Endothelial Cells Promote the Colorectal Cancer Stem Cell Phenotype Through a Soluble Form of Jagged-1

Cancer Cell. 2013 Feb 11;23(2):171-85. doi: 10.1016/j.ccr.2012.12.021. Epub 2013 Jan 31.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ADAM Proteins / antagonists & inhibitors
  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Animals
  • Antineoplastic Agents / pharmacology
  • Biomarkers / metabolism
  • Calcium-Binding Proteins / antagonists & inhibitors
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cell Communication
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Culture Media, Conditioned / pharmacology
  • Drug Resistance, Neoplasm
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology*
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Jagged-1 Protein
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / secondary*
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Peptide Fragments / pharmacology
  • Phenotype
  • RNA, Small Interfering / genetics
  • Receptors, Notch / metabolism*
  • Serrate-Jagged Proteins
  • Signal Transduction
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Biomarkers
  • Calcium-Binding Proteins
  • Culture Media, Conditioned
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Membrane Proteins
  • Peptide Fragments
  • RNA, Small Interfering
  • Receptors, Notch
  • Serrate-Jagged Proteins
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, mouse