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Farmakis D, Stravopodis DJ, Prombona A. TH301 Emerges as a Novel Anti-Oncogenic Agent for Human Pancreatic Cancer Cells: The Dispensable Roles of p53, CRY2 and BMAL1 in TH301-Induced CDKN1A/p21 CIP1/WAF1 Upregulation. Int J Mol Sci 2024; 26:178. [PMID: 39796036 PMCID: PMC11720130 DOI: 10.3390/ijms26010178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/21/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
Background: Pancreatic Ductal Adeno-Carcinoma (PDAC) is a highly aggressive cancer, with limited treatment options. Disruption of the circadian clock, which regulates key cellular processes, has been implicated in PDAC initiation and progression. Hence, targeting circadian clock components may offer new therapeutic opportunities for the disease. This study investigates the cytopathic effects of TH301, a novel CRY2 stabilizer, on PDAC cells, aiming to evaluate its potential as a novel therapeutic agent. Methods: PDAC cell lines (AsPC-1, BxPC-3 and PANC-1) were treated with TH301, and cell viability, cell cycle progression, apoptosis, autophagy, circadian gene, and protein expression profiles were analyzed, using MTT assay, flow cytometry, Western blotting, and RT-qPCR technologies. Results: TH301 proved to significantly decrease cell viability and to induce cell cycle arrest at the G1-phase across all PDAC cell lines herein examined, especially the AsPC-1 and BxPC-3 ones. It caused dose-dependent apoptosis and autophagy, and it synergized with Chloroquine and Oxaliplatin to enhance anti-oncogenicity. The remarkable induction of p21 by TH301 was shown to follow clock- and p53-independent patterns, thereby indicating the critical engagement of alternative mechanisms. Conclusions: TH301 demonstrates significant anti-cancer activities in PDAC cells, thus serving as a promising new therapeutic agent, which can also synergize with approved treatment schemes by targeting pathways beyond circadian clock regulation. Altogether, TH301 likely opens new therapeutic windows for the successful management of pancreatic cancer in clinical practice.
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Affiliation(s)
- Danae Farmakis
- Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), Panepistimiopolis, Zografou, 157 01 Athens, Greece;
- Laboratory of Chronobiology, Institute of Biosciences and Applications (IBA), National Centre for Scientific Research (NCSR) “Demokritos”, 153 41 Aghia Paraskevi, Greece;
| | - Dimitrios J. Stravopodis
- Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), Panepistimiopolis, Zografou, 157 01 Athens, Greece;
| | - Anastasia Prombona
- Laboratory of Chronobiology, Institute of Biosciences and Applications (IBA), National Centre for Scientific Research (NCSR) “Demokritos”, 153 41 Aghia Paraskevi, Greece;
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Wagle MM, Kedige AR, Kabekkodu SP, Mallya S. Integrated Bioinformatics Analysis Identifies Crucial Biochemical Processes Shared between Pancreatitis and Pancreatic Ductal Adenocarcinoma. Asian Pac J Cancer Prev 2023; 24:1601-1610. [PMID: 37247279 PMCID: PMC10495878 DOI: 10.31557/apjcp.2023.24.5.1601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 05/15/2023] [Indexed: 05/31/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy associated with rapid progression and an abysmal prognosis. Previous research has shown that chronic pancreatitis can significantly increase the risk of developing PDAC. The overarching hypothesis is that some of the biological processes disrupted during the inflammatory stage tend to show significant dysregulation, even in cancer. This might explain why chronic inflammation increases the risk of carcinogenesis and uncontrolled proliferation. Here, we try to pinpoint such complex processes by comparing the expression profiles of pancreatitis and PDAC tissues. METHODS We analyzed a total of six gene expression datasets retrieved from the EMBL-EBI ArrayExpress and NCBI GEO databases, which included 306 PDAC, 68 pancreatitis and 172 normal pancreatic samples. The disrupted genes identified were used to perform downstream analysis for ontology, interaction, enriched pathways, potential druggability, promoter methylation, and the associated prognostic value. Further, we performed expression analysis based on gender, patient's drinking habit, race, and pancreatitis status. RESULTS Our study identified 45 genes with altered expression levels shared between PDAC and pancreatitis. Over-representation analysis revealed that protein digestion and absorption, ECM-receptor interaction, PI3k-Akt signaling, and proteoglycans in cancer pathways as significantly enriched. Module analysis identified 15 hub genes, of which 14 were found to be in the druggable genome category. CONCLUSION In summary, we have identified critical genes and various biochemical processes disrupted at a molecular level. These results can provide valuable insights into certain events leading to carcinogenesis, and therefore help identify novel therapeutic targets to improve PDAC treatment in the future.
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Affiliation(s)
- Manoj M Wagle
- School of Mathematics and Statistics and Computational Systems Biology Group, Children’s Medical Research Institute, University of Sydney, New South Wales, Australia.
- Department of Bioinformatics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Karnataka, India.
| | - Ananya Rao Kedige
- Department of Bioinformatics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Karnataka, India.
- Université Grenoble Alpes, CNRS, CEA, Grenoble, France.
| | - Shama P Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Karnataka, India.
| | - Sandeep Mallya
- Department of Bioinformatics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Karnataka, India.
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The Molecular and Cellular Strategies of Glioblastoma and Non-Small-Cell Lung Cancer Cells Conferring Radioresistance. Int J Mol Sci 2022; 23:ijms232113577. [PMID: 36362359 PMCID: PMC9656305 DOI: 10.3390/ijms232113577] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/02/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022] Open
Abstract
Ionizing radiation (IR) has been shown to play a crucial role in the treatment of glioblastoma (GBM; grade IV) and non-small-cell lung cancer (NSCLC). Nevertheless, recent studies have indicated that radiotherapy can offer only palliation owing to the radioresistance of GBM and NSCLC. Therefore, delineating the major radioresistance mechanisms may provide novel therapeutic approaches to sensitize these diseases to IR and improve patient outcomes. This review provides insights into the molecular and cellular mechanisms underlying GBM and NSCLC radioresistance, where it sheds light on the role played by cancer stem cells (CSCs), as well as discusses comprehensively how the cellular dormancy/non-proliferating state and polyploidy impact on their survival and relapse post-IR exposure.
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Smith C, Zheng W, Dong J, Wang Y, Lai J, Liu X, Yin F. Tumor microenvironment in pancreatic ductal adenocarcinoma: Implications in immunotherapy. World J Gastroenterol 2022; 28:3297-3313. [PMID: 36158269 PMCID: PMC9346457 DOI: 10.3748/wjg.v28.i27.3297] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 04/22/2022] [Accepted: 06/20/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most aggressive and lethal cancers. Surgical resection is the only curable treatment option, but it is available for only a small fraction of patients at the time of diagnosis. With current therapeutic regimens, the average 5-year survival rate is less than 10% in pancreatic cancer patients. Immunotherapy has emerged as one of the most promising treatment options for multiple solid tumors of advanced stage. However, its clinical efficacy is suboptimal in most clinical trials on pancreatic cancer. Current studies have suggested that the tumor microenvironment is likely the underlying barrier affecting immunotherapy drug efficacy in pancreatic cancer. In this review, we discuss the role of the tumor microenvironment in pancreatic cancer and the latest advances in immunotherapy on pancreatic cancer.
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Affiliation(s)
- Caitlyn Smith
- Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, United States
| | - Wei Zheng
- Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Jixin Dong
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Yaohong Wang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, United States
| | - Jinping Lai
- Department of Pathology and Laboratory Medicine, Kaiser Permanente Sacramento Medical Center, Sacramento, CA 95825, United States
| | - Xiuli Liu
- Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, United States
| | - Feng Yin
- Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, MO 65212, United States
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Emerging Role of miR-345 and Its Effective Delivery as a Potential Therapeutic Candidate in Pancreatic Cancer and Other Cancers. Pharmaceutics 2021; 13:pharmaceutics13121987. [PMID: 34959269 PMCID: PMC8707074 DOI: 10.3390/pharmaceutics13121987] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/16/2021] [Accepted: 11/18/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality, poor prognosis, and palliative treatments, due to the rapid upregulation of alternative compensatory pathways and desmoplastic reaction. miRNAs, small non-coding RNAs, have been recently identified as key players regulating cancer pathogenesis. Dysregulated miRNAs are associated with molecular pathways involved in tumor development, metastasis, and chemoresistance in PDAC, as well as other cancers. Targeted treatment strategies that alter miRNA levels in cancers have promising potential as therapeutic interventions. miRNA-345 (miR-345) plays a critical role in tumor suppression and is differentially expressed in various cancers, including pancreatic cancer (PC). The underlying mechanism(s) and delivery strategies of miR-345 have been investigated by us previously. Here, we summarize the potential therapeutic roles of miR-345 in different cancers, with emphasis on PDAC, for miRNA drug discovery, development, status, and implications. Further, we focus on miRNA nanodelivery system(s), based on different materials and nanoformulations, specifically for the delivery of miR-345.
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Sarantis P, Koustas E, Papadimitropoulou A, Papavassiliou AG, Karamouzis MV. Pancreatic ductal adenocarcinoma: Treatment hurdles, tumor microenvironment and immunotherapy. World J Gastrointest Oncol 2020; 12:173-181. [PMID: 32104548 PMCID: PMC7031151 DOI: 10.4251/wjgo.v12.i2.173] [Citation(s) in RCA: 213] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 11/28/2019] [Accepted: 12/15/2019] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, with an average 5-year survival rate of less than 10%. Unfortunately, the majority of patients have unresectable, locally advanced, or metastatic disease at the time of diagnosis. Moreover, traditional treatments such as chemotherapy, surgery, and radiation have not been shown to significantly improve survival. Recently, there has been a swift increase in cancer treatments that incorporate immunotherapy-based strategies to target all the stepwise events required for tumor initiation and progression. The results in melanoma, non-small-cell lung cancer and renal cell carcinoma are very encouraging. Unfortunately, the application of checkpoint inhibitors, including anti-CTLA4, anti-PD-1, and anti-PD-L1 antibodies, in pancreatic cancer has been disappointing. Many studies have revealed that the PDAC microenvironment supports tumor growth, promotes metastasis and consists of a physical barrier to drug delivery. Combination therapies hold great promise for enhancing immune responses to achieve a better therapeutic effect. In this review, we provide an outline of why pancreatic cancer is so lethal and of the treatment hurdles that exist. Particular emphasis is given to the role of the tumor microenvironment, and some of the latest and most promising studies on immunotherapy in PDAC are also presented.
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Affiliation(s)
- Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Adriana Papadimitropoulou
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece
| | - Athanasios G Papavassiliou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Michalis V Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
- First Department of Internal Medicine, “Laiko” General Hospital, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
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Begum A, McMillan RH, Chang YT, Penchev VR, N.V. R, Maitra A, Goggins MG, Eshelman JR, Wolfgang CL, Rasheed ZA, Matsui W. Direct Interactions With Cancer-Associated Fibroblasts Lead to Enhanced Pancreatic Cancer Stem Cell Function. Pancreas 2019; 48:329-334. [PMID: 30747824 PMCID: PMC6411432 DOI: 10.1097/mpa.0000000000001249] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Cancer-associated fibroblasts (CAFs) play an important role in the progression of pancreatic ductal adenocarcinoma (PDAC) by promoting tumor cell migration and drug resistance. We determined the impact of CAFs on PDAC cancer stem cells (CSCs). METHODS Fibroblast cell lines from patients' tumors were cocultured with PDAC cells and examined for clonogenic growth and self-renewal using colony-forming assays and migration in vitro. Changes in the frequency of CSCs was determined by flow cytometry. The effect of integrin-focal adhesion kinase (FAK) signaling on CAF-mediated clonogenic growth was evaluated using short hairpin RNAs against β1 integrin and FAK as well as a small-molecule FAK inhibitor. RESULTS Cancer-associated fibroblasts enhanced PDAC clonogenic growth, self-renewal, and migration that was associated with an increase in the frequency of CSCs. These fibroblast cells were activated by PDAC cells and increased collagen synthesis resulting in FAK activation in PDAC cells. Knockdown of β1-integrin and FAK or the inhibition of FAK kinase activity in PDAC cells abrogated the impact of CAFs on clonogenic growth. CONCLUSION Therefore, CAFs enhance PDAC clonogenic growth, self-renewal, and the frequency of CSCs through type I collagen production that enhances integrin-FAK signaling in PDAC cells.
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Affiliation(s)
- Asma Begum
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ross H. McMillan
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Yu-Tai Chang
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Vesselin R. Penchev
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Rajeshkumar N.V.
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Anirban Maitra
- Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Michael G. Goggins
- Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - James R. Eshelman
- Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Christopher L. Wolfgang
- Department of Surgery, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Zeshaan A. Rasheed
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - William Matsui
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
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8
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Prasad S, Ramachandran S, Gupta N, Kaushik I, Srivastava SK. Cancer cells stemness: A doorstep to targeted therapy. Biochim Biophys Acta Mol Basis Dis 2019; 1866:165424. [PMID: 30818002 DOI: 10.1016/j.bbadis.2019.02.019] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 02/15/2019] [Accepted: 02/20/2019] [Indexed: 02/07/2023]
Abstract
Recent advances in research on cancer have led to understand the pathogenesis of cancer and development of new anticancer drugs. Despite of these advancements, many tumors have been found to recur, undergo metastasis and develop resistance to therapy. Accumulated evidences suggest that small population of cancer cells known as cancer stem cells (CSC) are responsible for reconstitution and propagation of the disease. CSCs possess the ability to self-renew, differentiate and proliferate like normal stem cells. CSCs also appear to have resistance to anti-cancer therapies and subsequent relapse. The underlying stemness properties of the CSCs are reliant on multiple molecular targets such as signaling pathways, cell surface molecules, tumor microenvironment, apoptotic pathways, microRNA, stem cell differentiation, and drug resistance markers. Thus an effective therapeutic strategy relies on targeting CSCs to overcome the possible tumor relapse and chemoresistance. The targeted inhibition of these stem cell biomarkers is one of the promising approaches to eliminate cancer stemness. This review article summarizes possible targets of cancer cell stemness for the complete treatment of cancer.
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Affiliation(s)
- Sahdeo Prasad
- Department of Immunotherapeutics and Biotechnology, and Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | - Sharavan Ramachandran
- Department of Immunotherapeutics and Biotechnology, and Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | - Nehal Gupta
- Department of Immunotherapeutics and Biotechnology, and Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | - Itishree Kaushik
- Department of Immunotherapeutics and Biotechnology, and Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | - Sanjay K Srivastava
- Department of Immunotherapeutics and Biotechnology, and Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA.
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9
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Uz M, Kalaga M, Pothuraju R, Ju J, Junker WM, Batra SK, Mallapragada S, Rachagani S. Dual delivery nanoscale device for miR-345 and gemcitabine co-delivery to treat pancreatic cancer. J Control Release 2019; 294:237-246. [PMID: 30576747 PMCID: PMC6379902 DOI: 10.1016/j.jconrel.2018.12.031] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 12/17/2018] [Indexed: 12/16/2022]
Abstract
A polymeric dual delivery nanoscale device (DDND) was designed for combined delivery of microRNA (miR-345) and gemcitabine (GEM) to treat pancreatic cancer (PC). This temperature and pH-responsive pentablock copolymer system was able to restore miR-345, making xenograft tumors more susceptible to GEM, the standard therapy for PC. Restoration using DDND treatment results in sonic hedgehog signaling down regulation, which decreases desmoplasia, thereby resulting in improved GEM perfusion to the tumor and better therapeutic outcomes. The release of miR-345 and GEM could be tuned by using the DDND in the form of micelles or in the form of thermoreversible gels, based on polymer concentration. The DDNDs enabled miR-345 stability and sustained co-release of miR-345 and GEM, thereby facilitating dose-sparing use of GEM. Further, enhanced in vitro cellular uptake due to amphiphilic character, and endosomal escape because of the cationic end blocks led to efficient transfection with DDNDs. The combined DDND treatment enabled efficient reduction in cell viability of Capan-1 and CD18/HPAF cells in vitro compared with either GEM or miR-345 treatment alone. Mice carrying xenograft tumors treated with DDNDs carrying both miR-345 and GEM combination therapy displayed reduced tumor growth and less metastasis in distant organs compared to individual drug treatments. Immunohistochemical analysis of the xenograft tissues revealed significant down regulation of desmoplastic reaction, SHH, Gli-1, MUC4, and Ki67 compared to control groups.
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Affiliation(s)
- Metin Uz
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA
| | - Manisha Kalaga
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ramesh Pothuraju
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Juhyung Ju
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA
| | - Wade M Junker
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Sanguine Diagnostics and Therapeutics, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer & Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surya Mallapragada
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA.
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
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Hemming ML, Lawlor MA, Andersen JL, Hagan T, Chipashvili O, Scott TG, Raut CP, Sicinska E, Armstrong SA, Demetri GD, Bradner JE, Ganz PA, Tomlinson G, Olopade OI, Couch FJ, Wang X, Lindor NM, Pankratz VS, Radice P, Manoukian S, Peissel B, Zaffaroni D, Barile M, Viel A, Allavena A, Dall'Olio V, Peterlongo P, Szabo CI, Zikan M, Claes K, Poppe B, Foretova L, Mai PL, Greene MH, Rennert G, Lejbkowicz F, Glendon G, Ozcelik H, Andrulis IL, Thomassen M, Gerdes AM, Sunde L, Cruger D, Birk Jensen U, Caligo M, Friedman E, Kaufman B, Laitman Y, Milgrom R, Dubrovsky M, Cohen S, Borg A, Jernström H, Lindblom A, Rantala J, Stenmark-Askmalm M, Melin B, Nathanson K, Domchek S, Jakubowska A, Lubinski J, Huzarski T, Osorio A, Lasa A, Durán M, Tejada MI, Godino J, Benitez J, Hamann U, Kriege M, Hoogerbrugge N, van der Luijt RB, van Asperen CJ, Devilee P, Meijers-Heijboer EJ, Blok MJ, Aalfs CM, Hogervorst F, Rookus M, Cook M, Oliver C, Frost D, Conroy D, Evans DG, Lalloo F, Pichert G, Davidson R, Cole T, Cook J, Paterson J, Hodgson S, Morrison PJ, Porteous ME, Walker L, Kennedy MJ, Dorkins H, Peock S, Godwin AK, Stoppa-Lyonnet D, de Pauw A, Mazoyer S, Bonadona V, Lasset C, Dreyfus H, Leroux D, Hardouin A, Berthet P, Faivre L, Loustalot C, Noguchi T, Sobol H, Rouleau E, Nogues C, Frénay M, Vénat-Bouvet L, Hopper JL, Daly MB, Terry MB, John EM, Buys SS, Yassin Y, Miron A, Goldgar D, Singer CF, Dressler AC, Gschwantler-Kaulich D, Pfeiler G, Hansen TVO, Jønson L, Agnarsson BA, Kirchhoff T, Offit K, Devlin V, Dutra-Clarke A, Piedmonte M, Rodriguez GC, Wakeley K, Boggess JF, Basil J, Schwartz PE, Blank SV, Toland AE, Montagna M, Casella C, Imyanitov E, Tihomirova L, Blanco I, Lazaro C, Ramus SJ, Sucheston L, Karlan BY, Gross J, Schmutzler R, Wappenschmidt B, Engel C, Meindl A, Lochmann M, Arnold N, Heidemann S, Varon-Mateeva R, Niederacher D, Sutter C, Deissler H, Gadzicki D, Preisler-Adams S, Kast K, Schönbuchner I, Caldes T, de la Hoya M, Aittomäki K, Nevanlinna H, Simard J, Spurdle AB, Holland H, Chen X, Platte R, Chenevix-Trench G, Easton DF. Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and Are Targetable by BET Bromodomain Inhibition. Cancer Res 2019. [PMID: 18483246 DOI: 10.1158/0008-5472] [Citation(s) in RCA: 733] [Impact Index Per Article: 122.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm characterized by activating mutations in the related receptor tyrosine kinases KIT and PDGFRA. GIST relies on expression of these unamplified receptor tyrosine kinase (RTK) genes through a large enhancer domain, resulting in high expression levels of the oncogene required for tumor growth. Although kinase inhibition is an effective therapy for many patients with GIST, disease progression from kinase-resistant mutations is common and no other effective classes of systemic therapy exist. In this study, we identify regulatory regions of the KIT enhancer essential for KIT gene expression and GIST cell viability. Given the dependence of GIST upon enhancer-driven expression of RTKs, we hypothesized that the enhancer domains could be therapeutically targeted by a BET bromodomain inhibitor (BBI). Treatment of GIST cells with BBIs led to cell-cycle arrest, apoptosis, and cell death, with unique sensitivity in GIST cells arising from attenuation of the KIT enhancer domain and reduced KIT gene expression. BBI treatment in KIT-dependent GIST cells produced genome-wide changes in the H3K27ac enhancer landscape and gene expression program, which was also seen with direct KIT inhibition using a tyrosine kinase inhibitor (TKI). Combination treatment with BBI and TKI led to superior cytotoxic effects in vitro and in vivo, with BBI preventing tumor growth in TKI-resistant xenografts. Resistance to select BBI in GIST was attributable to drug efflux pumps. These results define a therapeutic vulnerability and clinical strategy for targeting oncogenic kinase dependency in GIST. SIGNIFICANCE: Expression and activity of mutant KIT is essential for driving the majority of GIST neoplasms, which can be therapeutically targeted using BET bromodomain inhibitors.
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Affiliation(s)
- Matthew L Hemming
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. .,Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Matthew A Lawlor
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jessica L Andersen
- Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Timothy Hagan
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Otari Chipashvili
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Thomas G Scott
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Chandrajit P Raut
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Ewa Sicinska
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Scott A Armstrong
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - George D Demetri
- Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.,Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - James E Bradner
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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11
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Adamska A, Falasca M. ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: What is the way forward? World J Gastroenterol 2018; 24:3222-3238. [PMID: 30090003 PMCID: PMC6079284 DOI: 10.3748/wjg.v24.i29.3222] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 05/31/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasing understanding of the mechanisms of chemoresistance in cancer and the role of ATP-binding cassette (ABC) transporters in this resistance, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet. In spite of the discovery of potent pharmacological modulators of ABC transporters, the results obtained in clinical trials have been so far disappointing, with high toxicity levels impairing their successful administration to the patients. Critically, although ABC transporters have been mostly studied for their involvement in development of multidrug resistance (MDR), in recent years the contribution of ABC transporters to cancer initiation and progression has emerged as an important area of research, the understanding of which could significantly influence the development of more specific and efficient therapies. In this review, we explore the role of ABC transporters in the development and progression of malignancies, with focus on PDAC. Their established involvement in development of MDR will be also presented. Moreover, an emerging role for ABC transporters as prognostic tools for patients' survival will be discussed, demonstrating the therapeutic potential of ABC transporters in cancer therapy.
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Affiliation(s)
- Aleksandra Adamska
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth 6102, WA, Australia
| | - Marco Falasca
- Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth 6102, WA, Australia
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12
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He W, Wu J, Shi J, Huo YM, Dai W, Geng J, Lu P, Yang MW, Fang Y, Wang W, Zhang ZG, Habtezion A, Sun YW, Xue J. IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer. Cancer Res 2018; 78:3293-3305. [PMID: 29572224 DOI: 10.1158/0008-5472.can-17-3131] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 12/13/2017] [Accepted: 03/19/2018] [Indexed: 11/16/2022]
Abstract
Chronic inflammation is a feature of pancreatic cancer, but little is known about how immune cells or immune cell-related signals affect pancreatic cancer stemness and development. Our previous work showed that IL22/IL22RA1 plays a vital role in acute and chronic pancreatitis progression by mediating cross-talk between immune cells and acinar cells or stellate cells, respectively. Here, we find IL22RA1 is highly but heterogeneously expressed in pancreatic cancer cells, with high expression associated with poor prognosis of patients with pancreatic cancer. The IL22RA1hi population from pancreatic cancer harbored higher stemness potential and tumorigenicity. Notably, IL22 promoted pancreatic cancer stemness via IL22RA1/STAT3 signaling, establishing the mechanism of regulation of cancer stemness by microenvironmental factors. Moreover, STAT3 was indispensable for the maintenance of IL22RA1hi cells. Overall, these findings provide a therapeutic strategy for patients with PDAC with high expression of IL22RA1.Significance: IL22RA1/STAT3 signaling enhances stemness and tumorigenicity in pancreatic cancer. Cancer Res; 78(12); 3293-305. ©2018 AACR.
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Affiliation(s)
- Weizhi He
- State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jinghua Wu
- State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Juanjuan Shi
- State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yan-Miao Huo
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wentao Dai
- Shanghai Center for Bioinformation Technology & Shanghai Engineering Research Center of Pharmaceutical Translation, Shanghai, China
| | - Jing Geng
- State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ping Lu
- State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Min-Wei Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuan Fang
- Department of General Surgery & Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Wang
- Department of General Surgery & Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi-Gang Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California.
| | - Yong-Wei Sun
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Jing Xue
- State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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13
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δ-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis. Oncotarget 2018; 8:31554-31567. [PMID: 28404939 PMCID: PMC5458229 DOI: 10.18632/oncotarget.15767] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 01/27/2017] [Indexed: 01/06/2023] Open
Abstract
The growth, metastasis, and chemotherapy resistance of pancreatic ductal adenocarcinoma (PDAC) is characterized by the activation and growth of tumor-initiating cells in distant organs that have stem-like properties. Thus, inhibiting growth of these cells may prevent PDAC growth and metastases. We have demonstrated that δ-tocotrienol, a natural form of vitamin E (VEDT), is bioactive against cancer, delays progression, and prevents metastases in transgenic mouse models of PDAC. In this report, we provide the first evidence that VEDT selectively inhibits PDAC stem-like cells. VEDT inhibited the viability, survival, self-renewal, and expression of Oct4 and Sox2 transcription factors in 3 models of PDAC stem-like cells. In addition, VEDT inhibited the migration, invasion, and several biomarkers of epithelial-to-mesenchymal transition and angiogenesis in PDAC cells and tumors. These processes are critical for tumor metastases. Furthermore, in the L3.6pl orthotopic model of PDAC metastases, VEDT significantly inhibited growth and metastases of these cells. Finally, in an orthotopic xenograft model of human PDAC stem-like cells, we showed that VEDT significantly retarded the growth and metastases of gemcitabine-resistant PDAC human stem-like cells. Because VEDT has been shown to be safe and to reach bioactive levels in humans, this work supports investigating VEDT for chemoprevention of PDAC metastases.
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14
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Boone BA, Zeh HJ, Bahary N. Autophagy Inhibition in Pancreatic Adenocarcinoma. Clin Colorectal Cancer 2018; 17:25-31. [PMID: 29223362 DOI: 10.1016/j.clcc.2017.10.013] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 10/22/2017] [Accepted: 10/24/2017] [Indexed: 01/28/2023]
Abstract
Although some progress has been made in recent years with the development of more effective chemotherapy regimens, new treatment approaches are needed to improve outcomes for patients with pancreatic adenocarcinoma. The cellular process of autophagy, a cell survival mechanism that allows cancer cells to survive the hazardous conditions of the tumor microenvironment and treatment, has emerged as a viable target in pancreatic cancer. We review the mechanism of autophagy, its role in pancreatic carcinogenesis, the preclinical and clinical evidence supporting targeting autophagy in patients with pancreatic adenocarcinoma, and areas of future investigation that hold promise for improving this treatment approach.
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Affiliation(s)
- Brian A Boone
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Herbert J Zeh
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Nathan Bahary
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA.
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15
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Biziota E, Mavroeidis L, Hatzimichael E, Pappas P. Metronomic chemotherapy: A potent macerator of cancer by inducing angiogenesis suppression and antitumor immune activation. Cancer Lett 2016; 400:243-251. [PMID: 28017892 DOI: 10.1016/j.canlet.2016.12.018] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 12/14/2016] [Accepted: 12/15/2016] [Indexed: 01/09/2023]
Abstract
Metronomic chemotherapy is a low dosing treatment strategy that attracts growing scientific and clinical interest. It refers to dense and uninterrupted administration of low doses of chemotherapeutic agents (without prolonged drug free intervals) over extended periods of time. Cancer chemotherapy is conventionally given in cycles of maximum tolerated doses (MTD) with the aim of inducing maximum cancer cell apoptosis. In contrast, the primary target of metronomic chemotherapy is the tumor's neovasculature. This is relevant to the emerging concept that tumors exist in a complex microenvironment of cancer cells, stromal cells and supporting vessels. In addition to its anti-angiogenetic properties, metronomic chemotherapy halts tumor growth by activating anti-tumor immunity, thus decreasing the acquired resistance to conventional chemotherapy. Herein, we present a review of the literature that provides a scientific basis for the merits of chemotherapy when administered on a metronomic schedule.
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Affiliation(s)
- Eirini Biziota
- Department of Medical Oncology, University Hospital of Evros, Alexandroupolis, 68 100, Greece.
| | - Leonidas Mavroeidis
- Department of Pharmacology, Faculty of Medicine, School of Life Sciences, University of Ioannina, Ioannina, 451 10, Greece.
| | | | - Periklis Pappas
- Department of Pharmacology, Faculty of Medicine, School of Life Sciences, University of Ioannina, Ioannina, 451 10, Greece.
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16
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Human pancreatic cancer progression: an anarchy among CCN-siblings. J Cell Commun Signal 2016; 10:207-216. [PMID: 27541366 DOI: 10.1007/s12079-016-0343-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Accepted: 07/27/2016] [Indexed: 02/07/2023] Open
Abstract
Decades of basic and translational studies have identified the mechanisms by which pancreatic cancer cells use molecular pathways to hijack the normal homeostasis of the pancreas, promoting pancreatic cancer initiation, progression, and metastasis, as well as drug resistance. These molecular pathways were explored to develop targeted therapies to prevent or cure this fatal disease. Regrettably, the studies found that majority of the molecular events that dictate carcinogenic growth in the pancreas are non-actionable (potential non-responder groups of targeted therapy). In this review we discuss exciting discoveries on CCN-siblings that reveal how CCN-family members contribute to the different aspects of the development of pancreatic cancer with special emphasis on therapy.
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17
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Skoda J, Hermanova M, Loja T, Nemec P, Neradil J, Karasek P, Veselska R. Co-Expression of Cancer Stem Cell Markers Corresponds to a Pro-Tumorigenic Expression Profile in Pancreatic Adenocarcinoma. PLoS One 2016; 11:e0159255. [PMID: 27414409 PMCID: PMC4945008 DOI: 10.1371/journal.pone.0159255] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 06/29/2016] [Indexed: 01/12/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Its dismal prognosis is often attributed to the presence of cancer stem cells (CSCs) that have been identified in PDAC using various markers. However, the co-expression of all of these markers has not yet been evaluated. Furthermore, studies that compare the expression levels of CSC markers in PDAC tumor samples and in cell lines derived directly from those tumors are lacking. Here, we analyzed the expression of putative CSC markers—CD24, CD44, epithelial cell adhesion molecule (EpCAM), CD133, and nestin—by immunofluorescence, flow cytometry and quantitative PCR in 3 PDAC-derived cell lines and by immunohistochemistry in 3 corresponding tumor samples. We showed high expression of the examined CSC markers among all of the cell lines and tumor samples, with the exception of CD24 and CD44, which were enriched under in vitro conditions compared with tumor tissues. The proportions of cells positive for the remaining markers were comparable to those detected in the corresponding tumors. Co-expression analysis using flow cytometry revealed that CD24+/CD44+/EpCAM+/CD133+ cells represented a significant population of the cells (range, 43 to 72%) among the cell lines. The highest proportion of CD24+/CD44+/EpCAM+/CD133+ cells was detected in the cell line derived from the tumor of a patient with the shortest survival. Using gene expression profiling, we further identified the specific pro-tumorigenic expression profile of this cell line compared with the profiles of the other two cell lines. Together, CD24+/CD44+/EpCAM+/CD133+ cells are present in PDAC cell lines derived from primary tumors, and their increased proportion corresponds with a pro-tumorigenic gene expression profile.
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Affiliation(s)
- Jan Skoda
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Marketa Hermanova
- 1st Department of Pathological Anatomy, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Tomas Loja
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Pavel Nemec
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Jakub Neradil
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Petr Karasek
- Department of Complex Oncology Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Renata Veselska
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic
- * E-mail:
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18
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WANG WENJIE, WU MENGYAO, SHEN MENG, ZHI QIAOMING, LIU ZEYI, GONG FEIRAN, TAO MIN, LI WEI. Cantharidin and norcantharidin impair stemness of pancreatic cancer cells by repressing the β-catenin pathway and strengthen the cytotoxicity of gemcitabine and erlotinib. Int J Oncol 2015; 47:1912-22. [DOI: 10.3892/ijo.2015.3156] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 08/20/2015] [Indexed: 11/06/2022] Open
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19
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Miyake T, Honma Y, Urano T, Kato N, Suzumiya J. Combined treatment with tamoxifen and a fusicoccin derivative (ISIR-042) to overcome resistance to therapy and to enhance the antitumor activity of 5-fluorouracil and gemcitabine in pancreatic cancer cells. Int J Oncol 2015; 47:315-24. [PMID: 25936828 DOI: 10.3892/ijo.2015.2979] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 03/31/2015] [Indexed: 11/05/2022] Open
Abstract
Although progress has been made in chemotherapeutic strategies against pancreatic cancer, overall survival has not significantly improved over the past decade. Thus, the development of better therapeutic regimens remains a high priority. Pancreatic cancer cell lines were treated with tamoxifen, a novel antitumor fusicoccin derivative (ISIR-042), and anticancer drugs, and their effects on cell growth, signaling and gene expression were determined. Xenografts of Panc-1 cells were treated with tamoxifen, ISIR-042 and 5-fluorouracil (5FU) to determine the effects on tumor growth. The inhibition of the growth of pancreatic cancer cells induced by tamoxifen was effectively reduced by α-tocopherol, a membrane stabilizer. ISIR-042 produced synergistic effects with tamoxifen in inhibiting cell growth. Tamoxifen elevated lipid peroxidation and the release of cytochrome c, and these effects of tamoxifen were reduced by α-tocopherol. ISIR-042 significantly inhibited colony formation and the expression of stemness-related genes of pancreatic cancer cells. The triple combination of tamoxifen, ISIR-042, and 5FU or gemcitabine was effective at inhibiting cell growth and the appearance of drug-resistant cells. This combined treatment significantly inhibited the growth of Panc-1 cells as xenografts without apparent adverse effects. The triple combination of tamoxifen and ISIR-042 with 5FU or gemcitabine may be highly effective against pancreatic cancer by overcoming resistance to therapy.
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Affiliation(s)
- Takaaki Miyake
- Department of Oncology/Hematology, School of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan
| | - Yoshio Honma
- Department of Oncology/Hematology, School of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan
| | - Takeshi Urano
- Department of Biochemistry, School of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan
| | - Nobuo Kato
- The Institute of Scientific and Industrial Research, Osaka University, Osaka 567-0047, Japan
| | - Junji Suzumiya
- Department of Oncology/Hematology, School of Medicine, Shimane University, Izumo, Shimane 693-8501, Japan
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20
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Cheng HB, Bo Y, Shen WX, Ren XG, Tan JN, Jia ZR, Xu CL. Longikaurin E induces apoptosis of pancreatic cancer cells via modulation of the p38 and PI3K/AKT pathways by ROS. Naunyn Schmiedebergs Arch Pharmacol 2015; 388:623-34. [PMID: 25743573 DOI: 10.1007/s00210-015-1107-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Accepted: 02/16/2015] [Indexed: 12/22/2022]
Abstract
Pancreatic cancer is a devastating disease with a poor prognosis. It ranks as the fourth or fifth most common cancer in men and women and has the lowest 5-year survival rate. Therefore, there is an urgent need to develop novel therapeutic agents for pancreatic cancer. Longikaurin E (LE), which is derived from the traditional herbal medicine Rabdosia longituba, had been reported to have anti-proliferative and pro-apoptotic properties in several types of cancers. In this study, we investigated the cytotoxic properties of LE against pancreatic cancer cells and explored the mechanism behind the observed apoptosis. Pancreatic cancer cell lines cultured in the presence of LE exhibited dose- and time-dependent growth suppression by clone formation, methylthiazoltetrazolium assay, lactate dehydrogenase cytotoxicity assay, and fluorescence-activated cell sorting analysis, respectively. In addition, these culture conditions also induced the generation of cellular reactive oxygen species (ROS). In order to determine the mechanisms underlying LE-induced cytotoxicity, we used reverse transcription polymerase chain reaction and Western blot analysis in the pancreatic cancer cell line PANC1. The results showed that the expression of Bax was noticeably upregulated and the expression levels of Bcl-2, Bcl-XL, survivin, and c-Myc were significantly downregulated. We also observed increased p38 phosphorylation and decreased phosphorylation of the PI3K/AKT pathway. Interestingly, we also found that LE activated caspase-3. However, N-acetyl-L-cysteine, a kind of antioxidant, reversed all of these cellular activities. In conclusion, this study suggested that LE induced apoptosis of pancreatic cancer cells via ROS generation to modulate the p38 and PI3K/AKT pathways and could be a promising anti-pancreatic agent.
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Affiliation(s)
- Hai-bo Cheng
- Translational Medicine Research Center, Nanjing University of Chinese Medicine, No. 138, Xianlin Road, Nanjing, Jiangsu, People's Republic of China
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21
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Subramaniam D, Thombre R, Dhar A, Anant S. DNA methyltransferases: a novel target for prevention and therapy. Front Oncol 2014; 4:80. [PMID: 24822169 PMCID: PMC4013461 DOI: 10.3389/fonc.2014.00080] [Citation(s) in RCA: 320] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 03/31/2014] [Indexed: 12/14/2022] Open
Abstract
Cancer is the second leading cause of death in US. Despite the emergence of new, targeted agents, and the use of various therapeutic combinations, none of the available treatment options are curative in patients with advanced cancer. Epigenetic alterations are increasingly recognized as valuable targets for the development of cancer therapies. DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is the predominant epigenetic modification in mammals. DNMT1, the major enzyme responsible for maintenance of the DNA methylation pattern is located at the replication fork and methylates newly biosynthesized DNA. DNMT2 or TRDMT1, the smallest mammalian DNMT is believed to participate in the recognition of DNA damage, DNA recombination, and mutation repair. It is composed solely of the C-terminal domain, and does not possess the regulatory N-terminal region. The levels of DNMTs, especially those of DNMT3B, DNMT3A, and DNMT3L, are often increased in various cancer tissues and cell lines, which may partially account for the hypermethylation of promoter CpG-rich regions of tumor suppressor genes in a variety of malignancies. Moreover, it has been shown to function in self-renewal and maintenance of colon cancer stem cells and need to be studied in several cancers. Inhibition of DNMTs has demonstrated reduction in tumor formation in part through the increased expression of tumor suppressor genes. Hence, DNMTs can potentially be used as anti-cancer targets. Dietary phytochemicals also inhibit DNMTs and cancer stem cells; this represents a promising approach for the prevention and treatment of many cancers.
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Affiliation(s)
- Dharmalingam Subramaniam
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center , Kansas City, KS , USA ; The University of Kansas Cancer Center , Kansas City, KS , USA
| | - Ravi Thombre
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center , Kansas City, KS , USA
| | - Animesh Dhar
- The University of Kansas Cancer Center , Kansas City, KS , USA ; Department of Cancer Biology, The University of Kansas Medical Center , Kansas City, KS , USA
| | - Shrikant Anant
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center , Kansas City, KS , USA ; The University of Kansas Cancer Center , Kansas City, KS , USA ; Department of Cancer Biology, The University of Kansas Medical Center , Kansas City, KS , USA
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22
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Orza A, Casciano D, Biris A. Nanomaterials for targeted drug delivery to cancer stem cells. Drug Metab Rev 2014; 46:191-206. [DOI: 10.3109/03602532.2014.900566] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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23
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Williams SA, Anderson WC, Santaguida MT, Dylla SJ. Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century. J Transl Med 2013; 93:970-82. [PMID: 23917877 DOI: 10.1038/labinvest.2013.92] [Citation(s) in RCA: 153] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Revised: 05/27/2013] [Accepted: 06/13/2013] [Indexed: 12/12/2022] Open
Abstract
Cancer is a heterogeneous disease manifest in many forms. Tumor histopathology can differ significantly among patients and cellular heterogeneity within tumors is common. A primary goal of cancer biologists is to better understand tumorigenesis and cancer progression; however, the complex nature of tumors has posed a substantial challenge to unlocking cancer's secrets. The cancer stem cell (CSC) paradigm for the pathobiology of solid tumors appropriately acknowledges phenotypic and functional tumor cell heterogeneity observed in solid tumors and accounts for the disconnect between drug approval based on response and the general inability of approved therapies to meaningfully impact survival due to their failure to eradicate these most important of cellular targets. First proposed to exist decades ago, CSC have only recently begun to be precisely identified due to technical advancements that facilitate identification, isolation, and interrogation of distinct tumor cell subpopulations with differing ability to form and perpetuate tumors. Precise identification of CSC populations and the complete hierarchy of cells within solid tumors will facilitate more accurate characterization of patient subtypes and ultimately contribute to more personalized and effective therapies. Rapid advancement in the understanding of tumor biology as it exists in patients requires cooperation among institutions, surgeons, pathologists, cancer biologists and patients alike, primarily because this translational research is best done with patient-derived tissue grown in the xenograft setting as patient-derived xenografts. This review calls for a broader change in the approaches taken to study cancer pathobiology, highlights what implications the CSC paradigm has for pathologists and cancer biologists alike, and calls for greater collaboration between institutions, physicians and scientists in order to more rapidly advance our collective understanding of cancer.
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Affiliation(s)
- Samuel A Williams
- Cancer Biology, Stem CentRx, Inc., South San Francisco, CA 94080, USA
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24
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Cancer stem cell markers in head and neck squamous cell carcinoma. Stem Cells Int 2013; 2013:319489. [PMID: 23533441 PMCID: PMC3603684 DOI: 10.1155/2013/319489] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 01/23/2013] [Indexed: 12/22/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the world's top ten most common cancers. Current survival rates are poor with only 50% of patients expected to survive five years after diagnosis. The poor survival rate of HNSCC is partly attributable to the tendency for diagnosis at the late stage of the disease. One of the reasons for treatment failure is thought to be related to the presence of a subpopulation of cells within the tumour called cancer stem cells (CSCs). CSCs display stem cell-like characteristics that impart resistance to conventional treatment modalities and promote tumour initiation, progression, and metastasis. Specific markers for this population have been investigated in the hope of developing a deeper understanding of their role in the pathogenesis of HNSCC and elucidating novel therapeutic strategies.
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25
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Jia Q, Zhang X, Deng T, Gao J. Positive correlation of Oct4 and ABCG2 to chemotherapeutic resistance in CD90(+)CD133(+) liver cancer stem cells. Cell Reprogram 2013; 15:143-50. [PMID: 23438193 DOI: 10.1089/cell.2012.0048] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Liver cancer is one of the most common tumors worldwide and drug resistance is a major obstacle to successful therapy. The growing data show that cancer stem cells (CSCs), a rare subpopulation of cancer cells, might be an important mechanism of drug resistance. To explore the self-renewal ability and chemotherapy resistance in liver CSCs, we enriched CD90(+)CD133(+) hepatocellular carcinoma (HCC) CSCs using sphere formation, which was accomplished by cultivating HCC CSCs from established HCC cell lines (HepG2 line and Hep3B line). Cell proliferation capacity was detected using colony formation assays, and cell activity was detected using methyl thiazolyl tetrazolium (MTT) assays after doxorubicin treatment. Expression of CD90, CD133, Oct4, and ABCG2 mRNA and protein levels was detected by PCR and western blot, respectively, which showed that these genes were significantly overexpressed in liver CSCs compared to parental cells (p<0.05). Oct4 and ABCG2 are highly expressed in enriched CD90(+)CD133(+) liver CSCs and are closely associated with chemotherapy drug resistance. We postulated that liver CSCs maybe the cause of high recurrence in liver cancer.
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Affiliation(s)
- Qian Jia
- Department of Gastroenterology, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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Rodova M, Fu J, Watkins DN, Srivastava RK, Shankar S. Sonic hedgehog signaling inhibition provides opportunities for targeted therapy by sulforaphane in regulating pancreatic cancer stem cell self-renewal. PLoS One 2012; 7:e46083. [PMID: 23029396 PMCID: PMC3461003 DOI: 10.1371/journal.pone.0046083] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Accepted: 08/27/2012] [Indexed: 12/13/2022] Open
Abstract
Dysregulation of the sonic hedgehog (Shh) signaling pathway has been associated with cancer stem cells (CSC) and implicated in the initiation of pancreatic cancer. Pancreatic CSCs are rare tumor cells characterized by their ability to self-renew, and are responsible for tumor recurrence accompanied by resistance to current therapies. The lethality of these incurable, aggressive and invasive pancreatic tumors remains a daunting clinical challenge. Thus, the objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms by which sulforaphane (SFN), an active compound in cruciferous vegetables, inhibits self-renewal capacity of human pancreatic CSCs. Interestingly, we demonstrate here that Shh pathway is highly activated in pancreatic CSCs and plays important role in maintaining stemness by regulating the expression of stemness genes. Given the requirement for Hedgehog in pancreatic cancer, we investigated whether hedgehog blockade by SFN could target the stem cell population in pancreatic cancer. In an in vitro model, human pancreatic CSCs derived spheres were significantly inhibited on treatment with SFN, suggesting the clonogenic depletion of the CSCs. Interestingly, SFN inhibited the components of Shh pathway and Gli transcriptional activity. Interference of Shh-Gli signaling significantly blocked SFN-induced inhibitory effects demonstrating the requirement of an active pathway for the growth of pancreatic CSCs. SFN also inhibited downstream targets of Gli transcription by suppressing the expression of pluripotency maintaining factors (Nanog and Oct-4) as well as PDGFRα and Cyclin D1. Furthermore, SFN induced apoptosis by inhibition of BCL-2 and activation of caspases. Our data reveal the essential role of Shh-Gli signaling in controlling the characteristics of pancreatic CSCs. We propose that pancreatic cancer preventative effects of SFN may result from inhibition of the Shh pathway. Thus Sulforaphane potentially represents an inexpensive, safe and effective alternative for the management of pancreatic cancer.
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Affiliation(s)
- Mariana Rodova
- Department of Pathology and Laboratory Medicine, The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, Kansas, United States of America
- Department of Pharmacology, Toxicology and Therapeutics, and Medicine, The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Junsheng Fu
- Department of Pathology and Laboratory Medicine, The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Dara Nall Watkins
- Department of Pathology and Laboratory Medicine, The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Rakesh K. Srivastava
- Department of Pharmacology, Toxicology and Therapeutics, and Medicine, The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Sharmila Shankar
- Department of Pathology and Laboratory Medicine, The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, Kansas, United States of America
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Abstract
Targeting of cancer stem cells (CSCs) has the potential to address the recalcitrance of pancreatic cancer to chemotherapy. In this issue of Cell Stem Cell, Lonardo et al. (2011) demonstrate that Nodal/Activin signaling is crucial for the maintenance and tumor-initiating capacity of pancreatic CSCs.
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Hassanein MK, Suetsugu A, Saji S, Moriwaki H, Bouvet M, Moossa AR, Hoffman RM. Stem-like and non-stem human pancreatic cancer cells distinguished by morphology and metastatic behavior. J Cell Biochem 2012; 112:3549-54. [PMID: 21780159 DOI: 10.1002/jcb.23282] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
We report here that XPA1 human pancreatic cancer cells are dimorphic. After injection in the spleen, XPA1 cells isolated from the primary tumor in the spleen were predominantly round; while cells isolated from the resulting liver metastasis and ascites were comprised of both round- and spindle-shaped cell types. Cancer cells previously grown in the spleen and re-implanted in the spleen developed large primary tumors in the spleen only. Cancer cells isolated from liver metastasis and re-transplanted to the spleen resulted in a primary tumor in the spleen and liver metastasis. Cancer cells derived from ascites and re-transplanted to the spleen developed primary tumors in the spleen and distant metastasis in the liver, lung, and diaphragm in addition to ascites formation. Spindle and round cells were differentially labeled with fluorescent proteins of different colors. After co-injection of the two cell types in the spleen, cells were isolated from the primary tumors, liver metastasis, and ascites and analyzed by color-coded fluorescence microscopy and fluorescence-activated cell sorting (FACS). No significant differences between the percentages of spindle-shaped and round cancer cells in the primary tumor and the liver metastasis were observed. However, spindle-shaped cancer cells were enriched in the ascites. One hundred percent of the spindle-shaped and round cancer cells expressed CD44, suggesting that morphology and metastatic behavior rather than CD44 expression can distinguish the stem-like cells of the XPA1 pancreatic cancer cell line. The spindle-shaped cancer cells had the greater capability for distant metastasis and ascites formation, suggesting they are stem-like cells, which can be readily targeted for therapy.
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Li C, Wu JJ, Hynes M, Dosch J, Sarkar B, Welling TH, Pasca di Magliano M, Simeone DM. c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology 2011; 141:2218-2227.e5. [PMID: 21864475 DOI: 10.1053/j.gastro.2011.08.009] [Citation(s) in RCA: 281] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2010] [Revised: 07/29/2011] [Accepted: 08/05/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Growth of many different tumor types requires a population of self-renewing cancer stem cells (CSCs). c-Met is a marker of normal mouse pancreatic stem and progenitor cells; we investigated whether it is also a marker of human pancreatic CSCs that might be developed as a therapeutic target. METHODS We studied growth of primary human pancreatic adenocarcinoma in NOD SCID mice. The self-renewal capability of pancreatic cancer cells that expressed high levels of c-Met (c-Met(high)) was assessed using in vitro sphere assays and compared with those that were c-Met negative or expressed low levels of c-Met. The tumorigenicity of c-Met(high) pancreatic cancer cells was evaluated in NOD SCID mice. RESULTS c-Met(high) cells readily formed spheres, whereas c-Met-negative cells did not. Use of the c-Met inhibitor XL184 or c-Met knockdown with small hairpin RNAs significantly inhibited tumor sphere formation. c-Met(high) cells had increased tumorigenic potential in mice; those that expressed c-Met and CD44 (0.5%-5% of the pancreatic cancer cells) had the capability for self-renewal and the highest tumorigenic potential of all cell populations studied. In pancreatic tumors established in NOD SCID mice, c-Met inhibitors slowed tumor growth and reduced the population of CSCs when given alone or in combination with gemcitabine. Administration of XL184 for 2 weeks after cardiac injection of cancer cells prevented the development of metastases. CONCLUSIONS c-Met is a new marker for pancreatic CSCs. It is required for growth and metastasis of pancreatic tumors in mice and is a therapeutic target for pancreatic cancer.
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Affiliation(s)
- Chenwei Li
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
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30
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Wakamatsu Y, Sakamoto N, Oo HZ, Naito Y, Uraoka N, Anami K, Sentani K, Oue N, Yasui W. Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer. Pathol Int 2011; 62:112-9. [DOI: 10.1111/j.1440-1827.2011.02760.x] [Citation(s) in RCA: 141] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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31
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Bao B, Ali S, Banerjee S, Wang Z, Logna F, Azmi AS, Kong D, Ahmad A, Li Y, Padhye S, Sarkar FH. Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res 2011; 72:335-45. [PMID: 22108826 DOI: 10.1158/0008-5472.can-11-2182] [Citation(s) in RCA: 224] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The histone methyltransferase EZH2 is a central epigenetic regulator of cell survival, proliferation, and cancer stem cell (CSC) function. EZH2 expression is increased in various human cancers, including highly aggressive pancreatic cancers, but the mechanisms underlying for its biologic effects are not yet well understood. In this study, we probed EZH2 function in pancreatic cancer using diflourinated-curcumin (CDF), a novel analogue of the turmeric spice component curcumin that has antioxidant properties. CDF decreased pancreatic cancer cell survival, clonogenicity, formation of pancreatospheres, invasive cell migration, and CSC function in human pancreatic cancer cells. These effects were associated with decreased expression of EZH2 and increased expression of a panel of tumor-suppressive microRNAs (miRNA), including let-7a, b, c, d, miR-26a, miR-101, miR-146a, andmiR-200b, c that are typically lost in pancreatic cancer. Mechanistic investigations revealed that reexpression of miR-101 was sufficient to limit the expression of EZH2 and the proinvasive cell surface adhesion molecule EpCAM. In an orthotopic xenograft model of human pancreatic cancer, administration of CDF inhibited tumor growth in a manner associated with reduced expression of EZH2, Notch-1, CD44, EpCAM, and Nanog and increased expression of let-7, miR-26a, and miR-101. Taken together, our results indicated that CDF inhibited pancreatic cancer tumor growth and aggressiveness by targeting an EZH2-miRNA regulatory circuit for epigenetically controlled gene expression.
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Affiliation(s)
- Bin Bao
- Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA
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Balasubramanian P, Yang L, Lang JC, Jatana KR, Schuller D, Agrawal A, Zborowski M, Chalmers JJ. Confocal images of circulating tumor cells obtained using a methodology and technology that removes normal cells. Mol Pharm 2009; 6:1402-8. [PMID: 19445481 DOI: 10.1021/mp9000519] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
A completely negative enrichment technology was used to detect circulating tumor cells, CTCs, in the peripheral blood of head and neck cancer patients. Of 32 blood samples, 63% contained CTCs and the number of CTCs identified per mL of blood collected ranged from 0 to 214. The final purity ranged from 1 CTC in 9 total cells to 1 CTC in 20,000 total cells, the final purity being both a function of the number of CTCs and the performance of the specific enrichment. Consistent with previous reports, CTC were positively identified if: (1) they contained a nucleus based on DAPI stain, (2) stained positive for cytokeratins, and (3) have a high nuclei to cytoplasmic ratio. In addition, for a blood sample to be considered positive for CTCs, the enriched sample must be positive for epithelial growth factor receptor, EGFR, as measured by RT-PCR. While most of the blood samples were obtained during surgery, a number were taken prior to and during surgery. In all of the pre- and postsurgery paired samples, significant numbers of CTCs were detected. A number of these enriched samples were observed under confocal microscope in addition to the microscopic observations under traditional wide-field fluorescent microscope. As expected, the FITC stained cytokeratins appeared in the cytoplasm and the average size of these positively stained cells, on the cytospin, was in the range of 8-12 mum. Future studies will involve the investigation if cancer stem cell and mesenchymal markers are present on these CTCs and correlations of patient outcome to the number and type of CTC present.
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Affiliation(s)
- Priya Balasubramanian
- William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, 125 Koffolt Laboratories, 140 West 19th Avenue, Columbus, Ohio 43210, USA
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33
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The cancer stem cell concept in progression of head and neck cancer. JOURNAL OF ONCOLOGY 2009; 2009:894064. [PMID: 20052382 PMCID: PMC2800367 DOI: 10.1155/2009/894064] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/13/2009] [Accepted: 09/14/2009] [Indexed: 01/06/2023]
Abstract
Human head and neck cancer (HNC) is a highly heterogeneous disease. Understanding the biology of HNC progression is necessary for the development of novel approaches to its prevention, early detection, and treatment. A current evolutional progression model has limitations in explaining the heterogeneity observed in a single tumor nest. Accumulating evidence supports the existence of cancer stem cells (CSCs) as small subpopulations in solid tumors, including HNC. These CSCs can be selected by appropriate cell surface markers, which are cancer type specific and have been confirmed by unique in vitro and in vivo assays. Selected CSC populations maintain a self-renewal capability and show aggressive behaviors, such as chemoresistance and metastasis. In addition to introducing the CSC concept in solid tumors, this short review summarizes current publications in HNC CSC and the prospective development and application of the CSC concept to HNC in the clinic.
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34
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Philip PA, Mooney M, Jaffe D, Eckhardt G, Moore M, Meropol N, Emens L, O'Reilly E, Korc M, Ellis L, Benedetti J, Rothenberg M, Willett C, Tempero M, Lowy A, Abbruzzese J, Simeone D, Hingorani S, Berlin J, Tepper J. Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment. J Clin Oncol 2009; 27:5660-9. [PMID: 19858397 DOI: 10.1200/jco.2009.21.9022] [Citation(s) in RCA: 188] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 5% because of microscopic or gross metastatic disease at time of diagnosis. The Clinical Trials Planning Meeting in pancreatic cancer was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to discuss the integration of basic and clinical knowledge in the design of clinical trials in PDAC. Major emphasis was placed on the enhancement of research to identify and validate the relevant targets and molecular pathways in PDAC, cancer stem cells, and the microenvironment. Emphasis was also placed on developing rational combinations of targeted agents and the development of predictive biomarkers to assist selection of patient subsets. The development of preclinical tumor models that are better predictive of human PDAC must be supported with wider availability to the research community. Phase III clinical trials should be implemented only if there is a meaningful clinical signal of efficacy and safety in the phase II setting. The emphasis must therefore be on performing well-designed phase II studies with uniform sets of basic entry and evaluation criteria with survival as a primary endpoint. Patients with either metastatic or locally advanced PDAC must be studied separately.
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Affiliation(s)
- Philip A Philip
- Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
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Yu X, Zhang Y, Chen C, Yao Q, Li M. Targeted drug delivery in pancreatic cancer. Biochim Biophys Acta Rev Cancer 2009; 1805:97-104. [PMID: 19853645 DOI: 10.1016/j.bbcan.2009.10.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2009] [Revised: 10/07/2009] [Accepted: 10/11/2009] [Indexed: 12/16/2022]
Abstract
Effective drug delivery in pancreatic cancer treatment remains a major challenge. Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. Recent advances in drug delivery systems hold great promise for improving cancer therapy. Using liposomes, nanoparticles, and carbon nanotubes to deliver cancer drugs and other therapeutic agents such as siRNA, suicide gene, oncolytic virus, small molecule inhibitor, and antibody has been a success in recent preclinical trials. However, how to improve the specificity and stability of the delivered drug using ligand or antibody directed delivery represent a major problem. Therefore, developing novel, specific, tumor-targeted drug delivery systems is urgently needed for this terrible disease. This review summarizes the current progress on targeted drug delivery in pancreatic cancer and provides important information on potential therapeutic targets for pancreatic cancer treatment.
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Affiliation(s)
- Xianjun Yu
- Michael E. DeBakey Department of Surgery, Molecular Surgeon Research Center, Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
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Pietra G, Manzini C, Vitale M, Balsamo M, Ognio E, Boitano M, Queirolo P, Moretta L, Mingari MC. Natural killer cells kill human melanoma cells with characteristics of cancer stem cells. Int Immunol 2009; 21:793-801. [DOI: 10.1093/intimm/dxp047] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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