title: Inhibition of Mast Cell-Derived Histamine Decreases Human Cholangiocarcinoma Growth and Differentiation via c-Kit/Stem Cell Factor-Dependent Signaling.
abstract: The tumor microenvironment of cholangiocarcinoma (CCA) is composed of numerous cells, including mast cells (MCs). MCs release histamine, which increases CCA progression and angiogenesis. Cholangiocytes secrete stem cell factor, which functions via the MC growth factor receptor c-Kit. Here, we show that cholangiocytes express histidine decarboxylase and its inhibition reduces CCA growth. MC recruitment in the tumor microenvironment increased CCA growth. MC infiltration and MC markers were detected by toluidine blue staining and real-time PCR in human biopsies and in tumors from athymic mice treated with saline, histamine, histidine decarboxylase inhibitor, or cromolyn sodium. Tumor growth, angiogenesis, and epithelial-mesenchymal transition (EMT)/extracellular matrix (ECM) markers were measured in mice treated with cromolyn sodium. In vitro, human CCA cells were treated with MC supernatant fluids before evaluating angiogenesis and EMT/ECM expression. Migration assays were performed with CCA cells treated with the stem cell factor inhibitor. MC supernatant fluids increased CCA histidine decarboxylase, vascular endothelial growth factor, and MC/EMT/ECM expression that decreased with pretreatment of cromolyn sodium. MCs were found in human biopsies. In mice treated with cromolyn sodium, MC infiltration and tumor growth decreased. Inhibition of CCA stem cell factor blocked MC migration and MC/EMT/ECM in CCA. MCs migrate into CCA tumor microenvironment via c-Kit/stem cell factor and increase tumor progression, angiogenesis, EMT switch, and ECM degradation.
authors.affiliation: Scott & White Digestive Disease Research Center, Temple, Texas.
authors.forename: Christopher
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Scott & White Digestive Disease Research Center, Temple, Texas.
authors.forename: Victoria
authors.initials: V
authors.lastname: Huynh
authors.affiliation: Scott & White Digestive Disease Research Center, Temple, Texas.
authors.forename: Laura
authors.initials: L
authors.lastname: Hargrove
authors.affiliation: Department of Research, Central Texas Veterans Health Care System, Temple, Texas.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Kennedy
authors.affiliation: Department of Research, Central Texas Veterans Health Care System, Temple, Texas.
authors.forename: Allyson
authors.initials: A
authors.lastname: Graf-Eaton
authors.affiliation: Department of Research, Central Texas Veterans Health Care System, Temple, Texas.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Owens
authors.affiliation: Department of Medical Physiology, Texas A&M Health Science Center, Temple, Texas.
authors.forename: Jerome P
authors.initials: JP
authors.lastname: Trzeciakowski
authors.affiliation: Scott & White Digestive Disease Research Center, Temple, Texas.
authors.forename: Kyle
authors.initials: K
authors.lastname: Hodges
authors.affiliation: Scott & White Digestive Disease Research Center, Temple, Texas; Department of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Scott & White Healthcare, Temple, Texas.
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
authors.affiliation: Scott & White Digestive Disease Research Center, Temple, Texas; Department of Medicine, Scott & White Healthcare, Temple, Texas.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Scott & White Digestive Disease Research Center, Temple, Texas; Department of Medicine, Scott & White Healthcare, Temple, Texas.
authors.forename: Lucas
authors.initials: L
authors.lastname: Wong
authors.affiliation: Scott & White Digestive Disease Research Center, Temple, Texas; Department of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medical Physiology, Texas A&M Health Science Center, Temple, Texas; Department of Medicine, Scott & White Healthcare, Temple, Texas.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.affiliation: Scott & White Digestive Disease Research Center, Temple, Texas; Department of Research, Central Texas Veterans Health Care System, Temple, Texas; Department of Medicine, Scott & White Healthcare, Temple, Texas. Electronic address: hfrancis@medicine.tamhsc.edu.
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000276:immunology / Q000473:pathology*; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000276:immunology / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000276:immunology; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D019089:Stem Cell Factor / Q000378:metabolism; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D019089:Stem Cell Factor; D006632:Histamine; D019009:Proto-Oncogene Proteins c-kit