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Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer

Verónica Rodilla1, Alberto Villanueva, Antonia Obrador-Hevia

  • 1Institut d'Investigació Biomèdica de Bellvitge Gran Via km 2.7, Hospitalet and Institut Municipal d'Investigacions Mèdiques-Hospital del Mar, Dr. Aiguader 88, 08003 Barcelona, Spain.

Proceedings of the National Academy of Sciences of the United States of America
|March 28, 2009
PubMed

Insights

Notch pathway activation, driven by beta-catenin-upregulated Jagged1, is crucial for intestinal tumorigenesis. This mechanism, observed in human cancers, impacts tumor cell differentiation and blood vessel formation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The role of Notch signaling in beta-catenin-dependent tumorigenesis, particularly in colorectal cancer, remains unclear.
  • Understanding the mechanisms of Notch activation and its pathway contribution is essential for cancer research.

Purpose of the Study:

  • To elucidate the mechanistic link between Wnt/beta-catenin and Notch signaling in colorectal cancer.
  • To investigate the contribution of Notch pathway activation to intestinal tumorigenesis.

Main Methods:

  • Microarray analysis to identify genes regulated by both Wnt/beta-catenin and Notch pathways.
  • In vivo studies using mouse models (APC(Min/+) and Jagged1(+/Delta) crosses) and tumor xenografts.
  • Analysis of human tumor samples from Familial Adenomatous Polyposis patients.

Main Results:

  • Identified genes downstream of Wnt/beta-catenin directly regulated by Notch.
  • Demonstrated beta-catenin-mediated transcriptional activation of Notch-ligand Jagged1, placing Notch downstream of Wnt.
  • Showed that Notch activation is required for intestinal tumorigenesis and impacts tumor cell differentiation and vasculogenesis.

Conclusions:

  • Notch activation, mediated by beta-catenin-induced Jagged1 upregulation, is a critical requirement for intestinal tumorigenesis.
  • The identified mechanism operates in human colorectal cancers, including those in Familial Adenomatous Polyposis patients.
  • The Notch pathway influences tumor cell differentiation and vasculogenesis, while proliferation is dependent on both Notch and Wnt/beta-catenin pathways.

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