title: Inhibition of histidine decarboxylase ablates the autocrine tumorigenic effects of histamine in human cholangiocarcinoma.
abstract: BACKGROUND
  In several tumours the endogenous activity of histidine decarboxylase (HDC), the enzyme stimulating histamine synthesis, sustains the autocrine trophic effect of histamine on cancer progression. Cholangiocarcinoma is a biliary cancer with limited treatment options. Histamine interacts with four G-protein coupled receptors, H1-H4 histamine receptors (HRs).
  
  
  OBJECTIVE
  To determine the effects of histamine stimulation and inhibition of histamine synthesis (by modulation of HDC) on cholangiocarcinoma growth.
  
  
  METHODS
  In vitro studies were performed using multiple human cholangiocarcinoma lines. The expression levels of the histamine synthetic machinery and HRs were evaluated along with the effects of histamine stimulation and inhibition on cholangiocarcinoma proliferation. A xenograft tumour model was used to measure tumour volume after treatment with histamine or inhibition of histamine synthesis by manipulation of HDC. Vascular endothelial growth factor (VEGF) expression was measured in cholangiocarcinoma cells concomitant with the evaluation of the expression of CD31 in endothelial cells in the tumour microenvironment.
  
  
  RESULTS
  Cholangiocarcinoma cells display (1) enhanced HDC and decreased monoamine oxidase B expression resulting in increased histamine secretion; and (2) increased expression of H1-H4 HRs. Inhibition of HDC and antagonising H1HR decreased histamine secretion in Mz-ChA-1 cells. Long-term treatment with histamine increased proliferation and VEGF expression in cholangiocarcinoma that was blocked by HDC inhibitor and the H1HR antagonist. In nude mice, histamine increased tumour growth (up to 25%) and VEGF expression whereas inhibition of histamine synthesis (by reduction of HDC) ablated the autocrine stimulation of histamine on tumour growth (~80%) and VEGF expression. No changes in angiogenesis (evaluated by changes in CD31 immunoreactivity) were detected in the in vivo treatment groups.
  
  
  CONCLUSIONS
  The novel concept that an autocrine loop (consisting of enhanced histamine synthesis by HDC) sustains cholangiocarcinoma growth is proposed. Drug targeting of HDC may be important for treatment of patients with cholangiocarcinoma.
authors.affiliation: Division of Research, Central Texas Veterans Health Care System, Scott & White and Texas A&M Health Science Center, College of Medicine, Temple, Texas 76504, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.forename: Paolo
authors.initials: P
authors.lastname: Onori
authors.forename: Mellanie
authors.initials: M
authors.lastname: White
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Taylor
authors.initials: T
authors.lastname: Francis
authors.forename: John F
authors.initials: JF
authors.lastname: Greene
authors.forename: Steve
authors.initials: S
authors.lastname: Tran
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Meininger
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006632:Histamine / Q000378:metabolism*; D006640:Histidine Decarboxylase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011968:Receptors, Histamine / Q000378:metabolism; D046888:Tissue Array Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011968:Receptors, Histamine; D042461:Vascular Endothelial Growth Factor A; D006632:Histamine; D006640:Histidine Decarboxylase