Notch3 signalling promotes tumour growth in colorectal cancer

J Pathol. 2011 Aug;224(4):448-60. doi: 10.1002/path.2895. Epub 2011 May 19.


Increased Notch1 activity has been observed in intestinal tumours, partially accomplished by β-catenin-mediated up-regulation of the Notch ligand Jagged-1. Whether further mechanisms of Notch activation exist and other Notch receptors might be involved is unclear. Microarray data indicated that Notch3 transcript levels are significantly up-regulated in primary and metastatic CRC samples compared to normal mucosa. Moreover, Notch3 protein was expressed at strong/moderate levels by 19.7% of 158 CRC samples analysed, and at weak levels by 51.2% of the samples. Intrigued by these findings, we sought to investigate whether Notch3 modulates oncogenic features of CRC cells. By exploiting xenografts of CRC cells with different tumourigenic properties in mice, we found that the aggressive phenotype was associated with altered expression of components of the Notch pathway, including Notch3, Delta-like 4 (DLL4), and Jagged-1 ligands. Stimulation with immobilized recombinant DLL4 or transduction with DLL4-expressing vectors dramatically increased Notch3 expression in CRC cells, associated with accelerated tumour growth. Forced expression of an active form of Notch3 mirrored the effects of DLL4 stimulation and increased tumour formation. Conversely, attenuation of Notch3 levels by shRNA resulted in perturbation of the cell cycle followed by reduction in cell proliferation, clonogenic capacity, and inhibition of tumour growth. Altogether, these findings indicate that Notch3 can modulate the tumourigenic properties of CRC cells and contributes to sustained Notch activity in DLL4-expressing tumours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Calcium-Binding Proteins / metabolism
  • Cell Transformation, Neoplastic / metabolism
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Jagged-1 Protein
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / physiology
  • Neoplasm Transplantation
  • Receptor, Notch3
  • Receptors, Notch / metabolism
  • Receptors, Notch / physiology*
  • Serrate-Jagged Proteins
  • Signal Transduction / physiology
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Up-Regulation


  • Adaptor Proteins, Signal Transducing
  • Calcium-Binding Proteins
  • DLL4 protein, human
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Membrane Proteins
  • NOTCH3 protein, human
  • Neoplasm Proteins
  • Receptor, Notch3
  • Receptors, Notch
  • Serrate-Jagged Proteins