Abstract 5255: The role of IGF1 signaling in site specific tumor metastasis: Regulating matrix metalloproteinase (MMP) expression
Notice bibliographique
Résumé
Abstract The phenomenon of site-specific metastasis has been recognized for decades but the underlying molecular mechanisms have only recently become better understood, mainly due to insight from gene and protein profiling strategies. One family of proteins that emerged as a determinant of the organ-specificity of metastasis is that of the matrix metalloproteinases (MMPs). We recently reported that Lewis lung carcinoma cells that are highly metastatic to the lung (M-27) changed their preferred site of metastasis from the lung to the liver upon ectopic expression of the human insulin like growth factor-I receptor (M27IGF-IR). This change was associated with an altered MMP profile as MMP-2 and MMP-14 were upregulated while MMP-3, MMP-9 and MMP-13 expression markedly decreased in these cells (1, 2). The objective of the present study was to investigate the molecular basis for the loss of MMP-3, -9, and -13 expression in these cells. These proteinases are regulated by inflammatory mediators and we indeed found that following treatment with TNF-α, the expression of MMP-3 and MMP-13 in M-27, but not in M27IGF-IR cells was significantly increased, suggesting that the NFκB pathway was altered by IGF-IR overexpression. When expression levels for mediators of the TNFR/IKK/IκBα/NFκB signaling pathway in these cells were analyzed using qRT-PCR and Western blotting, we found that in M27IGF-IR cells, the expression of IKKε but not of IKKα or IKKβ was also downregulated. Moreover when IKKε was ectopically expressed in these cells, basal proteinase levels increased and could be further induced by TNF-α treatment, suggesting that the responsiveness to TNF-α in these cells was restored and was IKKε – dependent. Finally, using RT-PCR and Western blotting, we also observed that in cells with increased IKKε levels, MMP-3 mRNA and protein levels could also be stimulated by phorbol 12-myristate 13-acetate (PMA) treatment, suggesting that PKC signaling in these cells was potentiated. Taken together, our results indicate that the altered MMP profile in M27IGF-IR was due, at least in part, to the downregulation of IKKε- a mediator of inflammation-induced signaling that was recently identified as a potential oncogene in breast cancer (3). They suggest that the MMP profile of the tumor cells is regulated through crosstalk between inflammatory signals, the IGF axis and the PKC system. Moreover, they imply that in addition to intrinsic tumor cell properties, the type of stimuli predominating in the microenvironment will ultimately determine the MMP expression profile and thereby control tumor expansion and metastasis in specific sites. Supported by Canadian Institute for Health Research grant MOP-81201 (to PB). References 1. Brodt, P. et al (2001) J. Biol. Chem. 276:33608-33615. 2. Li, S. et al (2009) Mol. Endocrinology 23:2013-25. 3. Boehm, J.S. et al (2007). Cell 129:1065-79. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5255. doi:10.1158/1538-7445.AM2011-5255
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) | 0,007 | 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 ».