ArticleCancer prevention research (Philadelphia, Pa.)2022
The COX-2-PGE2 Pathway Promotes Tumor Evasion in Colorectal Adenomas.
Article in Cancer prevention research (Philadelphia, Pa.), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
48 citing papers in PubMed, 1 synthesis or guideline pooled it, 62 citations in OpenAlex.
- Systematic review: The gut microbiota as a link between colorectal cancer and obesity.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2025Pooled it
- Photodynamic therapy based on indomethacin-conjugated photosensitizers: targeting cyclooxygenase-2 in cancer treatment.Medical gas research · 2026Review
- Colitis-associated colorectal carcinogenesis: molecular mechanisms and therapeutic potential.Molecular biomedicine · 2026Review
- PI3K/AKT signaling pathway: molecular crossroads in tumorigenesis and therapeutic innovation.Signal transduction and targeted therapy · 2026Review
- Current Strategies and Emerging Paradigms of Immunotherapy in Microsatellite Stable Colorectal Cancer: A Review Article.Clinical drug investigation · 2026Review
- Dual modulation of Wnt and inflammatory pathways by Gingerenone a inhibits colorectal tumorigenesis.Molecular biology reports · 2026Article
- Dual-Action NSAID-Gold(I) Alkynyl Hybrids for Synergistic Anti-Inflammatory and Anticancer Therapy of Colorectal Cancer.Inorganic chemistry · 2026Article
- Advances in immunotherapy for colorectal cancer: overcoming resistance in mismatch repair-proficient tumors.Cancer cell international · 2026Review
- Targeting inflammatory microenvironments: overcoming therapy resistance and immunosuppression.Molecular cancer · 2026Review
- Prostaglandin D2 axis impairs immunity against melanoma via dendritic cells and γδ T cells in middle-aged mice.Journal of immunology (Baltimore, Md. : 1950) · 2026Article
- Stage-Dependent Role of Eicosanoids in Colorectal Cancer.International journal of molecular sciences · 2026Article
- Genome-wide CRISPR Screening Reveals a PKA-Driven Resistance Mechanism to Metformin for Oral Cancer Prevention That Can Be Exploited by Combination with NSAIDs.Cancer prevention research (Philadelphia, Pa.) · 2026Article
- Risk factors for cutaneous immune-related adverse events: a systematic scoping review.Frontiers in immunology · 2026Article
- Metabolic reprogramming networks in the gastric cancer tumor microenvironment: an integrated axis of nutrient competition, metabolic crosstalk, and immunosuppression.Frontiers in immunology · 2026Review
- The Role of Prostaglandins as Major Inflammatory Mediators in Colorectal Cancer.International journal of molecular sciences · 2025Review
- Non-invasive colorectal cancer screening methods: focusing on diagnostic genetic and epigenetic markers.Cancer cell international · 2025Review
- Review
- Robot-Assisted Colorectal Cancer Surgery Mitigates Early Postoperative Immunosuppression and Angiogenesis.International journal of molecular sciences · 2025Article
- Turning cold tumors into hot tumors to ignite immunotherapy.Molecular cancer · 2025Review
- Integrating COX-2, stromal PD-L1, and T-cell infiltration enhances prognostic stratification in colorectal cancer.BMC cancer · 2025Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The mechanisms underlying the regulation of a checkpoint receptor, PD-1, in tumor-infiltrating immune cells during the development of colorectal cancer are not fully understood. Here we demonstrate that COX-2-derived PGE2, an inflammatory mediator and tumor promoter, induces PD-1 expression by enhancing NFκB's binding to the PD-1 promoter via an EP4-PI3K-Akt signaling pathway in both CD8+ T cells and macrophages. Moreover, PGE2 suppresses CD8+ T-cell proliferation and cytotoxicity against tumor cells and impairs macrophage phagocytosis of cancer cells via an EP4-PI3K-Akt-NFκB-PD-1 signaling pathway. In contrast, inhibiting the COX-2-PGE2-EP4 pathway increases intestinal CD8+ T-cell activation and proliferation and enhances intestinal macrophage phagocytosis of carcinoma cells accompanied by reduction of PD-1 expression in intestinal CD8+ T cells and macrophages in ApcMin/+ mice. PD-1 expression correlates well with COX-2 levels in human colorectal cancer specimens. Both elevated PD-1 and COX-2 are associated with poorer overall survival in patients with colorectal cancer. Our results uncover a novel role of PGE2 in tumor immune evasion. They may provide the rationale for developing new therapeutic approaches to subvert this process by targeting immune checkpoint pathways using EP4 antagonists. In addition, our findings reveal a novel mechanism explaining how NSAIDs reduce colorectal cancer risk by suppressing tumor immune evasion. PREVENTION RELEVANCE: These findings provide a potential explanation underlying the chemopreventive effect of NSAIDs on reducing colorectal cancer incidence during premalignancy and provide a rationale for developing EP4 antagonists for colorectal cancer prevention and treatment. Simply targeting PGE2 signaling alone may be efficacious in colorectal cancer prevention and treatment, avoiding side effects associated with NSAIDs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.