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1
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Hassan MS, Johnson C, Ponna S, Scofield D, Awasthi N, von Holzen U. Inhibition of Insulin-like Growth Factor 1 Receptor/Insulin Receptor Signaling by Small-Molecule Inhibitor BMS-754807 Leads to Improved Survival in Experimental Esophageal Adenocarcinoma. Cancers (Basel) 2024; 16:3175. [PMID: 39335147 PMCID: PMC11430189 DOI: 10.3390/cancers16183175] [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: 08/12/2024] [Revised: 09/04/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
The insulin-like growth factor-1 (IGF-1) and insulin axes are upregulated in obesity and obesity-associated esophageal adenocarcinoma (EAC). Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a contemporary nanotechnology-based paclitaxel (PT) bound to human albumin, ensuring its solubility in water rather than a toxic solvent. Here, we examined the benefits of inhibiting insulin-like growth factor-1 receptor/insulin receptor (IGF-1/IR) signaling and the enhancement of nab-paclitaxel effects by inclusion of the small-molecule inhibitor BMS-754807 using both in vitro and in vivo models of EAC. Using multiple EAC cell lines, BMS-754807 and nab-paclitaxel were evaluated as mono and combination therapies for in vitro effects on cell proliferation, cell death, and cell movement. We then analyzed the in vivo anticancer potency with survival improvement with BMS-754807 and nab-paclitaxel mono and combination therapies. BMS-754807 monotherapy suppressed in vitro cell proliferation and wound healing while increasing apoptosis. BMS-754807, when combined with nab-paclitaxel, enhanced those effects on the inhibition of cell proliferation, increment in cell apoptosis, and inhibition of wound healing. BMS-754807 with nab-paclitaxel produced substantially greater antitumor effects by increasing in vivo apoptosis, leading to increased mice survival compared to those of BMS-754807 or nab-paclitaxel monotherapy. Our outcomes support the use of BMS-754807, alone and in combination with nab-paclitaxel, as an efficient and innovative treatment choice for EAC.
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Affiliation(s)
- Md Sazzad Hassan
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA; (N.A.)
- Harper Cancer Research Institute, South Bend, IN 46617, USA
| | - Chloe Johnson
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Saisantosh Ponna
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Dimitri Scofield
- Department of Biology, Indiana University, South Bend, IN 47405, USA
| | - Niranjan Awasthi
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA; (N.A.)
- Harper Cancer Research Institute, South Bend, IN 46617, USA
| | - Urs von Holzen
- Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA; (N.A.)
- Harper Cancer Research Institute, South Bend, IN 46617, USA
- Goshen Center for Cancer Care, Goshen, IN 46526, USA
- School of Medicine, University of Basel, 4056 Basel, Switzerland
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Role of Obesity, Physical Exercise, Adipose Tissue-Skeletal Muscle Crosstalk and Molecular Advances in Barrett's Esophagus and Esophageal Adenocarcinoma. Int J Mol Sci 2022; 23:ijms23073942. [PMID: 35409299 PMCID: PMC8999972 DOI: 10.3390/ijms23073942] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 02/07/2023] Open
Abstract
Both obesity and esophageal adenocarcinoma (EAC) rates have increased sharply in the United States and Western Europe in recent years. EAC is a classic example of obesity-related cancer where the risk of EAC increases with increasing body mass index. Pathologically altered visceral fat in obesity appears to play a key role in this process. Visceral obesity may promote EAC by directly affecting gastroesophageal reflux disease and Barrett’s esophagus (BE), as well as a less reflux-dependent effect, including the release of pro-inflammatory adipokines and insulin resistance. Deregulation of adipokine production, such as the shift to an increased amount of leptin relative to “protective” adiponectin, has been implicated in the pathogenesis of BE and EAC. This review discusses not only the epidemiology and pathophysiology of obesity in BE and EAC, but also molecular alterations at the level of mRNA and proteins associated with these esophageal pathologies and the potential role of adipokines and myokines in these disorders. Particular attention is given to discussing the possible crosstalk of adipokines and myokines during exercise. It is concluded that lifestyle interventions to increase regular physical activity could be helpful as a promising strategy for preventing the development of BE and EAC.
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3
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McShane R, Arya S, Stewart AJ, Caie P, Bates M. Prognostic features of the tumour microenvironment in oesophageal adenocarcinoma. Biochim Biophys Acta Rev Cancer 2021; 1876:188598. [PMID: 34332022 DOI: 10.1016/j.bbcan.2021.188598] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 07/26/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Oesophageal adenocarcinoma (OAC) is a disease with an incredibly poor survival rate and a complex makeup. The growth and spread of OAC tumours are profoundly influenced by their surrounding microenvironment and the properties of the tumour itself. Constant crosstalk between the tumour and its microenvironment is key to the survival of the tumour and ultimately the death of the patient. The tumour microenvironment (TME) is composed of a complex milieu of cell types including cancer associated fibroblasts (CAFs) which make up the tumour stroma, endothelial cells which line blood and lymphatic vessels and infiltrating immune cell populations. These various cell types and the tumour constantly communicate through environmental cues including fluctuations in pH, hypoxia and the release of mitogens such as cytokines, chemokines and growth factors, many of which help promote malignant progression. Eventually clusters of tumour cells such as tumour buds break away and spread through the lymphatic system to nearby lymph nodes or enter the circulation forming secondary metastasis. Collectively, these factors need to be considered when assessing and treating patients clinically. This review aims to summarise the ways in which these various factors are currently assessed and how they relate to patient treatment and outcome at an individual level.
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Affiliation(s)
| | - Swati Arya
- School of Medicine, University of St Andrews, Fife, UK
| | | | - Peter Caie
- School of Medicine, University of St Andrews, Fife, UK
| | - Mark Bates
- Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Dublin 8, Ireland; Trinity St James's Cancer Institute, St James's Hospital, Dublin 8, Ireland.
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4
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Melo AM, Mylod E, Fitzgerald V, Donlon NE, Murphy DM, Foley EK, Bhardwaj A, Reynolds JV, Doherty DG, Lysaght J, Dunne MR, Conroy MJ. Tissue distribution of γδ T cell subsets in oesophageal adenocarcinoma. Clin Immunol 2021; 229:108797. [PMID: 34273585 DOI: 10.1016/j.clim.2021.108797] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 06/25/2021] [Accepted: 07/10/2021] [Indexed: 12/16/2022]
Abstract
The global obesity epidemic is contributing to increased prevalence of diseases fuelled by chronic inflammation, including cancer. Oesophageal adenocarcinoma (OAC) is an obesity-associated malignancy with increasing prevalence, dismal prognosis, and severely dysregulated immune processes. We previously reported that αβ T cells migrate to omentum and liver in OAC and contribute to inflammation in these tissues. Here, we assessed the tissue distribution and phenotype of gamma/delta (γδ) T cells in the blood, omentum, liver and tumour of OAC patients. Our data show that the Vδ1 and Vδ3 subsets of γδ T cells are most prevalent in omentum and liver of OAC patients. Furthermore, γδ T cells are predominantly pro-inflammatory in these tissues, and co-express IFN-γ and IL-17. Moreover, γδ T cells exhibit cytotoxic capabilities in OAC omentum and liver. This study provides the first indication that γδ T cells contribute to obesity-associated inflammation in OAC and might be exploited therapeutically.
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Affiliation(s)
- Ashanty M Melo
- Cancer Immunology and Immunotherapy Group, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland
| | - Eimear Mylod
- Cancer Immunology and Immunotherapy Group, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland
| | - Vivienne Fitzgerald
- Cancer Immunology and Immunotherapy Group, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland
| | - Noel E Donlon
- Cancer Immunology and Immunotherapy Group, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland
| | | | - Emma K Foley
- Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland
| | - Anshul Bhardwaj
- Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland
| | - John V Reynolds
- Gastro-Intestinal Medicine and Surgery, St. James's Hospital, Dublin 8, Ireland
| | | | - Joanne Lysaght
- Cancer Immunology and Immunotherapy Group, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland
| | - Margaret R Dunne
- Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland
| | - Melissa J Conroy
- Cancer Immunology and Immunotherapy Group, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland.
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5
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Elliott JA, Reynolds JV. Visceral Obesity, Metabolic Syndrome, and Esophageal Adenocarcinoma. Front Oncol 2021; 11:627270. [PMID: 33777773 PMCID: PMC7994523 DOI: 10.3389/fonc.2021.627270] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 02/19/2021] [Indexed: 12/16/2022] Open
Abstract
Esophageal adenocarcinoma (EAC) represents an exemplar of obesity-associated carcinogenesis, with a progressive increase in EAC risk with increased body mass index. In this context, there is increased focus on visceral adipose tissue and associated metabolic dysfunction, including hypertension, diabetes mellitus and hyperlipidemia, or combinations of these in the metabolic syndrome. Visceral obesity (VO) may promote EAC via both directly impacting on gastro-esophageal reflux disease and Barrett's esophagus, as well as via reflux-independent effects, involving adipokines, growth factors, insulin resistance, and the microbiome. In this review these pathways are explored, including the impact of VO on the tumor microenvironment, and on cancer outcomes. The current evidence-based literature regarding the role of dietary, lifestyle, pharmacologic and surgical interventions to modulate the risk of EAC is explored.
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Affiliation(s)
- Jessie A Elliott
- Trinity St. James's Cancer Institute, Trinity College Dublin and St. James's Hospital, Dublin, Ireland
| | - John V Reynolds
- Trinity St. James's Cancer Institute, Trinity College Dublin and St. James's Hospital, Dublin, Ireland
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6
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Dighe SG, Chen J, Yan L, He Q, Gharahkhani P, Onstad L, Levine DM, Palles C, Ye W, Gammon MD, Iyer PG, Anderson LA, Liu G, Wu AH, Dai JY, Chow WH, Risch HA, Lagergren J, Shaheen NJ, Bernstein L, Corley DA, Prenen H, deCaestecker J, MacDonald D, Moayyedi P, Barr H, Love SB, Chegwidden L, Attwood S, Watson P, Harrison R, Ott K, Moebus S, Venerito M, Lang H, Mayershofer R, Knapp M, Veits L, Gerges C, Weismüller J, Gockel I, Vashist Y, Nöthen MM, Izbicki JR, Manner H, Neuhaus H, Rösch T, Böhmer AC, Hölscher AH, Anders M, Pech O, Schumacher B, Schmidt C, Schmidt T, Noder T, Lorenz D, Vieth M, May A, Hess T, Kreuser N, Becker J, Ell C, Ambrosone CB, Moysich KB, MacGregor S, Tomlinson I, Whiteman DC, Jankowski J, Schumacher J, Vaughan TL, Madeleine MM, Hardie LJ, Buas MF. Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma. Carcinogenesis 2020; 42:369-377. [PMID: 33300568 PMCID: PMC8052954 DOI: 10.1093/carcin/bgaa132] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 10/21/2020] [Accepted: 12/08/2020] [Indexed: 12/21/2022] Open
Abstract
Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.
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Affiliation(s)
- Shruti G Dighe
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Jianhong Chen
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Li Yan
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Qianchuan He
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Puya Gharahkhani
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Lynn Onstad
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - David M Levine
- Department of Biostatistics, University of Washington, School of Public Health, Seattle, WA, USA
| | - Claire Palles
- Gastrointestinal Cancer Genetics Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Weimin Ye
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Marilie D Gammon
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA
| | - Prasad G Iyer
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Lesley A Anderson
- Department of Epidemiology and Public Health, Queen’s University of Belfast, Royal Group of Hospitals, Belfast, UK
| | - Geoffrey Liu
- Department of Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada
| | - Anna H Wu
- Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - James Y Dai
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Wong-Ho Chow
- Department of Epidemiology, MD Anderson Cancer Center, Houston, TX, USA
| | - Harvey A Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | - Jesper Lagergren
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden,Department of Surgery, School of Cancer and Pharmaceutical Sciences, King’s College London
| | - Nicholas J Shaheen
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Leslie Bernstein
- Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Douglas A Corley
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA,Gastroenterology, San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California, USA
| | - Hans Prenen
- Oncology Department, University Hospital Antwerp, Edegem, Belgium
| | - John deCaestecker
- Digestive Diseases Centre, University Hospitals of Leicester, Leicester, UK
| | - David MacDonald
- Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Paul Moayyedi
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Hugh Barr
- Department of Upper GI Surgery, Gloucestershire Royal Hospital, Gloucester, UK
| | - Sharon B Love
- Centre for Statistics in Medicine, University of Oxford, Oxford, UK; MRC Clinical Trials Unit at University College London, London, UK
| | - Laura Chegwidden
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
| | - Stephen Attwood
- Department of General Surgery, North Tyneside General Hospital, North Shields, UK
| | - Peter Watson
- Department of Medicine, Institute of Clinical Science, Royal Victoria Hospital, Belfast, UK
| | - Rebecca Harrison
- Department of Pathology, Leicester Royal Infirmary, Leicester, UK
| | - Katja Ott
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany,Department of General, Visceral and Thorax Surgery, RoMed Klinikum Rosenheim, Rosenheim, Germany
| | - Susanne Moebus
- Biometry and Epidemiology, Institute for Urban Public Health, University Hospitals, University of Duisburg-Essen, Essen, Germany
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Hauke Lang
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | | | - Michael Knapp
- Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany
| | - Lothar Veits
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | - Christian Gerges
- Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany
| | | | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Yogesh Vashist
- Department of Surgery, Asklepios Harzklinik Goslar, Goslar, Germany
| | - Markus M Nöthen
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany
| | - Jakob R Izbicki
- General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hendrik Manner
- Department of Internal Medicine II, Frankfurt Hoechst Hospital, Frankfurt, Germany
| | - Horst Neuhaus
- Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany
| | - Thomas Rösch
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Anne C Böhmer
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany
| | - Arnulf H Hölscher
- Clinic for General, Visceral and Trauma Surgery, Department of Surgery, Contilia Center for Esophageal Diseases. Elisabeth Hospital, Essen, Germany
| | - Mario Anders
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany,Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany
| | - Oliver Pech
- Department of Gastroenterology and Interventional Endoscopy, St. John of God Hospital, Regensburg, Germany
| | - Brigitte Schumacher
- Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany,Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany
| | - Claudia Schmidt
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Thomas Schmidt
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Tania Noder
- Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Dietmar Lorenz
- Department of General and Visceral Surgery, Sana Klinikum, Offenbach, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | - Andrea May
- Department of Gastroenterology, Oncology and Pneumology, Asklepios Paulinen Klinik, Wiesbaden, Germany
| | - Timo Hess
- Center for Human Genetics, University Hospital of Marburg, Marburg, Germany
| | - Nicole Kreuser
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Jessica Becker
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany
| | - Christian Ell
- Department of Medicine II, Sana Klinikum, Offenbach, Germany
| | - Christine B Ambrosone
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Kirsten B Moysich
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Stuart MacGregor
- Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Ian Tomlinson
- Gastrointestinal Cancer Genetics Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - David C Whiteman
- Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Janusz Jankowski
- Division of Medicine Kings Mill Hospital, Sherwood Hospitals NHS Trust, Nottinghamshire, UK,Comprehensive Clinical Trials Unit, University College London, London, UK,Dean’s Office, College of Medicine and Health Sciences (CMHS), AL Ain, UAE
| | | | - Thomas L Vaughan
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,Department of Epidemiology, University of Washington, School of Public Health, Seattle, WA, USA
| | - Margaret M Madeleine
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA,Department of Epidemiology, University of Washington, School of Public Health, Seattle, WA, USA
| | - Laura J Hardie
- Department of Epidemiology, University of Leeds, Leeds, UK,Correspondence may also be addressed to Laura J. Hardie. Tel: +44(0)113 343 7769;
| | - Matthew F Buas
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA,To whom correspondence should be addressed. Tel: +1 716-845-4754;
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Schlottmann F, Dreifuss NH, Patti MG. Obesity and esophageal cancer: GERD, Barrett´s esophagus, and molecular carcinogenic pathways. Expert Rev Gastroenterol Hepatol 2020; 14:425-433. [PMID: 32441160 DOI: 10.1080/17474124.2020.1764348] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 04/30/2020] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Increases in the rates of esophageal adenocarcinoma (EAC) have paralleled rises in the prevalence of overweight and obesity. Despite not being fully understood, obesity-related EAC seems to have different carcinogenic pathways. AREAS COVERED This comprehensive review will thoroughly evaluate the current literature, describing the underlying mechanisms that help understanding the strong association between obesity and esophageal cancer. EXPERT COMMENTARY The risk of esophageal cancer among obese individuals could be partially explained by several factors: high prevalence of GERD; linear association between central adiposity and Barrett´s esophagus development; low levels of adiponectin and high levels of leptin that alter cell proliferation processes; insulin-resistant state that creates a tumorigenesis environment; and changes in the esophageal microbiota due to unhealthy dietary habits that promote carcinogenesis. In addition, a large proportion of obese patients are undergoing sleeve gastrectomy which can worsen GERD or cause de novo reflux, esophagitis, and Barrett´s metaplasia.
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Affiliation(s)
| | - Nicolás H Dreifuss
- Department of Surgery, Hospital Alemán of Buenos Aires , Buenos Aires, Argentina
| | - Marco G Patti
- Department of Medicine and Surgery, University of North Carolina , Chapel Hill, NC, USA
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8
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Creemers A, Ebbing EA, Pelgrim TC, Lagarde SM, van Etten-Jamaludin FS, van Berge Henegouwen MI, Hulshof MCCM, Krishnadath KK, Meijer SL, Bijlsma MF, van Oijen MGH, van Laarhoven HWM. A systematic review and meta-analysis of prognostic biomarkers in resectable esophageal adenocarcinomas. Sci Rep 2018; 8:13281. [PMID: 30185893 PMCID: PMC6125467 DOI: 10.1038/s41598-018-31548-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 08/20/2018] [Indexed: 02/07/2023] Open
Abstract
Targeted therapy is lagging behind in esophageal adenocarcinoma (EAC). To guide the development of new treatment strategies, we provide an overview of the prognostic biomarkers in resectable EAC treated with curative intent. The Medline, Cochrane and EMBASE databases were systematically searched, focusing on overall survival (OS). The quality of the studies was assessed using a scoring system ranging from 0-7 points based on modified REMARK criteria. To evaluate all identified prognostic biomarkers, the hallmarks of cancer were adapted to fit all biomarkers based on their biological function in EAC, resulting in the features angiogenesis, cell adhesion and extra-cellular matrix remodeling, cell cycle, immune, invasion and metastasis, proliferation, and self-renewal. Pooled hazard ratios (HR) and 95% confidence intervals (CI) were derived by random effects meta-analyses performed on each hallmarks of cancer feature. Of the 3298 unique articles identified, 84 were included, with a mean quality of 5.9 points (range 3.5-7). The hallmarks of cancer feature 'immune' was most significantly associated with worse OS (HR 1.88, (95%CI 1.20-2.93)). Of the 82 unique prognostic biomarkers identified, meta-analyses showed prominent biomarkers, including COX-2, PAK-1, p14ARF, PD-L1, MET, LC3B, IGFBP7 and LGR5, associated to each hallmark of cancer.
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Affiliation(s)
- Aafke Creemers
- Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.
- Department of Medical Oncology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.
| | - Eva A Ebbing
- Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Medical Oncology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Thomas C Pelgrim
- Department of Medical Oncology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Sjoerd M Lagarde
- Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Faridi S van Etten-Jamaludin
- Department of Medical Library Science, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | | | - Maarten C C M Hulshof
- Department of Radiotherapy, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Kausilia K Krishnadath
- Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Gastroenterology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Sybren L Meijer
- Department of Pathology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Maarten F Bijlsma
- Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Martijn G H van Oijen
- Department of Medical Oncology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Hanneke W M van Laarhoven
- Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
- Department of Medical Oncology, Amsterdam UMC, Univ of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
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9
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Boshier PR, Heneghan R, Markar SR, Baracos VE, Low DE. Assessment of body composition and sarcopenia in patients with esophageal cancer: a systematic review and meta-analysis. Dis Esophagus 2018; 31:5006250. [PMID: 29846548 DOI: 10.1093/dote/doy047] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
There has recently been increased interest in the assessment of body composition in patients with esophageal cancer for the purpose of nutritional evaluation and prognostication. This systematic review and meta-analysis intends to summarize and critically evaluate the current literature concerning the assessment of body composition in patients with esophageal cancer and to assess its potential implication upon early and late outcomes. A systematic literature search (up to August, 2017) was conducted for studies describing the assessment of body composition in patients with esophageal and gastroesophageal junctional cancer. Meta-analysis of postoperative outcomes including long-term survival was performed using random effects models. Twenty-nine studies reported the assessment of body composition in 3193 patients. Methods used to assess body composition in patients with esophageal cancer included computerized tomography (n = 18 studies), bioelectrical impedance analysis (n = 10), and dual-energy X-ray absorptiometry (n = 1). Significant variability was observed in regard to study design and the criteria used to define individual parameters of body composition. Sarcopenic patients had a higher incidence of postoperative pulmonary complications (7 studies, OR 2.03, 95% CI 1.32-3.11, P = 0.001) after esophagectomy. Meta-analysis of six studies presenting long-term outcomes after esophagectomy identified significantly worse survival in patients who were sarcopenic (HR 1.70, 95% CI 1.33- 2.17, P < 0.0001). The assessment of body composition has the potential to become a clinically useful tool that could support decision-making in patients with esophageal cancer. Current evidence is however weakened by inconsistencies in methods of assessing and reporting body composition in this patient group.
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Affiliation(s)
- P R Boshier
- Department of Thoracic Surgery and Thoracic Oncology, Virginia Mason Medical Centre, Seattle, USA
- Department of Surgery and Cancer, Imperial College London, UK
| | - R Heneghan
- Department of Thoracic Surgery and Thoracic Oncology, Virginia Mason Medical Centre, Seattle, USA
| | - S R Markar
- Department of Surgery and Cancer, Imperial College London, UK
| | - V E Baracos
- Department of Oncology, University of Alberta, Edmonton, Canada
| | - D E Low
- Department of Thoracic Surgery and Thoracic Oncology, Virginia Mason Medical Centre, Seattle, USA
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10
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Breen KJ, O'Neill A, Murphy L, Fan Y, Boyce S, Fitzgerald N, Dorris E, Brady L, Finn SP, Hayes BD, Treacy A, Barrett C, Aziz MA, Kay EW, Fitzpatrick JM, Watson RWG. Investigating the role of the IGF axis as a predictor of biochemical recurrence in prostate cancer patients post-surgery. Prostate 2017; 77:1288-1300. [PMID: 28726241 DOI: 10.1002/pros.23389] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 06/22/2017] [Indexed: 12/30/2022]
Abstract
BACKGROUND Between 20% and 35% of prostate cancer (PCa) patients who undergo treatment with curative intent (ie, surgery or radiation therapy) for localized disease will experience biochemical recurrence (BCR). Alterations in the insulin-like growth factor (IGF) axis and PTEN expression have been implicated in the development and progression of several human tumors including PCa. We examined the expression of the insulin receptor (INSR), IGF-1 receptor (IGF-1R), PTEN, and AKT in radical prostatectomy tissue of patients who developed BCR post-surgery. METHODS Tissue microarrays (TMA) of 130 patients post-radical prostatectomy (65 = BCR, 65 = non-BCR) were stained by immunohistochemistry for INSR, IGF-1R, PTEN, and AKT using optimized antibody protocols. INSR, IGF1-R, PTEN, and AKT expression between benign and cancerous tissue, and different Gleason grades was assessed. Kaplan-Meier survival curves were used to examine the relationship between proteins expression and BCR. RESULTS INSR (P < 0.001), IGF-1R (P < 0.001), and AKT (P < 0.05) expression was significantly increased and PTEN (P < 0.001) was significantly decreased in cancerous versus benign tissue. There was no significant difference in INSR, IGF-1R, or AKT expression in the cancerous tissue of non-BCR versus BCR patients (P = 0.149, P = 0.990, P = 0.399, respectively). There was a significant decrease in PTEN expression in the malignant tissue of BCR versus non-BCR patients (P = 0.011). Combinational analysis of the tissue proteins identified a combination of decreased PTEN and increased AKT or increased INSR was associated with worst outcome. We found that in each case, our hypothesized worst group was most likely to experience BCR and this was significant for combinations of PTEN+INSR and PTEN+AKT but not PTEN+IGF-1R (P = 0.023, P = 0.028, P = 0.078, respectively). CONCLUSIONS Low PTEN is associated with BCR and this association is strongly modified by high INSR and high AKT expression. Measurement of these proteins could help inform appropriate patient selection for postoperative adjuvant therapy and prevent BCR.
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Affiliation(s)
- Kieran J Breen
- UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
| | - Amanda O'Neill
- UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
| | - Lisa Murphy
- UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
| | - Yue Fan
- UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
| | - Susie Boyce
- UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
- UCD School of Mathematical Sciences, Dublin, Ireland
| | - Noel Fitzgerald
- UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
| | - Emma Dorris
- UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
| | - Lauren Brady
- Department of Histopathology and Morbid Anatomy, Trinity Translational Medicine Institute, Trinity College, Dublin, Ireland
- Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | - Stephen P Finn
- Department of Histopathology and Morbid Anatomy, Trinity Translational Medicine Institute, Trinity College, Dublin, Ireland
- Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | - Brian D Hayes
- Department of Histopathology and Morbid Anatomy, Trinity Translational Medicine Institute, Trinity College, Dublin, Ireland
- Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | - Ann Treacy
- Department of Histopathology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Ciara Barrett
- Department of Histopathology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Mardiana Abdul Aziz
- Department of Histopathology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Elaine W Kay
- Department of Pathology, RCSI Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - John M Fitzpatrick
- UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
| | - R William G Watson
- UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland
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11
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Adachi Y, Nojima M, Mori M, Yamashita K, Yamano HO, Nakase H, Endo T, Wakai K, Sakata K, Tamakoshi A. Insulin-like growth factor-1, IGF binding protein-3, and the risk of esophageal cancer in a nested case-control study. World J Gastroenterol 2017; 23:3488-3495. [PMID: 28596684 PMCID: PMC5442084 DOI: 10.3748/wjg.v23.i19.3488] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 02/25/2017] [Accepted: 04/21/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the relationship between serum levels of insulin-like growth factor-1 (IGF1)/IGF-binding protein-3 (IGFBP3) and the risk of esophageal carcinoma. METHODS We assessed the relationship between the serum levels of these molecules and the risk of esophageal cancer in a prospective, nested case-control study of participants from the Japan Collaborative Cohort Study. A baseline survey was conducted from 1988 to 1990. Of the 110585 enrolled participants, 35% donated blood samples. Those who had been diagnosed with esophageal cancer were considered cases for nested case-control studies. A conditional logistic model was used to estimate odds ratios for the incidence of esophageal cancer associated with serum IGF1 and IGFBP3 levels. RESULTS Thirty-one cases and 86 controls were eligible for the present assessment. The molar ratio of IGF1/IGFBP3, which represents the free and active form of IGF1, was not correlated with the risk of esophageal carcinoma. A higher molar difference between IGFBP3 and IGF1, which estimates the free form of IGFBP3, was associated with a decreased risk of esophageal carcinoma (P = 0.0146), and people in the highest tertile had the lowest risk (OR = 0.107, 95%CI: 0.017-0.669). After adjustment for body mass index, tobacco use, and alcohol intake, the molar difference of IGFBP3-IGF1 was inversely correlated with the risk of esophageal carcinoma (P = 0.0150). CONCLUSION The free form of IGFBP3, which is estimated by this molar difference, may be inversely associated with esophageal cancer incidence.
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12
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Abdominal obesity and gastroesophageal cancer risk: systematic review and meta-analysis of prospective studies. Biosci Rep 2017; 37:BSR20160474. [PMID: 28336766 PMCID: PMC5426287 DOI: 10.1042/bsr20160474] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 03/07/2017] [Accepted: 03/22/2017] [Indexed: 12/26/2022] Open
Abstract
To systematically and quantitatively review the relation of abdominal obesity, as measured by waist circumference (WC) and waist to hip ratio (WHR), to total gastroesophageal cancer, gastric cancer (GC), and esophageal cancer. PubMed and Web of Science databases were searched for studies assessing the association between abdominal obesity and gastroesophageal cancer (GC and/or esophageal cancer) up to August 2016. A random-effect model was used to calculate the summary relative risks (RRs) and 95% confidence intervals (CIs). Seven prospective cohort studies – one publication included two separate cohorts – from six publications were included in the final analysis. A total of 2130 gastroesophageal cancer cases diagnosed amongst 913182 participants. Higher WC and WHR were significantly associated with increased risk of total gastroesophageal cancer (WC: RR 1.68, 95% CI: 1.38, 2.04; WHR: RR 1.49, 95% CI: 1.19, 1.88), GC (WC: RR 1.48, 95% CI: 1.24, 1.78; WHR: 1.33, 95% CI: 1.04, 1.70), and esophageal cancer (WC: RR 2.06, 95% CI: 1.30, 3.24; WHR: RR 1.99, 95% CI: 1.05, 3.75).Findings from our subgroup analyses showed non-significant positive associations between gastric non-cardia adenocarcinoma (GNCA) and both measures of abdominal adiposity, while gastric cardia adenocarcinoma (GCA) was positively associated with WC but not with WHR. On analysis restricted to studies that adjusted for body mass index (BMI), WC was positively associated with GC and esophageal cancer, whereas WHR was positively associated with risk of GC only. Although limited, the findings from our meta-analysis suggest the potential role of abdominal obesity in the etiology of gastric and esophageal cancers.
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13
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Lewitt MS. The Role of the Growth Hormone/Insulin-Like Growth Factor System in Visceral Adiposity. BIOCHEMISTRY INSIGHTS 2017; 10:1178626417703995. [PMID: 28469442 PMCID: PMC5404904 DOI: 10.1177/1178626417703995] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Accepted: 03/19/2017] [Indexed: 12/18/2022]
Abstract
There is substantial evidence that the growth hormone (GH)/insulin-like growth factor (IGF) system is involved in the pathophysiology of obesity. Both GH and IGF-I have direct effects on adipocyte proliferation and differentiation, and this system is involved in the cross-talk between adipose tissue, liver, and pituitary. Transgenic animal models have been of importance in identifying mechanisms underlying these interactions. It emerges that this system has key roles in visceral adiposity, and there is a rationale for targeting this system in the treatment of visceral obesity associated with GH deficiency, metabolic syndrome, and lipodystrophies. This evidence is reviewed, gaps in knowledge are highlighted, and recommendations are made for future research.
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Affiliation(s)
- Moira S Lewitt
- School of Health, Nursing & Midwifery, University of the West of Scotland, Paisley, UK
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14
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Role of Nampt and Visceral Adiposity in Esophagogastric Junction Adenocarcinoma. J Immunol Res 2017; 2017:3970605. [PMID: 28168205 PMCID: PMC5266808 DOI: 10.1155/2017/3970605] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 11/22/2016] [Indexed: 12/20/2022] Open
Abstract
Nampt including eNampt and iNampt may contribute to mediating obesity-associated cancers. This study investigated the role of Nampt in esophagogastric junction adenocarcinoma (EGA), a cancer strongly correlated with obesity. Visceral adiposity was defined by waist circumference or VFA. eNampt in sera were measured by enzyme-linked immunosorbent assay. iNampt expression in EGA was determined by PCR, western blot, and immunohistochemistry. Sera eNampt were significantly elevated in these overweight and obese patients, especially for viscerally obese patients, and positively correlated with BMI, waist circumference, VFA, and also primary tumor, regional lymph nodes, and TNM stage (P < 0.05). iNampt expression in both the mRNA and protein levels was upregulated in EGAs (P < 0.05). iNampt staining was found primarily in the cytoplasm and nuclei and significantly associated with tumor, lymph nodes, and TNM stage and also correlated positively with serum eNampt, BMI, total fat area, VFA, superficial fat area, and waist circumference (P < 0.05). iNampt, eNampt, tumor, lymph nodes, and TNM stage correlated to the survival of EGAs, and iNampt expression and TNM stage affected the prognosis independently (P < 0.05). This study highlighted the association of eNampt/iNampt with visceral obesity and a potential impact on the biology of EGA.
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15
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Abstract
A substantial increase in the incidence of oesophageal adenocarcinoma has been observed in Western countries during the past 30 years, which may be related to the parallel rise of the obesity prevalence. On the other hand, incidence rates of oesophageal squamous cell carcinomas, the other major histological type of oesophageal cancer, have remained relatively stable. Epidemiological research of the past decades has identified obesity as risk factor for oesophageal adenocarcinoma. Studies investigating general obesity as assessed by body mass index (BMI) provide evidence for a strong positive association with oesophageal adenocarcinoma. Studies investigating abdominal obesity in relation to oesophageal adenocarcinoma observed also positive associations, which may be independent of general obesity. Some studies indicate that early life obesity is also associated with higher risk of oesophageal adenocarcinoma, but it is as to date unclear whether these associations are independent of adult obesity. Part of the positive association between obesity and oesophageal adenocarcinoma may be explained through obesity-related mechanical promotion of gastroesophageal reflux disease, which is one of the main risk factors for oesophageal adenocarcinoma. Other lines of evidence point to an independent role of metabolic pathways modulating cell proliferation, apoptosis and cell growth such as pro-inflammatory cytokines, adipokines and insulin resistance, the role of which in oesophageal carcinogenesis is, however, as to date insufficiently understood. Studies investigating obesity in relation to squamous cell carcinoma observed inverse relationships, but the underlying mechanisms remain unclear.
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16
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Iwase T, Sangai T, Nagashima T, Sakakibara M, Sakakibara J, Hayama S, Ishigami E, Masuda T, Miyazaki M. Impact of body fat distribution on neoadjuvant chemotherapy outcomes in advanced breast cancer patients. Cancer Med 2015; 5:41-8. [PMID: 26626021 PMCID: PMC4708907 DOI: 10.1002/cam4.571] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 09/29/2015] [Accepted: 10/01/2015] [Indexed: 01/06/2023] Open
Abstract
Obesity is known to decrease the efficacy of neoadjuvant chemotherapy (NAC) against breast cancer; however, the relationship between actual body composition and NAC outcomes remains unknown. Therefore, we determined the effect of body composition on NAC outcomes. A total of 172 advanced breast cancer patients who underwent surgery after NAC were retrospectively analyzed. Body composition parameters including abdominal circumference (AC), subcutaneous fat area (SFA), visceral fat area (VFA), and skeletal muscle area (SMA) were calculated using computed tomography volume‐analyzing software. VFA/SFA ratio was used to evaluate visceral obesity. The associations of body composition parameters with pathological complete remission (pCR) and survival were analyzed. AC, SFA, and VFA were significantly correlated with body mass index (BMI) (all P < 0.05; r = 0.82, r = 0.71, and r = 0.78, respectively). AC, SFA, and VFA increased significantly and SMA decreased significantly after menopause (all P < 0.05). VFA/SFA ratio increased significantly after menopause, even though BMI remained unchanged. Body composition parameters were not associated with pCR. Distant disease‐free survival (DDFS) was significantly worse in the high VFA group than in the low VFA group (P < 0.05). Furthermore, in the high VFA group, postmenopausal patients had significantly shorter DDFS than premenopausal patients (P < 0.05). VFA was independently associated with DDFS in the multivariate analysis (P < 0.05). High visceral fat is associated with worse NAC outcomes in breast cancer patients, especially postmenopausal patients. Interventions targeting visceral fat accumulation will likely improve NAC outcomes.
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Affiliation(s)
- Toshiaki Iwase
- Department of General Surgery, Chiba Graduate School of Medicine, 2608677 1-8-1 Inohana Chuo-Ku, Chiba City, Chiba, Japan
| | - Takafumi Sangai
- Department of General Surgery, Chiba Graduate School of Medicine, 2608677 1-8-1 Inohana Chuo-Ku, Chiba City, Chiba, Japan
| | - Takeshi Nagashima
- Department of General Surgery, Chiba Graduate School of Medicine, 2608677 1-8-1 Inohana Chuo-Ku, Chiba City, Chiba, Japan
| | - Masahiro Sakakibara
- Department of General Surgery, Chiba Graduate School of Medicine, 2608677 1-8-1 Inohana Chuo-Ku, Chiba City, Chiba, Japan
| | - Junta Sakakibara
- Department of General Surgery, Chiba Graduate School of Medicine, 2608677 1-8-1 Inohana Chuo-Ku, Chiba City, Chiba, Japan
| | - Shouko Hayama
- Department of General Surgery, Chiba Graduate School of Medicine, 2608677 1-8-1 Inohana Chuo-Ku, Chiba City, Chiba, Japan
| | - Emi Ishigami
- Department of General Surgery, Chiba Graduate School of Medicine, 2608677 1-8-1 Inohana Chuo-Ku, Chiba City, Chiba, Japan
| | - Takahito Masuda
- Department of General Surgery, Chiba Graduate School of Medicine, 2608677 1-8-1 Inohana Chuo-Ku, Chiba City, Chiba, Japan
| | - Masaru Miyazaki
- Department of General Surgery, Chiba Graduate School of Medicine, 2608677 1-8-1 Inohana Chuo-Ku, Chiba City, Chiba, Japan
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17
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Abstract
Epidemiological studies have established an association between obesity, insulin resistance, type 2 diabetes and a number of cancer types. Research has focused predominantly on altered endocrine factors, growth factors and signalling pathways, with little known in man about the immune involvement in the relevant pathophysiological processes. Moreover, in an era of exciting new breakthroughs in cancer immunotherapy, there is also a need to study the safety and efficacy of immunotherapeutics in the complex setting of inflammatory-driven obesity-associated cancer. This review addresses key immune cell subsets underpinning obesity-associated inflammation and describes how such immune compartments might be targeted to prevent and treat obesity-associated cancer. We propose that the modulation, metabolism, migration and abundance of pro- and anti-inflammatory cells and tumour-specific T cells might be therapeutically altered to both restore immune balance, alleviating pathological inflammation, and to improve anti-tumour immune responses in obesity-associated cancer.
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18
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Abstract
There has been a substantial increase in the incidence of esophageal adenocarcinoma over the past 40 years. Meta-analyses of large prospective cohorts and population-based case-control studies demonstrate consistent associations between obesity and the development of adenocarcinoma of the esophagus and esophago-gastric junction, with an approximate doubling of risk of esophageal adenocarcinoma among patients who are obese, and an almost five-fold increased risk among those with BMI >40 kg/m2. The pathologic precursor, specialized intestinal metaplasia in Barrett's esophagus, is also associated with increased adiposity. Epidemiologic evidence suggests that this cancer risk is not solely due to increased gastro-esophageal reflux, and that adipose tissue itself, in particular visceral adipose, may fuel carcinogenesis through the production of adipokines, cytokines, growth factors, and increased inflammation. The robust epidemiologic evidence linking obesity with esophageal adenocarcinoma makes it an exemplar model for investigating the molecular mechanisms underpinning obesity-associated malignant progression, which are discussed in this review.
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Affiliation(s)
- Jessie A Elliott
- a 1 Department of Surgery, Trinity Centre for Health Sciences, Trinity College Dublin & St. James' Hospital, Dublin 8, Ireland
- b 2 Diabetes Complications Research Centre, Conway Institute of Biomedical and Biomolecular Research, University College Dublin, Dublin 4, Ireland
| | - Claire L Donohoe
- a 1 Department of Surgery, Trinity Centre for Health Sciences, Trinity College Dublin & St. James' Hospital, Dublin 8, Ireland
| | - John V Reynolds
- a 1 Department of Surgery, Trinity Centre for Health Sciences, Trinity College Dublin & St. James' Hospital, Dublin 8, Ireland
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19
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De Bruijn K, Biermann K, Shapiro J, Dogan F, Spaander M, Janssen J, Wijnhoven B, Borsboom G, Hofland L, van Eijck C. Absence or low IGF-1R-expression in esophageal adenocarcinoma is associated with tumor invasiveness and radicality of surgical resection. J Surg Oncol 2015; 111:1047-53. [DOI: 10.1002/jso.23923] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 04/08/2015] [Indexed: 12/15/2022]
Affiliation(s)
- Kirstin De Bruijn
- Department of Surgery; Erasmus University Medical Center; Rotterdam The Netherlands
| | - Katharina Biermann
- Department of Pathology; Erasmus University Medical Center; Rotterdam The Netherlands
| | - Joel Shapiro
- Department of Surgery; Erasmus University Medical Center; Rotterdam The Netherlands
| | - Fadime Dogan
- Department of Internal Medicine; Division of Endocrinology; Erasmus University Medical Center; Rotterdam The Netherlands
| | - Manon Spaander
- Department of Gastroenterology and Hepatology; Erasmus University Medical Center; Rotterdam The Netherlands
| | - Joseph Janssen
- Department of Internal Medicine; Division of Endocrinology; Erasmus University Medical Center; Rotterdam The Netherlands
| | - Bas Wijnhoven
- Department of Surgery; Erasmus University Medical Center; Rotterdam The Netherlands
| | - Gerard Borsboom
- Department of Public Health; Erasmus University Medical Center; Rotterdam The Netherlands
| | - Leo Hofland
- Department of Internal Medicine; Division of Endocrinology; Erasmus University Medical Center; Rotterdam The Netherlands
| | - Casper van Eijck
- Department of Surgery; Erasmus University Medical Center; Rotterdam The Netherlands
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20
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Dale OT, Aleksic T, Shah KA, Han C, Mehanna H, Rapozo DCM, Sheard JDH, Goodyear P, Upile NS, Robinson M, Jones TM, Winter S, Macaulay VM. IGF-1R expression is associated with HPV-negative status and adverse survival in head and neck squamous cell cancer. Carcinogenesis 2015; 36:648-55. [PMID: 25896444 DOI: 10.1093/carcin/bgv053] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2024] Open
Abstract
Head and neck squamous cell carcinomas (HNSCC) are treated with surgery, radiotherapy and cisplatin-based chemotherapy, but survival from locally-advanced disease remains poor, particularly in patients whose tumors are negative for Human papillomavirus (HPV). Type 1 IGF receptor (IGF-1R) is known to promote tumorigenesis and resistance to cancer therapeutics. Here, we assessed IGF-1R immunohistochemistry on tissue microarrays containing 852 cores from 346 HNSCC patients with primary tumors in the oropharynx (n = 231), larynx (85), hypopharynx (28), oral cavity (2). Of these, 236 (68%) were HPV-negative, 110 (32%) positive. IGF-1R was detected in the cell membrane of 36% and cytoplasm of 92% of HNSCCs; in 64 cases with matched normal tonsillar epithelium, IGF-1R was overexpressed in the HNSCCs (P < 0.001). Overall survival (OS) and disease-specific survival (DSS) were reduced in patients whose tumors contained high membrane IGF-1R [OS: hazard ratio (HR) = 1.63, P = 0.006; DSS: HR = 1.63, P = 0.016], cytoplasmic IGF-1R (OS: HR = 1.58, P = 0.009; DSS: HR = 1.58, P = 0.024) and total IGF-1R (OS: HR = 2.02, P < 0.001; DSS: HR = 2.2, P < 0.001). High tumor IGF-1R showed significant association with high-tumor T-stage (P < 0.001) and HPV-negativity (P < 0.001), and was associated with shorter OS when considering patients with HPV-positive (P = 0.01) and negative (P = 0.006) tumors separately. IGF-1R was independently associated with survival in multivariate analysis including HPV, but not when lymphovascular invasion, perineural spread and T-stage were included. Of these factors, only IGF-1R can be manipulated; the association of IGF-1R with aggressive disease supports experimental incorporation of anti-IGF-1R agents into multimodality treatment programs for HPV-negative and high IGF-1R HPV-positive HNSCC.
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Affiliation(s)
- Oliver T Dale
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7LJ, UK, The Blenheim Head and Neck Unit, Churchill Hospital, Oxford OX3 7LE, UK, Present address: ENT Department, University Hospital Bristol, Bristol BS2 8EG, UK
| | - Tamara Aleksic
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7LJ, UK
| | - Ketan A Shah
- Department of Cellular Pathology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Cheng Han
- Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford OX3 7LE, UK
| | - Hisham Mehanna
- Institute of Head and Neck Studies and Education (INHANSE), University of Birmingham, Birmingham B15 2TT, UK
| | - Davy C M Rapozo
- Institute of Head and Neck Studies and Education (INHANSE), University of Birmingham, Birmingham B15 2TT, UK
| | - Jon D H Sheard
- Department of Cellular Pathology, Aintree University Hospitals NHS Foundation Trust, Liverpool L9 7AL, UK
| | - Paul Goodyear
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L3 9TA, UK and
| | - Navdeep S Upile
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L3 9TA, UK and
| | - Max Robinson
- School of Dental Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4BW, UK
| | - Terence M Jones
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L3 9TA, UK and
| | - Stuart Winter
- The Blenheim Head and Neck Unit, Churchill Hospital, Oxford OX3 7LE, UK
| | - Valentine M Macaulay
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7LJ, UK, Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford OX3 7LE, UK,
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21
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Harada K, Baba Y, Ishimoto T, Kosumi K, Tokunaga R, Izumi D, Ida S, Imamura Y, Iwagami S, Miyamoto Y, Sakamoto Y, Yoshida N, Watanabe M, Baba H. Low Visceral Fat Content is Associated with Poor Prognosis in a Database of 507 Upper Gastrointestinal Cancers. Ann Surg Oncol 2015; 22:3946-53. [PMID: 25712800 DOI: 10.1245/s10434-015-4432-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Indexed: 12/29/2022]
Abstract
BACKGROUND Excess visceral adipose tissue may promote cancer development and progression via an obesity-related metabolic derangements, including adipocytokine-related inflammation, insulin resistance, and hypoxia. The relationship between visceral fat content and patient prognosis has been reported in some types of cancers, but not in the upper gastrointestinal cancer. The purpose of this retrospective study was to investigate the relationship between visceral fat status and clinical outcome in patients with upper gastrointestinal cancers (esophageal cancer and gastric cancer) treated by surgical resection. METHODS This retrospective study was conducted in a single, academic hospital in Kumamoto, Japan, and involved 507 patients with upper gastrointestinal cancers between April 2005 and December 2010. Preoperative visceral fat content was quantified by radiologic measures using standard computed tomography scans. RESULTS Higher visceral fat mount was correlated with male sex, presence of preoperative comorbidity, absence of preoperative therapy, low tumor depth, low tumor stage, and gastric cancer. Compared to high visceral fat cases, low visceral fat cases experienced a higher overall mortality rate [log-rank p = 0.0050; univariate hazard ratio (HR) = 1.73, 95 % confidence interval (CI) 1.16-2.54; p = 0.0075; multivariate HR 1.57; 95 % CI 1.02-2.37; p = 0.031]. Interestingly, the influence of low visceral fat on patient outcome was modified by age at surgery (p for interaction = 0.036); low visceral fat was associated with a poor prognosis, especially in elderly patients (log-rank p < 0.0001). CONCLUSION Visceral fat content in the upper gastrointestinal cancers was associated with a poor prognosis, thus suggesting that it has potential for use as a prognostic biomarker.
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Affiliation(s)
- Kazuto Harada
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Yoshifumi Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Takatsugu Ishimoto
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Keisuke Kosumi
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Ryuma Tokunaga
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Daisuke Izumi
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Satoshi Ida
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Yu Imamura
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Shiro Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Yasuo Sakamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Naoya Yoshida
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan.
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22
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Alexandre L, Long E, Beales ILP. Pathophysiological mechanisms linking obesity and esophageal adenocarcinoma. World J Gastrointest Pathophysiol 2014; 5:534-549. [PMID: 25400997 PMCID: PMC4231518 DOI: 10.4291/wjgp.v5.i4.534] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 08/07/2014] [Accepted: 09/04/2014] [Indexed: 02/06/2023] Open
Abstract
In recent decades there has been a dramatic rise in the incidence of esophageal adenocarcinoma (EAC) in the developed world. Over approximately the same period there has also been an increase in the prevalence of obesity. Obesity, especially visceral obesity, is an important independent risk factor for the development of gastro-esophageal reflux disease, Barrett's esophagus and EAC. Although the simplest explanation is that this mediated by the mechanical effects of abdominal obesity promoting gastro-esophageal reflux, the epidemiological data suggest that the EAC-promoting effects are independent of reflux. Several, not mutually exclusive, mechanisms have been implicated, which may have different effects at various points along the reflux-Barrett's-cancer pathway. These mechanisms include a reduction in the prevalence of Helicobacter pylori infection enhancing gastric acidity and possibly appetite by increasing gastric ghrelin secretion, induction of both low-grade systemic inflammation by factors secreted by adipose tissue and the metabolic syndrome with insulin-resistance. Obesity is associated with enhanced secretion of leptin and decreased secretion of adiponectin from adipose tissue and both increased leptin and decreased adiponectin have been shown to be independent risk factors for progression to EAC. Leptin and adiponectin have a set of mutually antagonistic actions on Barrett's cells which appear to influence the progression of malignant behaviour. At present no drugs are of proven benefit to prevent obesity associated EAC. Roux-en-Y reconstruction is the preferred bariatric surgical option for weight loss in patients with reflux. Statins and aspirin may have chemopreventative effects and are indicated for their circulatory benefits.
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Abstract
The incidence of oesophageal adenocarcinoma has increased dramatically in the developed world in the last half century. Over approximately the same period there has been an increase in the prevalence of obesity. Multiple epidemiological studies and meta-analyses have confirmed that obesity, especially abdominal, visceral obesity, is a risk factor for gastro-oesophageal reflux, Barrett's oesophagus and oesophageal adenocarcinoma. Although visceral obesity enhances gastro-oesophageal reflux, the available data also show that visceral obesity increases the risk of Barrett's oesophagus and adenocarcinoma via reflux-independent mechanisms. Several possible mechanisms could link obesity with the risk of oesophageal adenocarcinoma in addition to mechanical effects increasing reflux. These include reduced gastric Helicobacter pylori infection, altered intestinal microbiome, factors related to lifestyle, the metabolic syndrome and associated low-grade inflammation induced by obesity and the secretion of mediators by adipocytes which may directly influence the oesophageal epithelium. Of these adipocyte-derived mediators, increased leptin levels have been independently associated with progression to oesophageal adenocarcinoma and in laboratory studies leptin enhances malignant behaviours in cell lines. Adiponectin is also secreted by adipocytes and levels decline with obesity: decreased serum adiponectin levels are associated with malignant progression in Barrett's oesophagus and experimentally adiponectin exerts anticancer effects in Barrett's cell lines and inhibits growth factor signalling. At present there are no proven chemopreventative interventions that may reduce the incidence of obesity-associated oesophageal cancer: observational studies suggest that the combined use of a statin and aspirin or another cyclo-oxygenase inhibitor is associated with a significantly reduced cancer incidence in patients with Barrett's oesophagus.
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Affiliation(s)
- Elizabeth Long
- Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK
| | - Ian L P Beales
- Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK
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24
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O'Sullivan KE, Phelan JJ, O'Hanlon C, Lysaght J, O'Sullivan JN, Reynolds JV. The role of inflammation in cancer of the esophagus. Expert Rev Gastroenterol Hepatol 2014; 8:749-60. [PMID: 24857183 DOI: 10.1586/17474124.2014.913478] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Esophageal adenocarcinoma is the eighth most common malignancy worldwide. The overall prognosis is poor, with 5-year survival ranges of approximately 15-25%, and 30-50% for patients who can be treated with curative intent. There has been a marked increase in incidence of esophageal adenocarcinoma over the last 30 years, with chronic and severe reflux, diet and obesity identified as principal factors fuelling this rise in the West. Esophageal adenocarcinoma is an exemplar model of an inflammation-associated cancer. The key molecular pathways driving tumor development and influencing tumor biology are the subject of considerable research efforts, and is the principal focus of this review. In addition, the diverse range of changes occurring in the local immune response, tissue microenvironment, metabolic profile, intracellular signaling mechanisms and microRNA signatures are discussed, as well as novel targeted therapies.
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Affiliation(s)
- Katie E O'Sullivan
- Department of Surgery, Institute of Molecular Medicine, St. James Hospital, Dublin 8, Ireland
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25
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Tilg H, Moschen AR. Mechanisms behind the link between obesity and gastrointestinal cancers. Best Pract Res Clin Gastroenterol 2014; 28:599-610. [PMID: 25194178 DOI: 10.1016/j.bpg.2014.07.006] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 06/27/2014] [Accepted: 07/05/2014] [Indexed: 01/31/2023]
Abstract
Obesity and obesity-related disorders such as non-alcoholic fatty liver disease (NAFLD), metabolic syndrome and type 2 diabetes exhibit an increased risk of developing various gastrointestinal cancers. These malignancies include mainly esophageal, gastric, colorectal, pancreatic and hepatocellular carcinoma. Whereas underlying pathomechanisms remain unclear, chronic inflammation accompanying obesity has evolved in the last years as a crucial contributing factor. Obesity is also commonly characterized by inflammation in the organ where those cancers appear. Various pathways might participate involving rather diverse components such as innate immunity, (adipo)-cytokines such as adiponectin or leptin, insulin, insulin-like growth factors, the gut's microbiota and others. An imbalance in these systems could substantially contribute to chronic inflammation and subsequent cancer development. Future studies have to elucidate in more detail underlying mechanisms in the development of obesity-related carcinogensis and potential therapeutic strategies besides weight loss.
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Affiliation(s)
- Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Austria.
| | - Alexander R Moschen
- Department of Internal Medicine I, Gastroenterology, Endocrinology & Metabolism, Medical University Innsbruck, Austria
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26
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Howard JM, Cathcart MC, Healy L, Beddy P, Muldoon C, Pidgeon GP, Reynolds JV. Leptin and adiponectin receptor expression in oesophageal cancer. Br J Surg 2014; 101:643-52. [PMID: 24664553 DOI: 10.1002/bjs.9469] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2014] [Indexed: 01/12/2023]
Abstract
BACKGROUND Oesophageal adenocarcinoma is an exemplar model of an obesity-associated adenocarcinoma. Altered secretion of adipokines by visceral fat is believed to play a key role in tumorigenesis. This study examined leptin receptor (ObR) and adiponectin receptor (AdipoR1 and AdipoR2) expression in oesophageal cancer, and its relationship with patient obesity status, clinicopathological data and patient survival. METHODS Tissue microarrays were constructed from paraffin-embedded oesophagectomy specimens. ObR, AdipoR1 and AdipoR2 expression was quantified by immunohistochemistry. Anthropometric data were measured at the time of diagnosis, and obesity status was assessed using visceral fat area determined by computed tomography and body mass index. Receptor expression was correlated with various clinicopathological and anthropometric variables. Patient survival was estimated using the Kaplan-Meier method, and results compared between those with low versus high receptor expression. A Cox multivariable regression model was used to assess the relationship between survival and a number of co-variables. RESULTS All 125 tumours analysed expressed AdipoR1 and AdipoR2, whereas 96·8 per cent expressed ObR. There was no significant difference in tumour pathological features or patient obesity status between tumours with low versus high ObR expression. A high level of AdipoR1 expression was significantly associated with increased patient age, obesity and less advanced tumour (T) category. Expression of AdipoR2 was inversely associated with T category (P = 0.043). Low AdipoR1 expression was an independent predictor of improved overall survival (hazard ratio 0.56, 95 per cent confidence interval 0.35 to 0.90; P = 0.017). CONCLUSION The association between adiponectin receptor expression, obesity status and tumour category and survival suggests a potential mechanism linking obesity and oesophageal cancer.
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Affiliation(s)
- J M Howard
- Departments of Surgery, Trinity College Dublin, Dublin, Ireland
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27
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Alemán JO, Eusebi LH, Ricciardiello L, Patidar K, Sanyal AJ, Holt PR. Mechanisms of obesity-induced gastrointestinal neoplasia. Gastroenterology 2014; 146:357-373. [PMID: 24315827 PMCID: PMC3978703 DOI: 10.1053/j.gastro.2013.11.051] [Citation(s) in RCA: 148] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 10/30/2013] [Accepted: 11/14/2013] [Indexed: 02/06/2023]
Abstract
Obesity is among the fastest growing diseases worldwide; treatment is inadequate, and associated disorders, including gastrointestinal cancers, have high morbidity and mortality. An increased understanding of the mechanisms of obesity-induced carcinogenesis is required to develop methods to prevent or treat these cancers. In this report, we review the mechanisms of obesity-associated colorectal, esophageal, gastric, and pancreatic cancers and potential treatment strategies.
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Affiliation(s)
| | - Leonardo H. Eusebi
- Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Luigi Ricciardiello
- Department of Medical and Surgical Sciences, and Center for Applied Biomedical Research (CRBA), University of Bologna, Italy
| | - Kavish Patidar
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Arun J. Sanyal
- Virginia Commonwealth University School of Medicine, Richmond, VA, USA
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28
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Nagaraja V, Eslick GD. Forthcoming prognostic markers for esophageal cancer: a systematic review and meta-analysis. J Gastrointest Oncol 2014; 5:67-76. [PMID: 24490044 PMCID: PMC3904028 DOI: 10.3978/j.issn.2078-6891.2013.054] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Accepted: 11/07/2013] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND The incidence of esophageal cancer is rising, and survival rates remain poor. This meta-analysis summarizes five molecular mechanisms of disease progression, which are related to prognosis. PATIENTS AND METHODS A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane library, Google Scholar, Science Direct, and Web of Science. Original data was abstracted from each study and used to calculate a pooled event rate and 95% confidence interval (95% CI). RESULTS Our analysis included five octamer-binding transcription factor 4 (OCT4) studies (564 patients), six sex determining region Y-box 2 (SOX2) studies (336 patients), five oestrogen receptor (ER) studies (367 patients), seven MET or MNNG HOS Transforming gene (c-Met) studies (1,015 patients) and six insulin like growth factor receptor studies (764 patients). Incidence of OCT4 in SCC was 53.60% (95% CI: 0.182-0.857) and the overall hazard ratio for poor clinic outcome was 2.9 (95% CI: 1.843-4.565). The incidence of SOX2 in SCC was 69.2% (95% CI: 0.361-0.899) however, was associated with significant heterogeneity of 90.94%. The prevalence of Oestrogen receptor α and β in SCC were 37.90% (95% CI: 0.317-0.444) and 67.20% (95% CI: 0.314-0.901) respectively. The prevalence of MET in EAC was 33.20% (95% CI: 0.031-0.884) and the incidence of insulin-like growth factor-1 receptor (IGF-1R) in EAC was 67.70% (95% CI: 0.333-0.898). CONCLUSIONS Our results show that the status of ER, OCT4 and SOX2 expression correlates with the unfavourable prognosis in patients with esophageal squamous cell carcinoma (ESCC). This study also highlights the potential impact of the IGF-1R on the biology of EAC and the expression of Met was recognised as a significant prognostic factor. Our data supports the concept of IGF axis, ER, Met, OCT4 and SOX2 inhibition as (neo-) adjuvant treatment.
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Affiliation(s)
- Vinayak Nagaraja
- The Whiteley-Martin Research Centre, Discipline of Surgery, The Sydney Medical School Nepean, Penrith, New South Wales, Australia
| | - Guy D Eslick
- The Whiteley-Martin Research Centre, Discipline of Surgery, The Sydney Medical School Nepean, Penrith, New South Wales, Australia
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29
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Adachi Y, Ohashi H, Imsumran A, Yamamoto H, Matsunaga Y, Taniguchi H, Nosho K, Suzuki H, Sasaki Y, Arimura Y, Carbone DP, Imai K, Shinomura Y. The effect of IGF-I receptor blockade for human esophageal squamous cell carcinoma and adenocarcinoma. Tumour Biol 2014; 35:973-985. [PMID: 24026884 DOI: 10.1007/s13277-013-1131-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 08/21/2013] [Indexed: 12/31/2022] Open
Abstract
Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and tumor development, and this pathway has not been well studied in human esophageal carcinomas. Esophageal cancer is one of the human cancers with the worst prognosis and has two main histologies: squamous cell carcinomas (ESCC) and adenocarcinoma (EAC). Previously, we have reported that detection of the IGF axis may be useful for the prediction of recurrence and poor prognosis of ESCC. We have also shown the successful therapy for several gastrointestinal cancers using recombinant adenoviruses expressing dominant negative IGF-IR (ad-IGF-IR/dn). The aim of this study is to develop potential targeted therapeutics to IGF-IR and to assess the effect of IGF-IR blockade in both of these types of esophageal cancer. We determined immunohistochemical expression of IGF-IR in a tissue microarray. We then assessed the effect of IGF-IR blockade on signal transduction, proliferation, apoptosis, and motility. Ad-IGF-IR/dn, a tyrosine kinase inhibitor, BMS-536924, and adenovirus expressing shRNA for IGF-IR were used. IGF-IR expression was common in both tumor types but not in normal tissues. IGF-IR was detected in metastatic sites at similar levels compared to the primary site. IGF-IR inhibition suppressed proliferation and colony formation in both cancers. IGF-IR blockades up-regulated both stress- and chemotherapy-induced apoptosis and reduced migration. Although IGF-IR/dn blocked ligand-induced activation of Akt-1 mainly, BMS-536924 effectively blocked both activation of Akt and MAPK. The IGF axis might play a key role in tumor progression of esophageal carcinomas. The IGF-IR targeting strategies might thus be useful anticancer therapeutics for human esophageal malignancies.
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Affiliation(s)
- Yasushi Adachi
- First Department of Internal Medicine, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Japan,
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30
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Donohoe CL, O’Farrell NJ, Doyle SL, Reynolds JV. The role of obesity in gastrointestinal cancer: evidence and opinion. Therap Adv Gastroenterol 2014; 7:38-50. [PMID: 24381646 PMCID: PMC3871278 DOI: 10.1177/1756283x13501786] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
There is increasing recognition of the impact of being overweight and obese on the development of cancers at diverse sites including the gastrointestinal tract. Large epidemiological studies indicate that up to 14% of tumours may be related to obesity. Pathophysiological mechanisms underpinning this association are not well understood and so are discussed in this review.
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Affiliation(s)
- Claire L. Donohoe
- Department of Surgery, Trinity Centre for Health Sciences, Trinity College Dublin/ St James’ Hospital, Dublin, Ireland
| | - Naoimh J. O’Farrell
- Department of Surgery, Trinity Centre for Health Sciences, Trinity College Dublin/ St James’ Hospital, Dublin, Ireland
| | - Suzanne L. Doyle
- Department of Surgery, Trinity Centre for Health Sciences, Trinity College Dublin/ St James’ Hospital, Dublin, Ireland
| | - John V. Reynolds
- Department of Surgery, Trinity Centre for Health Sciences, Trinity College Dublin/ St James’ Hospital, Dublin 8, Ireland
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31
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Lahiff C, Schilling C, Cathcart MC, Mulligan N, Doran P, Muldoon C, Murray D, Pidgeon GP, Reynolds JV, MacMathuna P. Prognostic significance of neuroepithelial transforming gene 1 in adenocarcinoma of the oesophagogastric junction. Br J Surg 2013; 101:55-62. [DOI: 10.1002/bjs.9373] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2013] [Indexed: 01/24/2023]
Abstract
Abstract
Background
Neuroepithelial transforming gene 1 (NET1) mediates tumour invasion and metastasis in a number of cancers, including gastric adenocarcinoma. It is an indicator of poor prognosis in breast cancer and glioma. This study examined NET1 expression and its prognostic significance in patients with adenocarcinoma of the oesophagogastric junction (AOG).
Methods
NET1 expression was measured by immunohistochemistry in a tissue microarray, constructed from biobanked tissue collected over a 10-year interval, and linked to a prospectively maintained clinical database.
Results
Using the Siewert classification for AOG, type I tumours expressed significantly higher levels of NET1, with lowest expression in type III and intermediate levels in type II (P = 0·001). In patients with AOG type III, NET1-positive patients were more likely to be female (P = 0·043), have advanced stage cancer (P = 0.035), had a higher number of transmural cancers (P = 0·006) and had a significantly higher median number of positive lymph nodes (P = 0·029). In this subgroup, NET1-positive patients had worse median overall (15 versus 23 months; P = 0·025) and disease-free (11 versus 36 per cent; P = 0·025) survival compared with NET1-negative patients.
Conclusion
Although existing data show differences in clinical and prognostic indices across AOG subtypes, there are no studies showing differences in tumour biology. These data suggest NET1, a known mediator of an aggressive tumour phenotype in a number of gastrointestinal cancers, is expressed differentially across AOG subtypes and may be of prognostic significance in the clinical management of this condition.
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Affiliation(s)
- C Lahiff
- Gastrointestinal Unit, Mater Misericordiae Hospital, Dublin, Ireland
| | - C Schilling
- Department of Pathology, Mater Misericordiae Hospital, Dublin, Ireland
| | - M-C Cathcart
- Department of Surgery, St James's Hospital and Trinity College, Dublin, Ireland
| | - N Mulligan
- Department of Pathology, Mater Misericordiae Hospital, Dublin, Ireland
| | - P Doran
- University College Dublin School of Medicine and Medical Science, Dublin, Ireland
| | - C Muldoon
- Department of Pathology, St James's Hospital and Trinity College, Dublin, Ireland
| | - D Murray
- University College Dublin School of Medicine and Medical Science, Dublin, Ireland
| | - G P Pidgeon
- Department of Surgery, St James's Hospital and Trinity College, Dublin, Ireland
| | - J V Reynolds
- Department of Surgery, St James's Hospital and Trinity College, Dublin, Ireland
| | - P MacMathuna
- Gastrointestinal Unit, Mater Misericordiae Hospital, Dublin, Ireland
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32
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Zhao J, Lawless MW. Stop feeding cancer: pro-inflammatory role of visceral adiposity in liver cancer. Cytokine 2013; 64:626-37. [PMID: 24120848 DOI: 10.1016/j.cyto.2013.09.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Revised: 08/12/2013] [Accepted: 09/06/2013] [Indexed: 02/06/2023]
Abstract
Liver cancer is the fifth most common cancer in the world with an estimated over half a million new cases diagnosed every year. Due to the difficulty in early diagnosis and lack of treatment options, the prevalence of liver cancer continues to climb with a 5-year survival rate of between 6% and 11%. Coinciding with the rise of liver cancer, the prevalence of obesity has rapidly increased over the past two decades. Evidence from epidemiological studies demonstrates a higher risk of hepatocellular carcinoma (HCC) in obese individuals. Obesity is recognised as a low-grade inflammatory disease, this is of particular relevance as inflammation has been proposed as the seventh hallmark of cancer development with abdominal visceral adiposity considered as an important source of pro-inflammatory stimuli. Emerging evidence points towards the direct role of visceral adipose tissue rather than generalised body fat in carcinogenesis. Cytokines such as IL-6 and TNF-α secreted from visceral adipose tissue have been demonstrated to induce a chronic inflammatory condition predisposing the liver to a protumourigenic milieu. This review focuses on excess visceral adiposity rather than simple obesity; particularly adipokines and their implications for chronic inflammation, lipid accumulation, insulin resistance, Endoplasmic Reticulum (ER) stress and angiogenesis. Evidence of molecular signalling pathways that may give rise to the onset and progression of HCC in this context are depicted. Delineation of the pro-inflammatory role of visceral adiposity in liver cancer and its targeting will provide better rational and therapeutic approaches for HCC prevention and elimination. The concept of a central role for metabolism in cancer is the culmination of an effort that began with one of the 20th century's leading biochemists and Nobel laureate of 1931, Otto Warburg.
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Affiliation(s)
- Jun Zhao
- Experimental Medicine, UCD School of Medicine and Medical Science, Mater Misericordiae University Hospital, Dublin 7, Ireland
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Abstract
Cancer of the esophagus is an aggressive disease with early lymphatic and hematogenous dissemination and at present often considered as one clinical entity because of their comparable increasing incidence, prognosis and optimal treatment options. However, it is still a matter of debate whether these malignancies have the same pathogenesis and genotype. Despite recent advances, treatment of upper gastrointestinal malignancies remains a significant challenge. Molecular pathology has revealed many molecular mechanisms of disease progression, which are related to prognosis. Better knowledge of molecular bases may lead to new paradigms, improved prognostication, early diagnosis and individually tailored therapeutic options. This review summarizes the rationale, preclinical evidence, retrospective clinical analyses and the interim clinical data pertaining HER2 therapy and many other molecular pathways.
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Affiliation(s)
- Vinayak Nagaraja
- The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Sydney, NSW, Australia
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34
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Westley RL, May FEB. A twenty-first century cancer epidemic caused by obesity: the involvement of insulin, diabetes, and insulin-like growth factors. Int J Endocrinol 2013; 2013:632461. [PMID: 23983688 PMCID: PMC3747439 DOI: 10.1155/2013/632461] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Accepted: 03/25/2013] [Indexed: 02/08/2023] Open
Abstract
Obesity has reached epidemic proportions in the developed world. The progression from obesity to diabetes mellitus type 2, via metabolic syndrome, is recognised, and the significant associated increase in the risk of major human cancers acknowledged. We review the molecular basis of the involvement of morbidly high concentrations of endogenous or therapeutic insulin and of insulin-like growth factors in the progression from obesity to diabetes and finally to cancer. Epidemiological and biochemical studies establish the role of insulin and hyperinsulinaemia in cancer risk and progression. Insulin-like growth factors, IGF-1 and IGF-2, secreted by visceral or mammary adipose tissue have significant paracrine and endocrine effects. These effects can be exacerbated by increased steroid hormone production. Structural studies elucidate how each of the three ligands, insulin, IGF-1, and IGF-2, interacts differently with isoforms A and B of the insulin receptor and with type I IGF receptor and explain how these protagonists contribute to diabetes-associated cancer. The above should inform appropriate treatment of cancers that arise in obese individuals and in those with diabetes mellitus type 2. Novel drugs that target the insulin and insulin-like growth factor signal transduction pathways are in clinical trial and should be effective if appropriate biomarker-informed patient stratification is implemented.
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Affiliation(s)
- Rosalyne L. Westley
- Northern Institute for Cancer Research, Faculty of Medical Sciences, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
| | - Felicity E. B. May
- Northern Institute for Cancer Research, Faculty of Medical Sciences, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
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35
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Abstract
Answer questions and earn CME/CNE Esophageal adenocarcinoma (EAC) is characterized by 6 striking features: increasing incidence, male predominance, lack of preventive measures, opportunities for early detection, demanding surgical therapy and care, and poor prognosis. Reasons for its rapidly increasing incidence include the rising prevalence of gastroesophageal reflux and obesity, combined with the decreasing prevalence of Helicobacter pylori infection. The strong male predominance remains unexplained, but hormonal influence might play an important role. Future prevention might include the treatment of reflux or obesity or chemoprevention with nonsteroidal antiinflammatory drugs or statins, but no evidence-based preventive measures are currently available. Likely future developments include endoscopic screening of better defined high-risk groups for EAC. Individuals with Barrett esophagus might benefit from surveillance, at least those with dysplasia, but screening and surveillance strategies need careful evaluation to be feasible and cost-effective. The surgery for EAC is more extensive than virtually any other standard procedure, and postoperative survival, health-related quality of life, and nutrition need to be improved (eg, by improved treatment, better decision-making, and more individually tailored follow-up). Promising clinical developments include increased survival after preoperative chemoradiotherapy, the potentially reduced impact on health-related quality of life after minimally invasive surgery, and the new endoscopic therapies for dysplastic Barrett esophagus or early EAC. The overall survival rates are improving slightly, but poor prognosis remains a challenge.
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Affiliation(s)
- Jesper Lagergren
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
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Leggett CL, Nelsen EM, Tian J, Schleck C, Zinsmeister AR, Dunagan K, Locke GR, Wang KK, Talley NJ, Iyer PG. Metabolic syndrome as a risk factor for Barrett esophagus: a population-based case-control study. Mayo Clin Proc 2013; 88:157-65. [PMID: 23374619 PMCID: PMC3771537 DOI: 10.1016/j.mayocp.2012.09.017] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Revised: 09/14/2012] [Accepted: 09/21/2012] [Indexed: 02/08/2023]
Abstract
OBJECTIVES To assess the association between Barrett esophagus (BE) and the metabolic syndrome in patients with and without reflux symptoms and to determine whether this association is reflux independent and metabolically driven. PATIENTS AND METHODS Case patients with BE and controls were residents of Olmsted County, Minnesota (1999-2006). Two control groups (one with and one without symptoms of gastroesophageal reflux) were identified from a cohort of patients who had responded to a validated gastrointestinal symptom questionnaire. Cases and controls were individually matched by age, sex, and duration of follow-up. Controls did not have a known diagnosis of BE. The association of the metabolic syndrome and its individual components with BE was assessed using univariate and multivariate conditional logistic regression separately for each control group. RESULTS A total of 309 patients were included (103 BE cases, 103 controls with reflux symptoms, and 103 controls without reflux symptoms). A total of 64% of cases, 47% of controls with reflux symptoms, and 50% of controls without reflux symptoms had the metabolic syndrome. The metabolic syndrome was associated with a 2-fold increased risk of BE relative to those with (odds ratio, 2.00; 95% CI, 1.10-3.65; P=.02) and without (odds ratio, 1.90; 95% CI, 1.03-3.60; P=.04) reflux symptoms. This association was independent of smoking, alcohol consumption, and body mass index and remained robust with sensitivity analysis. CONCLUSION The metabolic syndrome is associated with BE independent of reflux symptoms, which may reflect a reflux-independent pathway of BE pathogenesis.
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Affiliation(s)
- Cadman L. Leggett
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester MN
| | - Eric M. Nelsen
- Department of Internal Medicine, Mayo Clinic, Rochester MN
| | - Jianmin Tian
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester MN
| | - Cathy Schleck
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester MN
| | - Alan R. Zinsmeister
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester MN
| | - Kelly Dunagan
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester MN
| | - G. Richard Locke
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester MN
| | - Kenneth K. Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester MN
| | - Nicholas J. Talley
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester MN
- Faculty of Health, The University of Newcastle, Australia
| | - Prasad G. Iyer
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester MN
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