A8 THE ROLE OF CYCLOOXYGENASE IN COLITIS-ASSOCIATED CANCER
Notice bibliographique
Résumé
Colorectal cancer (CRC) is the 2nd leading cause of cancer death in Canada. Inflammatory bowel disease (IBD), a chronic state of colonic inflammation, is a major risk factor for CRC. Despite the clear link between inflammation and cancer, the mechanism by which colitis leads to cancer is unknown. Doublecortin-like kinase-1 (Dclk1) is a marker of tuft cells, a rare and ill-defined cell type of the colon. We previously showed that Dclk1+ cells are quiescent, long-lived, and remain resistant to proliferation even upon mutation of the tumor suppressor APC. However, APC-mutated tuft cells become powerful cancer-initiating cells upon exposure to inflammation, but the mechanism by which this occurs remains unknown. Interestingly, Dclk1+ tuft cells express high levels of cyclooxygenase (COX)-1 and -2, the direct enzyme target of non-steroidal anti-inflammatory drugs (NSAIDs) which are known chemopreventative drugs in CRC. In the present study, we aim to determine the effects of COX inhibition by NSAIDs on colitis-associated colorectal cancer. Dclk1CreERT2/APCfl/fl mice were administered tamoxifen to induce an APC mutation in Dclk1-expressing cells. Mice were then exposed to the colitis-inducing agent dextran sodium sulfate (DSS), followed by daily treatment with Aspirin (non-selective COX inhibitor), celecoxib or rofecoxib (COX-2 inhibitors), SC-560 (COX-1 inhibitor), or vehicle, for the experiment duration. As a comparison, we followed a similar experimental protocol in the commonly used AOM/DSS model of CAC. The carcinogen azoxymethane (AOM) followed by DSS were administered to induce tumorigenesis. Sixteen weeks post-tamoxifen or AOM, colonic tumor number and size were examined to determine the effect of NSAIDs on tumor initiation and growth, respectively. Extent of inflammation was assessed by myeloperoxidase (MPO) activity and histology. Colonic tissue was taken for measurement of inflammatory mediators by qRT-PCR and of inflammatory eicosanoids by LC-MS. Treatment with Aspirin, but surprisingly, none of the COX-specific inhibitors, significantly reduced the number of both Dclk1+ cell-derived and AOM DSS-derived colonic tumors. There was no significant difference in tumor size or degree of colitis, as assessed by MPO activity and histology, between vehicle and NSAID-treated groups. Interestingly, LC-MS revelated that in DSS-colitis, the production of COX-mediated prostaglandins was significantly inhibited in Aspirin- and SC-560-treated mice, but not in mice treated with celecoxib. Aspirin was also associated with a significant reduction in Dclk1+ cells. These findings suggest a role for cyclooxygenase in colitis-associated cancer. Our results suggest that Aspirin is chemopreventative in CAC, potentially through inhibition of COX-1-mediated prostaglandins that may be critical for Dclk1+ cell survival. CIHR
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».