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Inhibition of histidine decarboxylase ablates the autocrine tumorigenic effects of histamine in human cholangiocarcinoma
- Source :
- Gut. 61:753-764
- Publication Year :
- 2011
- Publisher :
- BMJ, 2011.
-
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. Conclusion 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.
- Subjects :
- Male
Vascular Endothelial Growth Factor A
medicine.medical_specialty
Angiogenesis
Histamine secretion
Immunoblotting
Fluorescent Antibody Technique
Mice, Nude
Histidine Decarboxylase
Biology
liver
Real-Time Polymerase Chain Reaction
Article
Cholangiocarcinoma
Mice
chemistry.chemical_compound
Histamine receptor
Cell Line, Tumor
Internal medicine
Biomarkers, Tumor
medicine
Animals
Humans
Autocrine signalling
Mice, Inbred BALB C
Gastroenterology
Histidine decarboxylase
cholangiocarcinoma
histamine
Platelet Endothelial Cell Adhesion Molecule-1
Vascular endothelial growth factor
Vascular endothelial growth factor A
Bile Ducts, Intrahepatic
Cell Transformation, Neoplastic
Endocrinology
Bile Duct Neoplasms
chemistry
Tissue Array Analysis
Cancer research
Receptors, Histamine
Histamine
Subjects
Details
- ISSN :
- 14683288 and 00175749
- Volume :
- 61
- Database :
- OpenAIRE
- Journal :
- Gut
- Accession number :
- edsair.doi.dedup.....c8a145ca138ab8950017e73366a2e729