Abstract 2732: The role of Cdx transcription factors in intestinal tumorigenesis.
Notice bibliographique
Résumé
Abstract Mutations in the Adenomatous polyposis coli (APC) gene are an early causative event in human colorectal cancer (CRC). The Min mouse, which harbors mutations of APC, is a widely used model for CRC, although it presents with benign polyps restricted largely to the small intestine. The transcription factors Cdx1 and Cdx2 are expressed throughout the intestinal epithelium from early gut development, and persist throughout the life of the animal. Cdx1 null mice exhibit no intestinal phenotype while Cdx2 null mice die around embryonic day 3.5. Cdx2 heterozygotes, however, have an intestinal phenotype characterized by lesions in the pericaecal region and proximal colon suggestive of a role for Cdx2 in posteriorizing the intestinal tract. Consistent with this, recent studies using conditional knockout approaches show loss of Cdx2 from the developing or adult intestinal epithelium results in an anteriorized intestinal phenotype. Cdx2 loss has been detected in 30% of human CRC, and Cdx2 heterozygous-APC mutants exhibit an increase in polyp formation in the colon; similar results are seen with Cdx2 heterozygotes treated with the carcinogen azoxymethane. These studies suggest that Cdx2 has tumor suppressor properties, however the mechanism by which Cdx2 elicits this effect is unknown. We are using a Cre-lox system to conditionally delete Cdx2 from the adult intestine alone or in a heterozygous Min background. The tamoxifen-regulated Cre, under the spatial control of the villin promoter, is fused to a modified estrogen receptor ligand binding domain that responds only to tamoxifen. Sub-optimal tamoxifen treatment is used to effect partial loss of Cdx2 to circumvent the lethality inherent to Cdx2 loss in the adult intestine. Animals will be sacrificed commencing at 14 weeks post-treatment for analysis of intestinal lesions and compound mutants will be compared to mice deficient for Cdx2 or Min alone. Partial tamoxifen treatment was successful at yielding mice with chimeric loss of Cdx2. In contrast to germ-line Cdx2 heterozygotes, chimeric Cdx2 deletion did not produce hamartomas. In contrast, Cdx-Min compound mutants exhibited a faster trajectory of wasting compared to Min heterozygotes, necessitating endpointing by 14 weeks post-treatment. These compound mutant mice exhibited a three-fold increase in tumor incidence compared to Min controls, with an increased tumors size. Histologically, the small intestinal tumors that developed in the Cdx-Min background have an altered histological appearance compared to the adenomatous Min tumors. Proliferative cells and nuclear beta-catenin expression, seen within the Min tumors, were expanded in the Cdx-Min tumors, consistent with activation of the Wnt pathway in both tumor types. This work illustrates that the conditional Cdx2 allele is an effective tool for studying the role of this transcription factor in the adult intestine, and reaffirms an important role for Cdx2 in the genesis of intestinal cancers. Citation Format: Alexa Hryniuk, David Lohnes, Stephanie Grainger. The role of Cdx transcription factors in intestinal tumorigenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2732. doi:10.1158/1538-7445.AM2013-2732
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
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 tête enseignante, 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 ».