Abstract 1422: Cancer-associated fibroblasts influence the sensitivity of pancreatic cancer cells to gemcitabine in pancreatic ductal adenocarcinoma
Notice bibliographique
Résumé
Abstract Introduction: Pancreatic ductal adenocarcinoma is chemo- and radio-resistant, and has the worst survival rates of all cancers. Gemcitabine improves quality of life, but only provides modest survival benefits. Notably, pancreatic cancer is characterized by a strong “reactive” stroma in association with extensive fibroblast proliferation. Our hypothesis is that the large population of cancer-associated fibroblasts (CAFs) in pancreatic tumors produces a plethora of growth factors and cytokines which in turn, influence the sensitivity of pancreatic cancer cells to gemcitabine. Methods: Fourteen primary pancreatic cancer-associated fibroblast (CAF) lines were established in culture using freshly resected pancreatic tumor tissues from 14 different patients. To assess whether these CAFs influence chemosensitivity, MiaPaCa-2 pancreatic cancer cells were injected alone or co-injected with one of the CAF lines CAF11 subcutaneously into SCID mice. When tumors reached ∼200 mm3, mice bearing MiaPaCa-2 tumors or MiaPaCa-2+CAF11 tumors were treated with the vehicle control (0.9% saline) or gemcitabine (120 mg/kg, q7d, i.p.). Tumor volume was measured weekly. Concurrently, Affymetrix U133 plus 2.0 arrays were used to determine the differentially expressed genes in pancreatic CAFs vs. normal fibroblasts. The genes were then analyzed with Ingenuity Systems to identify network and canonical pathways that are altered in CAFs, and which may mediate chemosensitivity. Selected genes were further validated by RT-PCR, western blotting, or ELISA. Results: Gemcitabine was found to suppress the growth of MiaPaCa-2 tumors but not that of MiaPaCa-2+CAF11 tumors, suggesting that the presence of CAF11 renders MiaPaCa-2 cells more resistant to the drug. Affymetrix results showed that 1704 probe sets representing 1183 unique genes were differentially expressed by 2-fold or greater (P<0.05) in primary pancreatic CAFs, of which 382 gene were upregulated and 801 genes were downregulated. Thirty-four of these genes were mapped to the highest ranking network whose molecular functions include “cell cycle, cancer”. IL-6 was the most highly upregulated gene (8.3-fold; P=2.20e-05) in this network. Furthermore, 19 and 11 other genes were mapped to two significant canonical pathways, “hepatic fibrosis/hepatic stellate cell activation” and “IL-6 signaling”, respectively. IL-6 was the central component of both canonical pathways. RT-PCR and ELISA data confirmed the increased expression of IL-6 and other soluble factors in CAFs. Conclusion: Primary pancreatic CAFs secrete elevated levels of various growth factors and cytokines such as IL-6, which may promote survival of pancreatic cancer cells and reduce their sensitivity to gemcitabine. These soluble factors are potential therapeutic targets in pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1422.
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) | 0,003 | 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 ».