Abstract
We report a paracrine effect whereby endothelial cells (ECs) promote the cancer stem cell (CSC) phenotype of human colorectal cancer (CRC) cells. We showed that, without direct cell-cell contact, ECs secrete factors that promoted the CSC phenotype in CRC cells via Notch activation. In human CRC specimens, CD133 and Notch intracellular domain-positive CRC cells colocalized in perivascular regions. An EC-derived, soluble form of Jagged-1, via ADAM17 proteolytic activity, led to Notch activation in CRC cells in a paracrine manner; these effects were blocked by immunodepletion of Jagged-1 in EC-conditioned medium or blockade of ADAM17 activity. Collectively, ECs play an active role in promoting Notch signaling and the CSC phenotype by secreting soluble Jagged-1.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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ADAM Proteins / antagonists & inhibitors
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ADAM Proteins / genetics
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ADAM Proteins / metabolism
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ADAM17 Protein
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Animals
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Antineoplastic Agents / pharmacology
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Biomarkers / metabolism
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Calcium-Binding Proteins / antagonists & inhibitors
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism*
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Cell Communication
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology*
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Culture Media, Conditioned / pharmacology
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Drug Resistance, Neoplasm
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Endothelial Cells / metabolism
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Endothelial Cells / pathology*
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Humans
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Immunoblotting
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Immunoprecipitation
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Jagged-1 Protein
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / secondary*
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Nude
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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Peptide Fragments / pharmacology
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Phenotype
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RNA, Small Interfering / genetics
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Receptors, Notch / metabolism*
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Serrate-Jagged Proteins
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Signal Transduction
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Biomarkers
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Calcium-Binding Proteins
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Culture Media, Conditioned
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jag1 protein, mouse
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Jagged-1 Protein
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Membrane Proteins
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Peptide Fragments
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RNA, Small Interfering
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Receptors, Notch
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Serrate-Jagged Proteins
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ADAM Proteins
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ADAM17 Protein
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ADAM17 protein, human
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Adam17 protein, mouse