Abstract A34: Hypoxia signaling pathway is frequently involved in pediatric osteosarcoma microenvironment, as diagnostic and prognostic biomarkers, but also as new therapeutic targets
Notice bibliographique
Résumé
Abstract Osteosarcoma is the first bone cancer diagnosed in adolescent and young adults. Multiple studies involved a deregulation of osteoblast, osteoclast, or microenvironment genes in their development and progression. Nevertheless, no focus was already done in the oxygen-modulated environment of those cancers. Our objectives in this study were to determine, first, the presence of hypoxia deregulation in a cohort of pediatric osteosarcomas (pOS at diagnosis) and in 4 PDCLs (patient-derived cell lines from diagnostic samples). For this purpose, we performed CGHarray for 67 samples and a validation by semiquantitative PCR in another cohort of 20 samples. We also explored by immunohistochemistry in 30 tumor specimens protein expressions of key biomarkers from the hypoxic signaling pathway. Those biomarkers were validated and assessed functionally by immunofluorescence and Western blotting in PDCLs and paired xenografts. All those results in the pOS collections were correlated to survivals and response to first-line therapies. Secondly, the role of hypoxia modulation in PDCLs was determined using variations of oxygen levels from 21% to 5% on cell proliferation characteristics and protein parameters. Finally, to understand how the process of hypoxia is a potential target for pOS treatment, we inhibited different targets of the mTor/HIF1alpha pathway in those PDCLs. As expected, the hypoxia signaling pathway was highly expressed in pOS (tumor samples and PDCLs). Several biomarkers (for example, ULK1, USP33, VEGFR2, CCL7, etc.) were overexpressed in specific groups, linking them significantly to prognosis and a response to chemotherapy. Most of them were involved in the metabolism, autophagy, or angiogenic processes. The PDCLs also expressed in vitro and in xenografts several proteins of this hypoxic pathway as in tumors themselves (pS6, phosphor-mTor, pAKT, HIF1alpha, HIF2alpha). The induction of HIF1alpha during oxygen decrease is early and constant in PDCLs. mTor and HIF2alpha were not induced by the variation of oxygen and were constantly expressed in the cells. Surprisingly, most of the PDCLs increase their proliferation rate in hypoxic conditions, but do not change their microscopic aspects. Finally, the inhibition of mTor and HIF1alpha with rapamycine and irinotecan, respectively, decreases the cell proliferation with a complete inhibition of the targets. In conclusion, hypoxia seems to be frequently involved in pOS through different downstream signaling processes and might be a new potential way of treatment. Citation Format: Marina Pierrevelcin, Audrey Grain, Aurelien Tripp, Adeline Obrecht, Benoit Lhermitte, Noelle Weingertner, Nathalie Gaspar, Pascal Villa, Isabelle Lelong-Rebel, Françoise Redini, Monique Dontenwill, Natacha Entz-Werlé. Hypoxia signaling pathway is frequently involved in pediatric osteosarcoma microenvironment, as diagnostic and prognostic biomarkers, but also as new therapeutic targets [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A34.
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 ».