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Stromal Cell-Derived Factor 1α Mediates Resistance to mTOR-Directed Therapy in Pancreatic Cancer

التفاصيل البيبلوغرافية
العنوان: Stromal Cell-Derived Factor 1α Mediates Resistance to mTOR-Directed Therapy in Pancreatic Cancer
المؤلفون: Colin D. Weekes, Dongweon Song, John Arcaroli, Lora A. Wilson, Belen Rubio-Viqueira, George Cusatis, Elizabeth Garrett-Mayer, Wells A. Messersmith, Robert A. Winn, Manuel Hidalgo
المصدر: Neoplasia: An International Journal for Oncology Research, Vol 14, Iss 8, Pp 690-701 (2012)
بيانات النشر: Elsevier, 2012.
سنة النشر: 2012
المجموعة: LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: PURPOSE: The factors preventing the translation of preclinical findings supporting the clinical development mTOR-targeted therapy in pancreatic cancer therapy remain undetermined. Stromal cell.derived factor 1α (SDF-1α)-CXCR4 signaling was examined as a representative microenvironmental factor able to promote mTOR-targeted therapy resistance in pancreatic cancer. EXPERIMENTAL DESIGN: Primary pancreas explant xenografts and in vitro experiments were used to perform pharmacodynamic analyses of SDF-1α-CXCR4 regulation of the mTOR pathway. Combinatorial effects of CXCR4, EGFR, and mTOR pharmacologic inhibition were evaluated in temsirolimus-resistant and -sensitive xenografts. Intratumoral gene and protein expressions of mTOR pathway effectors cyclin D1, c-Myc, and VEGF were evaluated. RESULTS: Baseline intratumoral SDF-1α gene expression correlated with temsirolimus resistance in explant models. SDF-1α stimulation of pancreatic cells resulted in CXCR4-mediated PI3-kinase-dependent S6-RP phosphorylation (pS6-RP) on exposure to temsirolimus. Combinatorial therapy with AMD3465 (CXCR4 small-molecule inhibitor) and temsirolimus resulted in effective tumor growth inhibition to overcome temsirolimus resistance. In contrast, SDF-1α exposure induced a temsirolimus-resistant phenotype in temsirolimus-sensitive explants. AMD3465 inhibited CXCR4-mediated intratumoral S6-RP phosphorylation and cyclin D and c-myc gene expression. Next, CXCR4 promoted intratumoral EGFR expression in association with temsirolimus resistance. Treatment with AMD3465, temsirolimus- and erlotinib-mediated tumor growth inhibition to overcome temsirolimus resistance in the explant model. Lastly, SDF-1α-CXCR4 signaling increased intratumoral VEGF gene and protein expression. CONCLUSIONS: SDF-1α-CXCR4 signaling represents a microenvironmental factor that can maintain mTOR pathway fidelity to promote resistance to mTOR-targeted therapy in pancreatic cancer by a variety of mechanisms such as recruitment of EGFR signaling and angiogenesis.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1476-5586
1522-8002
Relation: http://www.sciencedirect.com/science/article/pii/S1476558612800030; https://doaj.org/toc/1476-5586; https://doaj.org/toc/1522-8002
DOI: 10.1593/neo.111810
URL الوصول: https://doaj.org/article/aba201eee29846aebff0ad9a9f9563f3
رقم الأكسشن: edsdoj.ba201eee29846aebff0ad9a9f9563f3
قاعدة البيانات: Directory of Open Access Journals
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