate (18%), stomach (17%), esophagus (14%), head & neck (12%), liver (8%) and colorectum (5%). Among women, the commonest are cancers of the breast (22%), cervix (20%), stomach (11%), esophagus (8%), head & neck (6%) and liver (5%). Breast cancer occurs at a notably early age, with 20% of those affected aged below 40. Lung cancer rates are notably low in this region (1.3%) relative to world estimates. Conclusion: Cancer distribution in Meru is nearly even between sexes. Our analysis suggests that the Meru region is a stomach cancer hotspot and that it also experiences elevated esophageal cancer levels.
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Hu C, Yang J, Su HY, Waldron RT, Zhi M, Li L, Xia Q, Pandol SJ, Lugea A. Yes-Associated Protein 1 Plays Major Roles in Pancreatic Stellate Cell Activation and Fibroinflammatory Responses. Front Physiol 2019; 10:1467. [PMID: 31849712 PMCID: PMC6901825 DOI: 10.3389/fphys.2019.01467] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 11/14/2019] [Indexed: 02/05/2023] Open
Abstract
Background: Yes-associated protein 1 (YAP), a transcriptional co-activator and major effector of the Hippo pathway, regulates cell differentiation and morphology in many cell types and supports aberrant tumor growth. Recent studies showed that YAP is expressed in pancreas tissues in pancreatic ductal adenocarcinoma (PDAC) patients and experimental models of PDAC, with YAP largely found in cancer cells and pancreatic stellate cells (PaSC) in the stroma. Methods and Results: We studied here the role of YAP in the activated phenotype of PaSC. We found that YAP is expressed at low levels in normal mouse pancreas, but protein levels significantly increased after pancreas inflammatory damage induced by repeated cerulein administration in wild-type mice or upon initiation of neoplastic transformation of the pancreas parenchyma in Ptf1-Cre;LSL-KrasG12D/+ (KC) mice. In these animal models, YAP upregulation occurred in parallel with activation and proliferation of PaSC. Consistent with these findings, we found robust YAP expression in culture-activated mouse and human PaSC but not in quiescent, freshly isolated cells. Fully activated PaSC isolated from KC mice or PDAC patient tissues exhibited robust nuclear YAP suggesting YAP transcriptional activity. Agents that induce quiescence such as the Bromodomain and Extra-Terminal (BET) inhibitor iBET151 and the p38 MAPK inhibitor SB203580 reduced YAP levels in PaSC. Stimulation of PaSC with the potent mitogen PDGF elicited marked YAP Ser127 phosphorylation. However, unexpectedly, this effect did not diminish YAP nuclear localization, suggesting that YAP phosphorylation at this site does not govern YAP cellular localization in PaSC. siRNA-mediated knockdown of YAP reduced PDGF-induced PaSC expansion in culture and blunted the persistent activation of Akt and ERK elicited by PDGF stimulation, supporting a role for YAP in PDGF-induced cell growth. YAP knockdown also blunted fibroinflammatory gene expression responses both in unstimulated and transforming growth factor beta 1 (TGFβ1)-stimulated PaSC. Conclusion: Our data suggest a central role for YAP in sustaining the activated phenotype and fibroinflammatory responses in PaSC. Moreover, our findings indicate that a complex crosstalk between YAP, TGFβ1, and PDGF pathways regulates PaSC activity and growth.
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Affiliation(s)
- Cheng Hu
- Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Jiayue Yang
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Endocrinology, Zhongda Hospital Southeast University, Nanjing, China
| | - Hsin-Yuan Su
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Richard T. Waldron
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Mengmeng Zhi
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Endocrinology, Zhongda Hospital Southeast University, Nanjing, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital Southeast University, Nanjing, China
| | - Qing Xia
- Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China
| | - Stephen J. Pandol
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Aurelia Lugea
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
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Matsuda Y. Age-related morphological changes in the pancreas and their association with pancreatic carcinogenesis. Pathol Int 2019; 69:450-462. [PMID: 31339204 DOI: 10.1111/pin.12837] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 06/26/2019] [Indexed: 12/14/2022]
Abstract
Age-related pathological changes in the pancreas have been unclear because they are often minor and nonspecific. However, recent studies have shown that they are closely related to various pathological conditions such as pancreatic cancer and diabetes mellitus. Knowledge of age-related changes is important to determine appropriate prevention, detection, and treatment strategies for various diseases observed in elderly patients. We present a review of the pathological age-related non-neoplastic changes in the exocrine pancreas such as pancreatic fatty replacement, lobulocentric pancreatic atrophy, pancreatic duct ectasia, and metaplasia of exocrine pancreas, as well as changes in islet cells. We have discussed common pancreatic neoplasms in elderly patients, such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMNs), and pancreatic ductal adenocarcinoma (PDAC). Age-related pathological changes play a key role in pancreatic carcinogenesis via telomere dysfunction. Further studies are warranted to clarify molecular mechanisms of pancreatic carcinogenesis in elderly patients.
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Affiliation(s)
- Yoko Matsuda
- Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kagawa, Japan
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da Cruz RS, Clarke J, Curi ACP, Al-Yawar A, Jin L, Baird A, Cruz MI, Kallakury B, de Assis S. Parental obesity programs pancreatic cancer development in offspring. Endocr Relat Cancer 2019; 26:511-523. [PMID: 30865925 PMCID: PMC6717698 DOI: 10.1530/erc-19-0016] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 03/13/2019] [Indexed: 12/12/2022]
Abstract
Epidemiological studies suggest that timing of obesity onset - and underlying metabolic dysfunction - is important in determining pancreatic cancer rates: early and young adult abdominal overweight/obesity is more strongly associated with this cancer than obesity that develops later in life. Parental obesity and overweight are associated with metabolic dysfunction and obesity in their children. Here, we evaluated the impact of parental overweight on offspring's susceptibility of pancreatic cancer using the P48Cre/+/KrasG12D/+ mouse model. Male mice were fed an obesity-inducing diet (OID) before conception and mated with females raised on a control diet (CO) to generate the offspring. In a separate experiment, pregnant dams were fed CO or OID throughout gestation. The resulting OID offspring from the maternal (OID-m) or paternal lineage (OID-p) were used to study body weight, metabolic parameters and pancreatic cancer development and for molecular analysis. Parental obesity increased offspring's body weight at birth, weaning and in adulthood compared to CO, with gender- and genotype-specific differences. OID-p and OID-m offspring showed metabolic disorder and accelerated development of high-grade PanIN/PDAC. OID offspring also had higher rates of acinar-to-ductal reprogramming assessed by CPA1+/SOX9+-positive pancreatic cells. Levels of Tenascin C (TNC), an ECM glycoprotein shown to suppress apoptosis, were elevated in OID offspring, particularly females. In line with that, OID offspring displayed increased collagen content and decreased apoptosis in pancreatic lesions compared to CO. An ancestral history of obesity through either the paternal or maternal lineages increases offspring's susceptibility to pancreatic cancer development.
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Matsuda Y, Tanaka M, Sawabe M, Mori S, Muramatsu M, Mieno MN, Ishiwata T, Arai T. The stem cell-specific intermediate filament nestin missense variation p.A1199P is associated with pancreatic cancer. Oncol Lett 2019; 17:4647-4654. [PMID: 30988821 DOI: 10.3892/ol.2019.10106] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 02/21/2019] [Indexed: 11/06/2022] Open
Abstract
The intermediate filament nestin is upregulated in stem/progenitor cells and cancers, and regulates cell proliferation, migration, invasion and stemness. The present study comparatively analyzed serial autopsies of Japanese patients (n=2,206; males, 1,225; females, 981; median, 80.7 years old; range, 33-104 years old) with malignant tumors of whole organs, with respect to the clinical information, and 5 single nucleotide polymorphisms of the nestin gene. p.A1199P associated with pancreatic cancer (odds ratio, 4.4; 95% confidence interval, 1.9-10.0, P=0.001) while it did not associate with malignant neoplasms in other organs. p.A1199P did not associate with precancerous lesions of the pancreas. Single nucleotide polymorphisms of nestin were not associated with sex, drinking, smoking, or body weight. In conclusion, the amino acid 1,199 of nestin is localized in the tail structure of the filament and polymerizes with other intermediate filament proteins. The present results suggest that missense variations of nestin affect pancreatic carcinogenesis in Japanese patients.
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Affiliation(s)
- Yoko Matsuda
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan
| | - Masashi Tanaka
- Department of Genomics for Longevity and Health, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan
| | - Motoji Sawabe
- Department of Molecular Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
| | - Seijiro Mori
- Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan
| | - Masaaki Muramatsu
- Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
| | - Makiko Naka Mieno
- Department of Medical Informatics, Center for Information, Jichi Medical University, Tochigi 329-0498, Japan
| | - Toshiyuki Ishiwata
- Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan
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Eissa MAL, Lerner L, Abdelfatah E, Shankar N, Canner JK, Hasan NM, Yaghoobi V, Huang B, Kerner Z, Takaesu F, Wolfgang C, Kwak R, Ruiz M, Tam M, Pisanic TR, Iacobuzio-Donahue CA, Hruban RH, He J, Wang TH, Wood LD, Sharma A, Ahuja N. Promoter methylation of ADAMTS1 and BNC1 as potential biomarkers for early detection of pancreatic cancer in blood. Clin Epigenetics 2019; 11:59. [PMID: 30953539 PMCID: PMC6451253 DOI: 10.1186/s13148-019-0650-0] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 03/10/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Despite improvements in cancer management, most pancreatic cancers are still diagnosed at an advanced stage. We have recently identified promoter DNA methylation of the genes ADAMTS1 and BNC1 as potential blood biomarkers of pancreas cancer. In this study, we validate this biomarker panel in peripheral cell-free tumor DNA of patients with pancreatic cancer. RESULTS Sensitivity and specificity for each gene are as follows: ADAMTS1 87.2% and 95.8% (AUC = 0.91; 95% CI 0.71-0.86) and BNC1 64.1% and 93.7% (AUC = 0.79; 95% CI 0.63-0.78). When using methylation of either gene as a combination panel, sensitivity increases to 97.3% and specificity to 91.6% (AUC = 0.95; 95% CI 0.77-0.90). Adding pre-operative CA 19-9 values to the combined two-gene methylation panel did not improve sensitivity. Methylation of ADAMTS1 was found to be positive in 87.5% (7/8) of stage I, 77.8% (7/9) of stage IIA, and 90% (18/20) of stage IIB disease. Similarly, BNC1 was positive in 62.5% (5/8) of stage I patients, 55.6% (5/9) of stage IIA, and 65% (13/20) of patients with stage IIB disease. The two-gene panel (ADAMTS1 and/or BNC1) was positive in 100% (8/8) of stage I, 88.9% (8/9) of stage IIA, and 100% (20/20) of stage IIB disease. The sensitivity and specificity of the two-gene panel for localized pancreatic cancer (stages I and II), where the cancer is eligible for surgical resection with curative potential, was 94.8% and 91.6% respectively. Additionally, the two-gene panel exhibited an AUC of 0.95 (95% CI 0.90-0.98) compared to 57.1% for CA 19-9 alone. CONCLUSION The methylation status of ADAMTS1 and BNC1 in cfDNA shows promise for detecting pancreatic cancer during the early stages when curative resection of the tumor is still possible. This minimally invasive blood-based biomarker panel could be used as a promising tool for diagnosis and screening in a select subset of high-risk populations.
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Affiliation(s)
- Maryam A L Eissa
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lane Lerner
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Eihab Abdelfatah
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nakul Shankar
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Joseph K Canner
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nesrin M Hasan
- Department of Surgery, Yale-New Haven Health, Yale University, School of Medicine, P.O. Box 208062, New Haven, CT, 06520-8062, USA
| | - Vesal Yaghoobi
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Barry Huang
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Zachary Kerner
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Felipe Takaesu
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Christopher Wolfgang
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ruby Kwak
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael Ruiz
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Matthew Tam
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Thomas R Pisanic
- Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, USA
| | - Christine A Iacobuzio-Donahue
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.,Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ralph H Hruban
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.,The Sol Goldman Pancreatic Cancer Research Center, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Jin He
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Tza-Huei Wang
- Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, USA
| | - Laura D Wood
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.,The Sol Goldman Pancreatic Cancer Research Center, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Anup Sharma
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Surgery, Yale-New Haven Health, Yale University, School of Medicine, P.O. Box 208062, New Haven, CT, 06520-8062, USA
| | - Nita Ahuja
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. .,Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. .,The Sol Goldman Pancreatic Cancer Research Center, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD, USA. .,Department of Surgery, Yale-New Haven Health, Yale University, School of Medicine, P.O. Box 208062, New Haven, CT, 06520-8062, USA.
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Gordon-Dseagu VL, Devesa SS, Goggins M, Stolzenberg-Solomon R. Pancreatic cancer incidence trends: evidence from the Surveillance, Epidemiology and End Results (SEER) population-based data. Int J Epidemiol 2019; 47:427-439. [PMID: 29149259 DOI: 10.1093/ije/dyx232] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2017] [Indexed: 12/14/2022] Open
Abstract
Background Annual pancreatic cancer incidence rates have been increasing. We examine pancreatic cancer incidence trends by demographics and histologic type. Methods Data from the Surveillance, Epidemiology and End Results (SEER) registries were available to assess temporal trends and pancreatic cancer rates from 1974 to 2013. Results Pancreatic cancer incidence rates declined between the 1970s and 1990s but increased from 1994 to 2013 among White males. Among non-Hispanic White and Hispanic males, the annual percent change (APC) in incidence between 1992 and 2013 was 0.84% and 0.73%, respectively. Rates also rose among White non-Hispanic, Hispanic and Asian females (APC = 0.81%, 0.56% and 1.23%, respectively) and even more rapidly among females aged 25-34 years (APC > 2.5%). Rates among Black males and females remained unchanged, but higher compared with the other racial/ethnic groups. By histologic type, the increases were greatest for non-secretory endocrine cancers ( > 6%), followed by ductal adenocarcinomas (∼5%) and adenocarcinoma, NOS (∼1.4%)-the largest histologic subgroup of pancreatic cancer. Rates for mucinous adenocarcinomas and poorly specified pancreatic cancer decreased. Overall, incidence rates during 2000-13 were higher among males than females [MF incidence rate ratio (IRR) = 1.28]. The IRR was >1.00 at all ages ≥ 35, but rates among females were higher at younger ages (IRRs 15-24: 0.66, 25-34: 0.81). The MF IRRs for most of the histologic types were elevated among males apart from solid pseudopapillary adenocarcinoma and cystic carcinomas (IRR = 0.22, confidence interval: 0.14-0.34 and 0.52, 0.41-0.65, respectively). Conclusion Pancreatic cancer has been increasing overall, but patterns differ by demographic group and histologic type. Many of the trends parallel changing prevalence of lifestyle risk factors such as smoking, overweight and obesity, and diabetes in the USA, particularly for pancreatic adenocarcinoma, and improved diagnosis methods during the past 40 years.
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Affiliation(s)
- Vanessa L Gordon-Dseagu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20850, USA
| | - Susan S Devesa
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20850, USA
| | | | - Rachael Stolzenberg-Solomon
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20850, USA
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Abstract
Primary cultures of pancreatic stellate cells (PSCs) remain an important basis for in vitro study. However, effective methods for isolating abundant PSCs are currently lacking. This purpose of this chapter is to report our novel approach to isolating PSCs from normal rat pancreas and human pancreatic ductal adenocarcinoma (PDAC) tissue. Normal PSCs were isolated with enzyme digestion and ladder centrifugation with Nycodenz solution. Isolated PSCs were cultured in DMEM/F12 containing 10% fetal bovine serum. Cancer-associated PSCs were obtained by an outgrow method from fresh human PDAC tissues. Isolated activated PSCs were cultured in DMEM/F12 containing 20% fetal bovine serum. With our modification, normal pancreas tissue yields an adequate number of PSCs (approximately 0.5-5 million/g pancreas) for in vitro studies, and the cell viability was about 90%. And a modified outgrowth method made tissue blocks attached more tightly and significantly shortened the outgrowth time of the activated cells. Our modification in PSC isolation methods significantly increased the isolation efficiency and shortened the culture period, thus facilitating future PSC-related research.
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Exploring the insulin secretory properties of the PGD2-GPR44/DP2 axis in vitro and in a randomized phase-1 trial of type 2 diabetes patients. PLoS One 2018; 13:e0208998. [PMID: 30557325 PMCID: PMC6296667 DOI: 10.1371/journal.pone.0208998] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 10/08/2018] [Indexed: 12/27/2022] Open
Abstract
Aims/Hypothesis GPR44 (DP2, PTGDR2, CRTh2) is the receptor for the pro-inflammatory mediator prostaglandin D2 (PGD2) and it is enriched in human islets. In rodent islets, PGD2 is produced in response to glucose, suggesting that the PGD2-GPR44/DP2 axis may play a role in human islet function during hyperglycemia. Consequently, the aim of this work was to elucidate the insulinotropic role of GPR44 antagonism in vitro in human beta-cells and in type 2 diabetes (T2DM) patients. Methods We determined the drive on PGD2 secretion by glucose and IL-1beta, as well as, the impact on insulin secretion by pharmacological GPR44/DP2 antagonism (AZD1981) in human islets and beta-cells in vitro. To test if metabolic control would be improved by antagonizing a hyperglycemia-driven increased PGD2 tone, we performed a proof-of-mechanism study in 20 T2DM patients (average 54 years, HbA1c 9.4%, BMI 31.6 kg/m2). The randomized, double-blind, placebo-controlled cross-over study consisted of two three-day treatment periods (AZD1981 or placebo) separated by a three-day wash-out period. Mixed meal tolerance test (MMTT) and intravenous graded glucose infusion (GGI) was performed at start and end of each treatment period. Assessment of AZD1981 pharmacokinetics, glucose, insulin, C-peptide, glucagon, GLP-1, and PGD2 pathway biomarkers were performed. Results We found (1) that PGD2 is produced in human islet in response to high glucose or IL-1beta, but likely by stellate cells rather than endocrine cells; (2) that PGD2 suppresses both glucose and GLP-1 induced insulin secretion in vitro; and (3) that the GPR44/DP2 antagonist (AZD1981) in human beta-cells normalizes insulin secretion. However, AZD1981 had no impact on neither glucose nor incretin dependent insulin secretion in humans (GGI AUC C-peptide 1-2h and MMTT AUC Glucose 0-4h LS mean ratios vs placebo of 0.94 (80% CI of 0.90–0.98, p = 0.12) and 0.99 (90% CI of 0.94–1.05, p = 0.45), despite reaching the expected antagonist exposure. Conclusion/Interpretation Pharmacological inhibition of the PGD2-GPR44/DP2 axis has no major impact on the modulation of acute insulin secretion in T2DM patients. Trial registration ClinicalTrials.gov NCT02367066.
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Wang JL, Quan Q, Ji R, Guo XY, Zhang JM, Li X, Liu YG. Isorhamnetin suppresses PANC-1 pancreatic cancer cell proliferation through S phase arrest. Biomed Pharmacother 2018; 108:925-933. [PMID: 30372904 DOI: 10.1016/j.biopha.2018.09.105] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 09/03/2018] [Accepted: 09/18/2018] [Indexed: 02/07/2023] Open
Abstract
Isorhamnetin, a flavonoid ingredient derived from Vernonia anthelmintica (L.) Willd., has shown a spectrum of antitumor activity. However, the chemopreventive potential of isorhamnetin on advanced pancreatic cancer and the underlying molecular mechanism remain unknown. In the current study, treatment of the advanced pancreatic adenocarcinoma cell line PANC-1 with isorhamnetin resulted in robust cell growth arrest. PI-annexin V double staining and Hoechst 33258 staining revealed that isorhamnetin moderately induced early apoptosis without morphological alterations of nuclei. Instead, isorhamnetin caused cell cycle S-phase arrest through downregulation of cyclin A. In addition, isorhamnetin decreased the phosphorylation levels of MEK and ERK in the Ras/MAPK pathway, which is involved in regulating cell proliferation, differentiation and apoptosis. Wound-healing experiments demonstrated isorhamnetin significantly reduced the migratory behavior of PANC-1 cells. Altogether, the present study suggests that isorhamnetin may be a potential agent for prevention of pancreatic carcinoma.
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Affiliation(s)
- Jia-Li Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Qinghua Quan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Ruifang Ji
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xiao-Yu Guo
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Jia-Mei Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xia Li
- Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
| | - Yong-Gang Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.
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Hsieh MH, Sun LM, Lin CL, Hsieh MJ, Hsu CY, Kao CH. Development of a prediction model for pancreatic cancer in patients with type 2 diabetes using logistic regression and artificial neural network models. Cancer Manag Res 2018; 10:6317-6324. [PMID: 30568493 PMCID: PMC6267763 DOI: 10.2147/cmar.s180791] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Objectives Patients with type 2 diabetes (T2DM) are suggested to have a higher risk of developing pancreatic cancer. We used two models to predict pancreatic cancer risk among patients with T2DM. Methods The original data used for this investigation were retrieved from the National Health Insurance Research Database of Taiwan. The prediction models included the available possible risk factors for pancreatic cancer. The data were split into training and test sets: 97.5% of the data were used as the training set and 2.5% of the data were used as the test set. Logistic regression (LR) and artificial neural network (ANN) models were implemented using Python (Version 3.7.0). The F1, precision, and recall were compared between the LR and the ANN models. The areas under the receiver operating characteristic (ROC) curves of the prediction models were also compared. Results The metrics used in this study indicated that the LR model more accurately predicted pancreatic cancer than the ANN model. For the LR model, the area under the ROC curve in the prediction of pancreatic cancer was 0.727, indicating a good fit. Conclusion Using this LR model, our results suggested that we could appropriately predict pancreatic cancer risk in patients with T2DM in Taiwan.
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Affiliation(s)
- Meng Hsuen Hsieh
- Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, USA
| | - Li-Min Sun
- Department of Radiation Oncology, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan, Republic of China
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan, Republic of China.,College of Medicine, China Medical University, Taichung, Taiwan, Republic of China
| | - Meng-Ju Hsieh
- Department of Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Chung-Y Hsu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, Republic of China,
| | - Chia-Hung Kao
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, Republic of China, .,Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan, Republic of China, .,Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan, Republic of China,
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Wang HC, Hung WC, Chen LT, Pan MR. From Friend to Enemy: Dissecting the Functional Alteration of Immunoregulatory Components during Pancreatic Tumorigenesis. Int J Mol Sci 2018; 19:E3584. [PMID: 30428588 PMCID: PMC6274888 DOI: 10.3390/ijms19113584] [Citation(s) in RCA: 6] [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: 10/17/2018] [Revised: 11/09/2018] [Accepted: 11/11/2018] [Indexed: 12/21/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of approximately 8%. More than 80% of patients are diagnosed at an unresectable stage due to metastases or local extension. Immune system reactivation in patients by immunotherapy may eliminate tumor cells and is a new strategy for cancer treatment. The anti-CTLA-4 antibody ipilimumab and anti-PD-1 antibodies pembrolizumab and nivolumab have been approved for cancer therapy in different countries. However, the results of immunotherapy on PDAC are unsatisfactory. The low response rate may be due to poor immunogenicity with low tumor mutational burden in pancreatic cancer cells and desmoplasia that prevents the accumulation of immune cells in tumors. The immunosuppressive tumor microenvironment in PDAC is important in tumor progression and treatment resistance. Switching from an immune tolerance to immune activation status is crucial to overcome the inability of self-defense in cancer. Therefore, thoroughly elucidation of the roles of various immune-related factors, tumor microenvironment, and tumor cells in the development of PDAC may provide appropriate direction to target inflammatory pathway activation as a new therapeutic strategy for preventing and treating this cancer.
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Affiliation(s)
- Hui-Ching Wang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Wen-Chun Hung
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
- Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan.
| | - Mei-Ren Pan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
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Liang XH, Yan D, Zhao JX, Ding W, Xu XJ, Wang XY. Interaction of polymorphisms in xeroderma pigmentosum group C with cigarette smoking and pancreatic cancer risk. Oncol Lett 2018; 16:5631-5638. [PMID: 30344718 PMCID: PMC6176251 DOI: 10.3892/ol.2018.9350] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 06/08/2018] [Indexed: 12/18/2022] Open
Abstract
The aim of the present study was to evaluate the association between xeroderma pigmentosum group C (XPC) polymorphisms and pancreatic cancer (PC) risk. A total of 7 XPC tagging SNPs (tag-SNPs) were selected from the International HapMap Project Databases (rs2228001A/C, rs2470353G/C, rs2228000C/T, rs3731114C/G, rs3729587G/C, rs2607775C/G and rs3731055G/A) and were genotyped in 205 patients with PC and 230 non-cancer control subjects using a SNaPshot assay. The C allelic gene frequency of rs2470353 was higher in patients with PC compared with that in the control group (P=0.003). Compared with the GG gene type, PC risk was increased in subjects with GC and GC+CC gene types (P=0.012 and P=0.006, respectively). PC risk increased 3.505-fold for the subjects who were heavy smokers (tobacco, ≥25 packets/year) with the GC+CC gene type (P=0.008). The G allelic gene frequency of rs2607775 was higher in PC patients compared with that in the control group (P=0.003). Compared with the CC gene type, PC risk increased in subjects with CG and CG+GG gene types (P=0.013 and P=0.005, respectively). Furthermore, PC risk increased 3.950-fold in subjects who were heavy smokers (tobacco, ≥25 packets/year) with the CG+GG gene type (P=0.001). Haplotype analysis further revealed that the CCC haplotype of rs2228000, rs3731114 and rs3729587 increased PC risk (odds ratio, 1.610; 95% confidence interval, 1.035–2.481; P=0.034). The present study revealed that XPC gene polymorphisms could increase the risk of PC in the study population, particularly among heavy smokers.
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Affiliation(s)
- Xiao-Hui Liang
- Department of Hypertension, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Dong Yan
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Jia-Xing Zhao
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Wei Ding
- Department of Hepatopancreatobiliary Surgery, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
| | - Xin-Jian Xu
- Department of Pancreatic Surgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Xi-Yan Wang
- Xinjiang Research Institute of Cancer Prevention and Control, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, P.R. China
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Overexpression of CBX3 in Pancreatic Adenocarcinoma Promotes Cell Cycle Transition-Associated Tumor Progression. Int J Mol Sci 2018; 19:ijms19061768. [PMID: 29903985 PMCID: PMC6032220 DOI: 10.3390/ijms19061768] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 05/28/2018] [Accepted: 06/12/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Previous studies showed that Chromobox protein homolog 3 (CBX3) was overexpressed in several types of human cancers, however its pattern and role in pancreatic adenocarcinoma (PAAD) has not yet been understood. The aim of this study was to identify the expression and function of CBX3 in PAAD. METHODS Data of transcriptomic and protein expression of CBX3 in PAAD were collected from different databases and analyzed. The in vitro and in vivo role of CBX3 in PAAD was examined. RESULTS CBX3 was overexpressed in human PAAD tissues, which was associated with poor prognosis of overall and disease-free survival of the patients. Overexpression of CBX3 induced the in vitro proliferation, anchorage-free growth, migration and invasion of the PAAD cells, and led to in vivo growth of orthotoptic PAAD tumors in mice. GO and KEGG pathway analysis, as well as experimental observation showed that CBX3 may be associated with cell cycle transition of PAAD cells, and cyclin-dependent kinase 1 (CDK1) and proliferating cell nuclear antigen (PCNA) may mediate the tumor-promoting action of CBX3. CDK1 knockdown attenuated the cell cycle transition, proliferation and invasion of CBX3-overexpressing PAAD cells. CONCLUSION Our findings suggest the tumor-promoting role of CBX3 in PAAD to be targeted by novel therapeutic strategies.
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Noguchi K, Konno M, Koseki J, Nishida N, Kawamoto K, Yamada D, Asaoka T, Noda T, Wada H, Gotoh K, Sakai D, Kudo T, Satoh T, Eguchi H, Doki Y, Mori M, Ishii H. The mitochondrial one-carbon metabolic pathway is associated with patient survival in pancreatic cancer. Oncol Lett 2018; 16:1827-1834. [PMID: 30008872 DOI: 10.3892/ol.2018.8795] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 03/17/2017] [Indexed: 12/31/2022] Open
Abstract
The expression levels of one-carbon metabolic enzymes were investigated and observed to be correlated with clinicopathological parameters in patients with pancreatic cancer. Mitochondrial one-carbon metabolism comprises a network of biological reactions that integrate nutrient status with nucleotide synthesis, amino acid metabolism, antioxidant reduced nicotinamide adenine dinucleotide phosphate production and epigenetic methylation processes. Previous studies have reported that the hyper-activation of mitochondrial one-carbon metabolism serves a significant role in malignant cancer phenotypes. A total of 103 patients underwent surgical resection of pancreatic ductal adenocarcinomas (PDAC) at Osaka University Hospital between April 2007 and December 2013 and were enrolled in this study. Subsequently, the expression of the one-carbon metabolic enzymes methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), aldehyde dehydrogenase 1 family member L2 (ALDH1L2), and serine hydroxymethyltransferase (SHMT2) was examined using immunohistochemical analysis. The immunohistochemical analyses demonstrated that patients with high expression levels of MTHFD2, ALDH1L2 or SHMT2 had significantly poor overall survival (OS) and disease-free survival (DFS) rates, as compared with patients with low expression levels. Furthermore, multivariate Cox proportional hazards analysis indicated that MTHFD2 and ALDH1L2 were independent prognostic factors for OS and DFS, whereas SHMT2 was not predictive of DFS. However, high and low expression levels of all three folate metabolic enzymes were significantly associated with improved OS and DFS, compared with the high expression of one or two folate metabolic enzymes. The expression levels of mitochondrial one-carbon metabolic enzymes are independent prognostic factors and potential therapeutic targets for future pancreatic cancer treatments.
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Affiliation(s)
- Kozo Noguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.,Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Masamitsu Konno
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Jun Koseki
- Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Naohiro Nishida
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Tadafumi Asaoka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Kunihito Gotoh
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Daisuke Sakai
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Toshihiro Kudo
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Taroh Satoh
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
| | - Hideshi Ishii
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.,Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
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Noguchi K, Konno M, Eguchi H, Kawamoto K, Mukai R, Nishida N, Koseki J, Wada H, Akita H, Satoh T, Marubashi S, Nagano H, Doki Y, Mori M, Ishii H. c-Met affects gemcitabine resistance during carcinogenesis in a mouse model of pancreatic cancer. Oncol Lett 2018; 16:1892-1898. [PMID: 30008881 DOI: 10.3892/ol.2018.8793] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 02/28/2018] [Indexed: 12/11/2022] Open
Abstract
Pancreatic adenocarcinoma is thought to develop from histologically identifiable intraductal lesions known as pancreatic intraepithelial neoplasias (PanINs), which exhibit similar morphological and genetic features to pancreatic ductal adenocarcinoma (PDAC). Therefore, a better understanding of the biological features underlying the progression of PanIN is essential to development more effective therapeutic interventions for PDAC. In recent years, numerous studies have reported that MET proto-oncogene receptor tyrosine kinase (c-MET) is a potential marker of pancreatic cancer stem cells (CSCs). CSCs have been revealed to initiate and propagate tumors in vitro and in vivo, and are associated with a chemoresistant phenotype. However, in vivo models using a xenograft approach are limited. In the present study, the morphological phenotype, molecular alteration and biological behavior of neoplasia in Pdx-1Cre/+, KrasLSL-G12D/+ and Metflox/flox and wild-type mice was analyzed. The results demonstrated that while oncogenic KrasLSL-G12D/+ increased PanIN initiation and significantly decreased survival rate compared with wild-type mice, no additive effect of c-Met receptor signaling on PanIN progression or prognosis was observed. Following gemcitabine administration, c-Met inhibition in Kras LSL-G12D/+ mice significantly decreased the total surface area of PanIN lesions and the number of anti-proliferation marker protein Ki-67 positive cells occupying PanIN lesions compared with Met+/+ mice. In conclusion, complete inhibition of the c-Met signaling pathway with chemotherapy may be useful for the treatment of pancreatic cancer.
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Affiliation(s)
- Kozo Noguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.,Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Masamitsu Konno
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Ryouta Mukai
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Naohiro Nishida
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Jun Koseki
- Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hirofumi Akita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Taroh Satoh
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Shigeru Marubashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hideshi Ishii
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.,Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
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Duan B, Hu J, Liu H, Wang Y, Li H, Liu S, Xie J, Owzar K, Abbruzzese J, Hurwitz H, Gao H, Wei Q. Genetic variants in the platelet-derived growth factor subunit B gene associated with pancreatic cancer risk. Int J Cancer 2018; 142:1322-1331. [PMID: 29168174 PMCID: PMC5805574 DOI: 10.1002/ijc.31171] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 10/12/2017] [Accepted: 11/06/2017] [Indexed: 02/06/2023]
Abstract
The platelet-derived growth factor (PDGF) signaling pathway plays important roles in development and progression of human cancers. In our study, we aimed to identify genetic variants of the PDGF pathway genes associated with pancreatic cancer (PC) risk in European populations using three published genome-wide association study datasets, which consisted of 9,381 cases and 7,719 controls. The expression quantitative trait loci (eQTL) analysis was also performed using data from the 1000 Genomes, TCGA and GTEx projects. As a result, we identified two potential susceptibility loci (rs5757573 and rs6001516) of PDGFB associated with PC risk [odds ratio (OR) = 1.10, 95% confidence interval (CI) = 1.05-1.16, and p = 4.70 × 10-5 for the rs5757573 C allele and 1.21, 1.11-1.32, and 2.01 × 10-5 for the rs6001516 T allele]. Haplotype analysis revealed that the C-T haplotype carriers had a significantly increased risk of PC than those carrying the T-C haplotype (OR = 1.23, 95% CI = 1.12-1.34, p =5.00 × 10-6 ). The multivariate regression model incorporating the number of unfavorable genotypes (NUGs) with age and sex showed that carriers with 1-2 NUGs, particularly among 60-70 age group or males, had an increased risk of PC, compared to those without NUG. Furthermore, the eQTL analysis revealed that both loci were correlated with a decreased mRNA expression level of PDGFB in lymphoblastoid cell lines and pancreatic tumor tissues (p = 0.015 and 0.071, respectively). Our results suggest that genetic variants in PDGFB may play a role in susceptibility to PC. Further population and functional validations of our findings are warranted.
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Affiliation(s)
- Bensong Duan
- Department of Gastroenterology, Institute of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai 20092, China
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Jiangfeng Hu
- Department of Gastroenterology, Institute of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai 20092, China
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Hongliang Liu
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Yanru Wang
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Hongyu Li
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Gastroenterology, Shenyang Northern Hospital, Shenyang, Liaoning 110840, China
| | - Shun Liu
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Jichun Xie
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USA
| | - Kouros Owzar
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USA
| | - James Abbruzzese
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Herbert Hurwitz
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Hengjun Gao
- Department of Gastroenterology, Institute of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai 20092, China
- National Engineering Center for Biochip at Shanghai, Shanghai 201203, China
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
- Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
- Department of Population Health Sciences, Duke University School of Medicine, Durham, NC 27710
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Prabhu KS, Achkar IW, Kuttikrishnan S, Akhtar S, Khan AQ, Siveen KS, Uddin S. Embelin: a benzoquinone possesses therapeutic potential for the treatment of human cancer. Future Med Chem 2018; 10:961-976. [PMID: 29620447 DOI: 10.4155/fmc-2017-0198] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/28/2023] Open
Abstract
Natural products have been gaining recognition and are becoming a significant part of research in the area of drug development and discovery. Phytochemicals derived from these sources have been comprehensively studied and have displayed a wide range of activities against many fatal diseases including cancer. One such product that has gained recognition from its pharmacological properties and nontoxic nature is embelin, obtained from Embelia ribes. Amid all the vivid pharmacological activities, embelin has gained its prominence in the area of cancer research. Embelin binds to the BIR3 domain of XIAP, preventing the association of XIAP and caspase-9 resulting in the suppression of cell growth, proliferation and migration of various types of cancer cells. Furthermore, embelin modulates anti-apoptotic pathways by suppressing the activity of NF-κB, PI3-kinase/AKT, JAK/STAT pathway - among others. The present review summarizes the various reported effects of embelin on different types of cancer cells and highlights the cellular mechanisms of action.
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Affiliation(s)
- Kirti S Prabhu
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Iman W Achkar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shilpa Kuttikrishnan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Sabah Akhtar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Kodapully S Siveen
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
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Eibl G, Cruz-Monserrate Z, Korc M, Petrov MS, Goodarzi MO, Fisher WE, Habtezion A, Lugea A, Pandol SJ, Hart PA, Andersen DK. Diabetes Mellitus and Obesity as Risk Factors for Pancreatic Cancer. J Acad Nutr Diet 2018; 118:555-567. [PMID: 28919082 PMCID: PMC5845842 DOI: 10.1016/j.jand.2017.07.005] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer. The worldwide estimates of its incidence and mortality in the general population are eight cases per 100,000 person-years and seven deaths per 100,000 person-years, and they are significantly higher in the United States than in the rest of the world. The incidence of this disease in the United States is more than 50,000 new cases in 2017. Indeed, total deaths due to PDAC are projected to increase dramatically to become the second leading cause of cancer-related deaths before 2030. Considering the failure to date to efficiently treat existing PDAC, increased effort should be undertaken to prevent this disease. A better understanding of the risk factors leading to PDAC development is of utmost importance to identify and formulate preventive strategies. Large epidemiologic and cohort studies have identified risk factors for the development of PDAC, including obesity and type 2 diabetes mellitus. This review highlights the current knowledge of obesity and type 2 diabetes as risk factors for PDAC development and progression, their interplay and underlying mechanisms, and the relation to diet. Research gaps and opportunities to address this deadly disease are also outlined.
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Naqvi AAT, Hasan GM, Hassan MI. Investigating the role of transcription factors of pancreas development in pancreatic cancer. Pancreatology 2018; 18:184-190. [PMID: 29289465 DOI: 10.1016/j.pan.2017.12.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 11/20/2017] [Accepted: 12/22/2017] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer (PC) is the seventh most common cause of cancer-related deaths worldwide that kills more than 300,000 people every year. Prognosis of PC is very poor with a five-year survival rate about 5%. The most common and highly observed type of PC is pancreatic ductal adenocarcinoma (PDAC). It is preceded by the progression of precursor lesions such as Pancreatic Intraepithelial Neoplasia (PanIN), Intraductal Papillary Neoplasm (IPMN) and Mucinous Cystic Neoplasm (MCN). PanIN is the most common among these premalignant lesions. Genes orchestrating the origin and differentiation of cells during organogenesis have the tendency to produce tumor cells in response to activating or inactivating mutations. Based on the following premise, we discuss the role of transcription factors (TFs) of pancreas development and cell fate differentiation in PC. Pancreas/duodenum homeobox protein 1 (PDX1), Pancreas transcription factor 1 subunit alpha (PTF1A), Nuclear receptor subfamily 5 group A member 2 (NR5A2), Hepatocyte nuclear factor 1-alpha (HNF1A) and Hepatocyte nuclear factor 1-beta (HNF1B) play vital role in the development and differentiation of pancreatic precursor cells. Mutated KRAS induces abnormalities in the regular function of these TFs which in turn cause abnormal cell growth and proliferation that leads to cancer. Thus, these TFs are highly susceptible for the origin of PC. Therefore, we propose that these TFs can be treated as therapeutic targets for the development of anticancer drugs.
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Affiliation(s)
- Ahmad Abu Turab Naqvi
- Center for Interdisciplinary Research in Basic Science, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Gulam Mustafa Hasan
- Department of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Md Imtaiyaz Hassan
- Center for Interdisciplinary Research in Basic Science, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India.
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Wu Q, Tian Y, Zhang J, Zhang H, Gu F, Lu Y, Zou S, Chen Y, Sun P, Xu M, Sun X, Xia C, Chi H, Ying Zhu A, Tang D, Wang D. Functions of pancreatic stellate cell-derived soluble factors in the microenvironment of pancreatic ductal carcinoma. Oncotarget 2017; 8:102721-102738. [PMID: 29254283 PMCID: PMC5731993 DOI: 10.18632/oncotarget.21970] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 09/21/2017] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer with poor prognosis because it is highly resistant to traditional chemotherapy and radiotherapy and it has a low rate of surgical resection eligibility. Pancreatic stellate cells (PSC) have become a research hotspot in recent years, and play a vital role in PDAC microenvironment by secreting soluble factors such as transforming growth factor β, interleukin-6, stromal cell-derived factor-1, hepatocyte growth factor and galectin-1. These PSC-derived cytokines and proteins contribute to PSC activation, participating in PDAC cell proliferation, migration, fibrosis, angiogenesis, immunosuppression, epithelial-mesenchymal transition, and chemoradiation resistance, leading to malignant outcome. Consequently, targeting these cytokines and proteins or their downstream signaling pathways is promising for treating PDAC.
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Affiliation(s)
- Qi Wu
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Ying Tian
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Jingqiu Zhang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
| | - Hongpeng Zhang
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Fengming Gu
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Yongdie Lu
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Shengnan Zou
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Yuji Chen
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Pengxiang Sun
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Mengyue Xu
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Xiaoming Sun
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Chao Xia
- Nanjing Medical University, Nanjing, P.R. China
| | - Hao Chi
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - A Ying Zhu
- Medical College of Yangzhou University, Yangzhou, P.R. China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
| | - Daorong Wang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou, P.R. China
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Alizadeh S, Shab-Bidar S, Mohtavinejad N, Djafarian K. A posteriori dietary patterns and risk of pancreatic and renal cancers. ACTA ACUST UNITED AC 2017. [DOI: 10.1108/nfs-03-2017-0053] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Purpose
Dietary patterns have been used to explore the association between dietary factors and risk of pancreatic cancer (PC) and renal cancer (RC); however, the association remains unclear. The purpose of this paper is to comprehensively review these associations.
Design/methodology/approach
Pertinent studies published prior to March 2016 were systematically searched and retrieved through PubMed and Scopus databases. Adjusted risk estimates were derived by comparing the highest with the lowest categories of dietary pattern scores and were combined by using the fixed-effects model when no substantial heterogeneity was observed; otherwise, the random-effects model was used.
Findings
A total of nine studies, five for PC (including 2,059 cases and 41,774 participants/controls) and four for RC (with 1,327 cases and 53,007 participants/controls), were included in this meta-analysis. A decreased risk of PC was shown for the highest compared with the lowest categories of the healthy dietary pattern (OR = 0.72, 95 per cent CI = 0.51-0.94, random effects (p-value for heterogeneity = 0.004)), whereas no significant association with Western dietary was observed (OR = 1.16, 95 per cent CI = 0.87-1.44, fixed effects). In the overall analysis, a significant association was found between the healthy dietary pattern and reduced risk of RC (OR = 0.59, 95 per cent CI = 0.48-0.71, fixed effects (p-value for heterogeneity = 0.459)), whereas the Western pattern was positively associated with risk of RC (OR = 1.42, 95 per cent CI = 1.14-1.69, fixed effects). For both cancers, the reduced risk associated with the healthy pattern was restricted to case-control, but not cohort, studies. Furthermore, drinking pattern was significantly related to reduced risk of RC (OR = 0.68, 95 per cent CI = 0.42-0.94).
Originality/value
To the authors’ knowledge, the present study is the first English document to summarize systematically the findings from observational studies in response to this question whether a posteriori dietary patterns are associated with susceptibility to the risk of renal and ovarian cancers.
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Matsuda Y, Tanaka M, Sawabe M, Mori S, Muramatsu M, Mieno MN, Furukawa T, Arai T. Relationship between pancreatic intraepithelial neoplasias, pancreatic ductal adenocarcinomas, and single nucleotide polymorphisms in autopsied elderly patients. Genes Chromosomes Cancer 2017. [DOI: 10.1002/gcc.22479] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
- Yoko Matsuda
- Department of Pathology; Tokyo Metropolitan Geriatric Hospital; Tokyo Japan
| | - Masashi Tanaka
- Department of Genomics for Longevity and Health; Tokyo Metropolitan Institute of Gerontology; Tokyo Japan
| | - Motoji Sawabe
- Molecular Pathophysiology, Graduate School of Health Care Science, Tokyo Medical and Dental University; Tokyo Japan
| | - Seijiro Mori
- Center for Promotion of Clinical Investigation, Tokyo Metropolitan Geriatric Hospital; Tokyo Japan
| | - Masaaki Muramatsu
- Department of Molecular Epidemiology; Medical Research Institute, Tokyo Medical and Dental University; Tokyo Japan
| | - Makiko Naka Mieno
- Department of Medical Informatics; Center for Information, Jichi Medical University; Tochigi Japan
| | - Toru Furukawa
- Institute for Integrated Medical Sciences, Tokyo Women's Medical University; Tokyo Japan
| | - Tomio Arai
- Department of Pathology; Tokyo Metropolitan Geriatric Hospital; Tokyo Japan
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Korc M, Jeon CY, Edderkaoui M, Pandol SJ, Petrov MS. Tobacco and alcohol as risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol 2017; 31:529-536. [PMID: 29195672 PMCID: PMC5747325 DOI: 10.1016/j.bpg.2017.09.001] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 08/25/2017] [Accepted: 09/03/2017] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is projected to become the leading cause of cancer deaths by 2050. The risk for pancreatic cancer may be reduced by up to 27% by modifying lifestyle risk factors, most notably tobacco smoking. Based on analysis of more than 2 million unselected individuals from general population, this article quantified the risk of pancreatic cancer in relation to lifelong tobacco smoking and alcohol consumption status, both alone and in combination. It also provided a state-of-the-art review of animal studies on the effect of tobacco smoke and alcohol on genetically engineered mouse models of pancreatic precursor lesions, as well as the role of immune microenvironment in pancreatic carcinogenesis activated by tobacco and alcohol.
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Affiliation(s)
- Murray Korc
- Departments of Medicine, Biochemistry and Molecular Biology, Indiana University School of Medicine, The Melvin and Bren Simon Cancer Center and the Pancreatic Cancer Signature Center, Indianapolis, USA
| | - Christie Y Jeon
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Mouad Edderkaoui
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Stephen J Pandol
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Maxim S Petrov
- Department of Surgery, University of Auckland, Auckland, New Zealand.
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Ooi M, Phan A, Nguyen NQ. Future role of endoscopic ultrasound in personalized management of pancreatic cancer. Endosc Ultrasound 2017; 6:300-307. [PMID: 29063873 PMCID: PMC5664850 DOI: 10.4103/eus.eus_84_17] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 09/08/2017] [Indexed: 12/27/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is aggressive and lethal with the majority of cases presenting with advanced unresectable disease due to delayed diagnosis. Despite improvement in surgery, chemotherapies, and intensive care medicine, the outcome of PDAC remains poor, which may relate to the tumor biology. Recent data suggest that PDAC is a "systemic cancer" with complex molecular or genomics derangement with marked heterogeneity. The ability to characterize the PDAC better by detailed evaluation of tissue biomarkers or genomics allows for improved prediction of prognosis and stratification of treatment, a concept known as "personalized cancer therapy." Using tissue from resected PDAC specimens has several weaknesses and is only possible in 20% of patients with PDAC. Endoscopic ultrasound (EUS)-guided biopsy overcomes these weaknesses, and with recent advancements in needle technology, tissue can be obtained for personalized cancer therapy for all patients with PDAC. This review aims to outline our current understanding of the molecular biology of PDAC specifically focusing on how EUS-guided biopsy may play a fundamental role in tissue acquisition, allowing for assessment and stratify therapy according to the individual cancer biology as we move toward the era of precision medicine.
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Affiliation(s)
- Marie Ooi
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
| | - An Phan
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
- Discipline of Medicine, University of Adelaide, Adelaide, Australia
| | - Nam Q. Nguyen
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia
- Discipline of Medicine, University of Adelaide, Adelaide, Australia
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