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Updated: Mar 22, 2026

Modeling Colitis-Associated Cancer with Azoxymethane AOM and Dextran Sulfate Sodium DSS
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Caspase-3/7 deficiency results in enhanced intestinal inflammation and reduced tumorigenesis

Wei Xie1,2, Laura Wyckaert1,2, Mike Vadi1,2

  • 1Molecular Signaling and Cell Death Unit, VIB-UGent Center for Inflammation Research, Flanders Institute for Biotechnology, Ghent, Belgium.

Science Advances
|March 20, 2026
PubMed

Insights

Caspase-3/7 in intestinal epithelial cells (IECs) protects against colitis and aids regeneration. However, its absence reduces colorectal cancer risk, suggesting a dual role in intestinal injury and disease.

Area of Science:

  • Gastroenterology
  • Cell Biology
  • Immunology

Background:

  • Aberrant intestinal epithelial cell (IEC) death is a hallmark of inflammatory bowel disease (IBD).
  • The specific roles and regulatory mechanisms of various cell death pathways (apoptosis, necroptosis, pyroptosis, ferroptosis) in intestinal inflammation are not fully understood.

Purpose of the Study:

  • To investigate the contribution of distinct IEC death pathways to intestinal inflammation and regeneration using the DSS colitis model.
  • To elucidate the specific role of caspase-3/7 in IECs during intestinal injury and colorectal cancer development.

Main Methods:

  • Utilized the DSS colitis model in mice with specific genetic deletions in IECs for apoptosis (Caspase-3/7), necroptosis (MLKL), pyroptosis (GSDME, GSDMD), and ferroptosis (GPX4).
  • Assessed colitis severity, mortality, tissue regeneration, stem cell proliferation, barrier integrity, and tumor formation in the AOM/DSS model.

Main Results:

  • Mice lacking caspase-3/7 in IECs exhibited exacerbated colitis, increased mortality, and impaired gut regeneration.
  • Caspase-3/7 deficiency in IECs led to reduced stem cell proliferation, increased inflammatory cell death, and compromised barrier function.
  • Despite heightened inflammation, caspase-3/7-deficient mice showed decreased tumor formation in a colorectal cancer model.

Conclusions:

  • Caspase-3/7 plays a critical protective role in regulating intestinal inflammation and promoting tissue regeneration.
  • While beneficial in acute injury, caspase-3/7 activity in IECs may promote tumorigenesis following intestinal damage.
  • Modulating caspase-3/7 presents a potential therapeutic avenue for both IBD and colorectal cancer.

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