MP61-01 ANTITUMOR ACTIVITY OF SULFATED ANGIOGENIC FRAGMENTS: A NOVEL HYALURONIDASE INHIBITOR
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Résumé
You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II1 Apr 2016MP61-01 ANTITUMOR ACTIVITY OF SULFATED ANGIOGENIC FRAGMENTS: A NOVEL HYALURONIDASE INHIBITOR Martin J.P. Hennig, Soum D. Lokeshwar, Shenelle N. Wilson, Andre R. Jordan, Juan Chipollini, Marie C. Hupe, Mario W. Kramer, Luis E. Lopez, Axel S. Merseburger, and Vinata B. Lokeshwar Martin J.P. HennigMartin J.P. Hennig More articles by this author , Soum D. LokeshwarSoum D. Lokeshwar More articles by this author , Shenelle N. WilsonShenelle N. Wilson More articles by this author , Andre R. JordanAndre R. Jordan More articles by this author , Juan ChipolliniJuan Chipollini More articles by this author , Marie C. HupeMarie C. Hupe More articles by this author , Mario W. KramerMario W. Kramer More articles by this author , Luis E. LopezLuis E. Lopez More articles by this author , Axel S. MerseburgerAxel S. Merseburger More articles by this author , and Vinata B. LokeshwarVinata B. Lokeshwar More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.875AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES HYAL1 hyaluronidase (HAase) degrades hyaluronic acid (HA) into angiogenic fragments (AGF) that support tumor growth and metastasis by promoting epithelial mesenchymal transition (EMT). Urinary HAase levels are sensitive markers for high-grade bladder cancer (BCa) and HYAL1 expression correlates with metastasis. We evaluated if sulfated AGF (sHA-F) inhibits HAase activity and is a potential targeted therapeutic agent in preclinical models of BCa. METHODS mRNA expression of EMT genes (β-catenin, Twist and Snail) was measured by q-PCR in 66 bladder tissue specimens (27 normal; 39 tumor); follow-up: 26±4.3 months; median 20 months. Effect of sHA-F (0-40 μg/ml) on cell proliferation, apoptosis, chemotactic motility and invasion was examined in HYAL1 expressing (253J-Lung, HT1376, UMUC-3), non-expressing (T24, RT4, TCCsUP) and normal bladder (Urotsa, SV-HUC1) cells. Effect of sHA-F on apoptosis, HA receptor (CD44, RHAMM), EMT markers was evaluated by q-PCR, immunoblotting, proximal ligation and PI-3K activity assays. Mechanism of action was examined by AGF addition and mAkt transfection. Antitumor activity of sHA-F (25-50 mg/kg) was tested in a 253J-Lung xenograft model by i.p. injection. RESULTS Snail and Twist levels were elevated in BCa tissues as compared to normal bladder (P<0.001) and correlated with metastasis (2-fold increase; P=0.028). β-catenin levels correlated with survival (χ2=4.3, p=0.038). At IC50 for HAase activity inhibition (5-20 μg/ml), sHA-F inhibited proliferation, motility and invasion only in HYAL1 expressing BCa cells (p<0.002). sHA-F caused a dose dependent 3-fold induction in apoptosis by activating caspases (3,8,9), PARP-cleavage and death receptor signaling. sHA-F downregulated transcript and/or protein levels of CD44, RHAMM, pAkt, β-catenin, pβ-catenin (S552), snail and twist by 2-5-fold, but increased pβcatenin ((T41/S45), pGSK-3α/β and E-cadherin levels. sHA-F inhibited CD44/PI-3K complex formation and PI-3K activity. AGF addition or mAkt overexpression attenuated sHA-F effects, but HYAL-1 expression sensitized RT4 cells to sHA-F. In 253J-L xenograft, 2-week treatment of sHA-F starting on the day of tumor cell injection or in palpable tumors significantly inhibited tumor growth (p<0.001) by abrogating angiogenesis and HA receptor-PI-3K/Akt signaling. CONCLUSIONS This is the first investigation into the therapeutic activity of sHA-F in any system (cancer or non-cancer) and demonstrates it as a potentital targeted non-toxic agent for BCa treatment. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e803 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Martin J.P. Hennig More articles by this author Soum D. Lokeshwar More articles by this author Shenelle N. Wilson More articles by this author Andre R. Jordan More articles by this author Juan Chipollini More articles by this author Marie C. Hupe More articles by this author Mario W. Kramer More articles by this author Luis E. Lopez More articles by this author Axel S. Merseburger More articles by this author Vinata B. Lokeshwar More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
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 | 0,001 | 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 ».