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Obesity and cancer risk: Emerging biological mechanisms and perspectives

  • Author Footnotes
    1 These authors contributed equally to the preparation of the manuscript.
    Konstantinos I. Avgerinos
    Footnotes
    1 These authors contributed equally to the preparation of the manuscript.
    Affiliations
    251 Airforce General Hospital, Kanellopoulou 3, 11525, Athens, Greece
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  • Author Footnotes
    1 These authors contributed equally to the preparation of the manuscript.
    Nikolaos Spyrou
    Footnotes
    1 These authors contributed equally to the preparation of the manuscript.
    Affiliations
    251 Airforce General Hospital, Kanellopoulou 3, 11525, Athens, Greece
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  • Christos S. Mantzoros
    Affiliations
    Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA
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  • Maria Dalamaga
    Correspondence
    Corresponding author at: National and Kapodistrian University of Athens, Medical School, Mikras Asias #27, Goudi, 11527 Athens, Greece.
    Affiliations
    Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, 11527 Athens, Greece
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  • Author Footnotes
    1 These authors contributed equally to the preparation of the manuscript.
Published:November 13, 2018DOI:https://doi.org/10.1016/j.metabol.2018.11.001

      Highlights

      • Excess body weight is associated with an increased risk for a range of malignancies.
      • The triad of obesity, insulin resistance and adipokine aberrations is linked to cancer.
      • Subclinical chronic low-grade inflammation and oxidative stress is another mechanism.
      • Altered gut microbiome contributes to inflammation and release of carcinogenic products.
      • Microenvironmental perturbations and circadian rhythm disruption are additional mechanisms.

      Abstract

      Continuously rising trends in obesity-related malignancies render this disease spectrum a public health priority. Worldwide, the burden of cancer attributable to obesity, expressed as population attributable fraction, is 11.9% in men and 13.1% in women. There is convincing evidence that excess body weight is associated with an increased risk for cancer of at least 13 anatomic sites, including endometrial, esophageal, renal and pancreatic adenocarcinomas; hepatocellular carcinoma; gastric cardia cancer; meningioma; multiple myeloma; colorectal, postmenopausal breast, ovarian, gallbladder and thyroid cancers. We first synopsize current epidemiologic evidence; the obesity paradox in cancer risk and mortality; the role of weight gain and weight loss in the modulation of cancer risk; reliable somatometric indicators for obesity and cancer research; and gender differences in obesity related cancers. We critically summarize emerging biological mechanisms linking obesity to cancer encompassing insulin resistance and abnormalities of the IGF-I system and signaling; sex hormones biosynthesis and pathway; subclinical chronic low-grade inflammation and oxidative stress; alterations in adipokine pathophysiology; factors deriving from ectopic fat deposition; microenvironment and cellular perturbations including vascular perturbations, epithelial-mesenchymal transition, endoplasmic reticulum stress and migrating adipose progenitor cells; disruption of circadian rhythms; dietary nutrients; factors with potential significance such as the altered intestinal microbiome; and mechanic factors in obesity and cancer. Future perspectives regarding prevention, diagnosis and therapeutics are discussed. The aim of this review is to investigate how the interplay of these main potential mechanisms and risk factors, exerts their effects on target tissues provoking them to acquire a cancerous phenotype.

      Abbreviations:

      Akt (v-Akt murine thymoma viral oncogene homolog), AMPK (5′ AMP-activated protein kinase), APC (Adenomatous Polyposis Coli), BC (breast cancer), BMI (body mass index), CAA (Cancer-Associated Adipocyte), COX (Cyclooxygenase), CRC (Colorectal Cancer), CRP (C-Reactive Protein), CVD (Cardiovascular Disease), DCA (Deoxycholic Acid), DM (diabetes mellitus), DNA (Deoxyribonucleic Acid), EC (Endometrial Cancer), EHBCCG (Endogenous Hormones and Breast Cancer Collaborative Group), EMT (Epithelial-Mesenchymal Transition), EPIC (European Prospective Investigation into Cancer and Nutrition), ER (endoplasmic reticulum), ERK 1/2 (extracellular signal-regulated kinase 1/2), FFA (Free Fatty Acid), GERD (Gastro-Esophageal Reflux), GLP (Glucagon Like Peptide), GSK3 (Glycogen synthase kinase-3), HCC (Hepatocellular Cancer), HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), HRT (Hormone Replacement Therapy), hsCRP (high sensitivity C-Reactive Protein), IARC (International Agency for Research on Cancer), IL (Interleukin), IGF (insulin-like growth factor), IGFBP (Insulin-like growth factor-binding protein), IR (Insulin Resistance), LES (Lower Esophageal Sphincter), LPS (Lipopolysaccharide), LTB-4 (Leukotriene B4), MAPK (mitogen-activated protein kinase), MSC (Mesenchymal Cell), Mets (Metabolic Syndrome), MHO (Metabolically Healthy Obesity), MMP (matrix metalloproteinase), MRI (Magnetic Resonance Imaging), mTOR (mammalian target of rapamycin), MUO (Metabolically Unhealthy Obesity), NAFLD (Non-alcoholic Fatty Liver Disease), Nampt (Nicotinamide phosphoribosyltransferase), NASH (Non-Alcoholic SteatoHepatitis), NF-κB (nuclear factor-κB), NHANES (National Health and Nutrition Examination Survey), NLR (Nucleotide Oligomerization Domain-line Receptor), NSAIDs (Non-steroidal anti-inflammatory drugs), NSCLC (Non-Small Cell Lung Cancer), PAF (Population Attributable Fraction), PAK1 (p21-activated kinase 1), PI3K (phosphatidylinositol 3-kinase), PPAR (Peroxisome Proliferator-Activated Receptors), PR (progesterone receptor), RCT (Randomized Controlled Trial), RNA (Ribonucleic acid), ROS (Reactive oxygene species), SAT (Subcutaneous Adipose Tissue), STAT (Signal Transducer and Activator of Transcription), TLR (Toll-like receptor), TNF-α (tumor necrosis factor-α), Treg (Regulatory T cell), TZD (thiazolidinediones), VAT (Visceral Adipose Tissue), VEGF (vascular endothelial growth factor), WAT (White Adipose Tissue), WC (Waist Circumference), WCRF/AICR (World Cancer Research Fund/American Institute for Cancer Research), WHR (Waist-to-Hip Ratio)

      Keywords

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