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Published on: February 28, 2017
Heterogeneity of Jagged1 expression in human and mouse intestinal tumors: implications for targeting Notch signaling
S Guilmeau1, M Flandez, J M Mariadason
1Oncology Department, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY, USA. sandra.guilmeau@inserm.fr
Abstract:
Inhibition of Notch signaling is effective in inhibiting colon tumorigenesis, but targeting specific components of the pathway may provide more effective strategies. Here we show that the expression of Jagged1, a ligand for canonical Notch signaling, was restricted to enteroendocrine cells or undetectable in the mucosa of the human small and large intestine, respectively. In contrast, increased expression characterized half of human colon tumors, although not all tumors with elevated Wnt signaling displayed elevated Jagged1. Increased Jagged1 was also present in intestinal tumors of Apc(1638N/+) and Apc(Min/+) mice, but to a higher level and more frequently in the former, and in 90% of mouse tumors Notch signaling was elevated when Jagged1 was elevated. In the human HT29Cl16E colonic carcinoma cell line, induction of goblet cell differentiation by contact inhibition of growth depended on the loss of Jagged1-mediated Notch activation, with signaling through Notch1 and Notch2 acting redundantly. Therefore, targeting of Jagged1 could be effective in downregulating Notch signaling in a subset of tumors, but may avoid the limiting gastrointestinal toxicity caused by pharmacological inhibition of Notch signaling.
Insights
Targeting Jagged1, a Notch pathway ligand, shows promise for colon cancer treatment. This approach may reduce tumor growth while minimizing side effects associated with broader Notch pathway inhibition.
Area of Science:
- Oncology
- Cell Signaling
- Gastrointestinal Cancer
Background:
- Notch signaling inhibition is a known strategy for colon tumorigenesis.
- Targeting specific pathway components may offer improved therapeutic strategies.
- Jagged1, a Notch ligand, plays a role in this pathway.
Purpose of the Study:
- To investigate the role and expression of Jagged1 in colon cancer.
- To determine if Jagged1 can be a viable therapeutic target.
- To assess the potential of Jagged1 targeting to mitigate Notch signaling toxicity.
Main Methods:
- Analysis of Jagged1 expression in human and mouse intestinal tissues and tumors.
- Correlation of Jagged1 expression with Wnt signaling and Notch pathway activation.
- In vitro studies using HT29Cl16E colonic carcinoma cell line to examine goblet cell differentiation and Notch activation.
Main Results:
- Jagged1 expression is restricted in normal intestine but elevated in human colon tumors and mouse intestinal tumors.
- Elevated Jagged1 correlates with increased Notch signaling in mouse models.
- Loss of Jagged1-mediated Notch activation is crucial for goblet cell differentiation in a colon cancer cell line.
Conclusions:
- Jagged1 is upregulated in a subset of colon tumors, suggesting it as a potential therapeutic target.
- Targeting Jagged1 could effectively downregulate Notch signaling in these tumors.
- This targeted approach may offer an alternative to broad Notch inhibition, potentially reducing gastrointestinal toxicity.
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