Activity of signaling pathways in hypoxic pancreatic and cervical tumor xenografts
Notice bibliographique
Résumé
B193 Tumor hypoxia is widespread in different cancer types and has been associated with poor prognosis. Current monolayer cell culture models suggest that signaling pathways including Src, STAT3 and AKT influence the transcription activity of hypoxia inducible factor-1α (HIF-1α) which affects biological processes including tumor angiogenesis, metastasis and survival. We determined the activity of these signaling proteins in hypoxic tumor regions compared to non-hypoxic regions as well as global tumor response to continuous in vivo hypoxia. Tumor hypoxia was measured based on the histological distribution of the fluorescently labeled 2-nitroimidazole agent EF5 in four murine xenograft models. In air exposed mice, the percent of hypoxic EF5-stained tumor regions ranged from a mean of 14% (BxPC-3) to 48% (PANC-1) for subcutaneously grown pancreatic xenografts, and 20% (ME180) to 27% (SiHa) for orthotopically grown cervical xenografts. A doubling of EF5-stained regions was achieved in BxPC-3 tumors with continuous exposure of mice to 7% O 2 for 3 hours compared to air control. Individual EF5-stained serial tissue sections were co-labeled with single antibodies against signaling proteins. Immunofluorescence image analysis (labeled percent area x intensity) showed a significant increase in the level of total Src protein in EF5 tumor regions compared to non-EF5 regions in all four tumor models (p≤0.05, Wilcoxon test). Additionally, the levels of total and activated Src (Y419) doubled (p=0.03) in EF5 tumor regions compared to non-EF5 regions of mice exposed to low O 2 levels, suggesting that levels of Src protein and activity are hypoxia inducible. There was a strong co-localization of activated Src and focal adhesion kinase (Y861-FAK) in EF5-stained regions of BxPC-3 tumors (r=0.74, p=0.006) in mice exposed either to air or 7% O 2 . This suggests that the cellular adhesion substrate FAK is important in Src-mediated hypoxia signaling in vivo . In contrast, BxPC-3 tumor xenografts of mice exposed to 7% O 2 showed a decrease in levels of STAT3 (S727) activity (p=0.004, Mann-Whitney test) despite no changes in total STAT3 levels in the entire tumor area. The continuous exposure to 7% O 2 did not affect levels of AKT (S473) activity. These results suggest an important role of Src in hypoxia-responsive signaling in vivo . The increased expression and enhanced activity of Src family tyrosine kinases have been associated with carcinogenesis in different tumor types. Also, Src is a common substrate of oncogenic signaling downstream of several growth factor receptors including EGFR, PDGFR and Met, and impacts on tumor cell adhesion, migration and invasion. A therapeutic strategy involving the use of Src inhibitors might be successful at targeting tumor growth as well as hypoxia-induced processes which lead to increased tumor aggressiveness.
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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 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 ».