title: The inflammatory inception of gallbladder cancer.
abstract: Gallbladder cancer is a lethal disease with notable geographical variations worldwide and a predilection towards women. Its main risk factor is prolonged exposure to gallstones, although bacterial infections and other inflammatory conditions are also associated. The recurrent cycles of gallbladder epithelium damage and repair enable a chronic inflammatory environment that promotes progressive morphological impairment through a metaplasia-dysplasia-carcinoma, along with cumulative genome instability. Inactivation of TP53, which is mutated in over 50% of GBC cases, seems to be the earliest and one of the most important carcinogenic pathways involved. Increased cell turnover and oxidative stress promote early alteration of TP53, cell cycle deregulation, apoptosis and replicative senescence. In this review, we will discuss evidence for the role of inflammation in gallbladder carcinogenesis obtained through epidemiological studies, genome-wide association studies, experimental carcinogenesis, morphogenetic studies and comparative studies with other inflammation-driven malignancies. The evidence strongly supports chronic, unresolved inflammation as the main carcinogenic mechanism of gallbladder cancer, regardless of the initial etiologic trigger. Given this central role of inflammation, evaluation of the potential for GBC prevention removing causes of inflammation or using anti-inflammatory drugs in high-risk populations may be warranted.
authors.affiliation: SciLifeLab, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Stockholm SE171 76, Sweden.
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Espinoza
authors.affiliation: Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), UC-Center for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Bizama
authors.affiliation: Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), UC-Center for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
authors.forename: Patricia
authors.initials: P
authors.lastname: García
authors.affiliation: Department of Public Health, Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
authors.forename: Catterina
authors.initials: C
authors.lastname: Ferreccio
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Milind
authors.initials: M
authors.lastname: Javle
authors.affiliation: Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Miquel
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda 20850, MD, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Koshiol
authors.affiliation: Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), UC-Center for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile. Electronic address: jcroa@med.puc.cl.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Roa
mesh_terms: D001327:Autoimmune Diseases / Q000150:complications; D001424:Bacterial Infections / Q000150:complications; D005706:Gallbladder Neoplasms / Q000209:etiology*; D042882:Gallstones / Q000150:complications; D006801:Humans; D007249:Inflammation / Q000150:complications*
keywords: Chronic inflammation; Gallbladder cancer; Gallstones; Metaplasia; Salmonella Typhi; TP53