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Changes in antitumor response in C57BL/6J-Min/+ mice during long-term administration of a selective cyclooxygenase-2
Adelaide M Carothers1, Amy E Moran, Nancy L Cho
1Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Abstract:
Selective cyclooxygenase-2 (COX-2) inhibitors are widely prescribed for severe arthritis and are currently under study in human chemoprevention trials. Recently, long-term use of these agents has come under scrutiny due to reports of treatment-associated cardiovascular toxicity. On short-term administration, the selective COX-2 inhibitor celecoxib inhibits adenoma growth in animal tumor models, including the C57BL/6J-Min/+ (Min/+) mouse. With uninterrupted long-term celecoxib administration, intestinal tumors in Min/+ mice initially regressed and then recurred to levels comparable with untreated controls. Celecoxib treatment initially suppressed COX-2 and prostaglandin E2 (PGE2) expression, but long-term use produced significantly higher levels of these molecules and reactivated PGE2-associated growth factor signaling pathways in tumor and normal tissues. These results indicate that COX-2 is an important chemoprevention target and that inhibition of this enzyme alters a paracrine enterocyte regulatory pathway. Chronic uninterrupted celecoxib treatment, however, induces untoward effects that enhance early progression events in intestinal tumorigenesis and may contribute to treatment toxicity.
Insights
Selective cyclooxygenase-2 (COX-2) inhibitors show promise for arthritis and cancer prevention. However, long-term use in mice led to tumor recurrence and increased toxicity, suggesting potential risks.
Area of Science:
- Gastroenterology
- Oncology
- Pharmacology
Background:
- Selective cyclooxygenase-2 (COX-2) inhibitors are used for arthritis and cancer chemoprevention.
- Concerns exist regarding cardiovascular toxicity associated with long-term COX-2 inhibitor use.
Purpose of the Study:
- To investigate the long-term effects of celecoxib, a selective COX-2 inhibitor, on intestinal tumorigenesis in a mouse model.
- To evaluate the impact of chronic celecoxib administration on COX-2 and prostaglandin E2 (PGE2) expression and associated signaling pathways.
Main Methods:
- Utilized the C57BL/6J-Min/+ (Min/+) mouse model for intestinal adenoma studies.
- Administered celecoxib long-term to assess tumor growth, regression, and recurrence.
- Monitored COX-2 and PGE2 expression levels and PGE2-associated growth factor signaling.
Main Results:
- Short-term celecoxib inhibited adenoma growth in Min/+ mice.
- Long-term celecoxib administration led to initial tumor regression followed by recurrence to control levels.
- Chronic celecoxib treatment increased COX-2 and PGE2 levels and reactivated PGE2-associated growth factor signaling.
Conclusions:
- COX-2 is a viable chemoprevention target, and its inhibition affects enterocyte regulation.
- Chronic, uninterrupted celecoxib treatment can promote intestinal tumor progression and may contribute to toxicity.
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