Abstract
Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Compounds / pharmacology
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Animals
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Anisoles / pharmacology
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Antineoplastic Agents / pharmacology*
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Benzeneacetamides / pharmacology*
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Bile Duct Neoplasms / drug therapy
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Bile Duct Neoplasms / metabolism*
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Bile Ducts, Intrahepatic / metabolism*
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cholangiocarcinoma / drug therapy
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Cholangiocarcinoma / metabolism*
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Clodronic Acid / administration & dosage
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Heterocyclic Compounds, 2-Ring / pharmacology
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Humans
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Keratins / metabolism
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Liposomes
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Macrophages / drug effects
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Macrophages / metabolism
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Male
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Mice, Nude
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Pyridines / pharmacology*
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Pyrimidines / pharmacology
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Pyrimidinones / pharmacology*
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Rats, Sprague-Dawley
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Tamoxifen / pharmacology
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Wnt Signaling Pathway*
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Xenograft Model Antitumor Assays
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beta Catenin / metabolism
Substances
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2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl)acetamide
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5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine
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AZD7507
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Aniline Compounds
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Anisoles
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Antineoplastic Agents
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Benzeneacetamides
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Bridged Bicyclo Compounds, Heterocyclic
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CTNNB1 protein, human
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Heterocyclic Compounds, 2-Ring
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ICG 001
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Liposomes
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Pyridines
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Pyrimidines
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Pyrimidinones
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beta Catenin
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Clodronic Acid
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Tamoxifen
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Keratins