Antiangiogenic and antitumor efficacy of EphA2 receptor antagonist
| Autor: | Hugh Zhao, Hong Chang, Susan Jones-Bolin, Pawel Dobrzanski, Candy Robinson, Bruce Ruggeri, Kathryn Hunter, Sonya Pritchard |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Angiogenesis medicine.medical_treatment Basic fibroblast growth factor Mice Nude Neovascularization Physiologic Angiogenesis Inhibitors Antineoplastic Agents Receptors Fc In Vitro Techniques Receptor tyrosine kinase Neovascularization Rats Sprague-Dawley chemistry.chemical_compound Mice Internal medicine medicine Animals Humans Receptor Aorta biology Growth factor Receptor EphA2 Erythropoietin-producing hepatocellular (Eph) receptor Vascular Endothelial Growth Factor Receptor-2 Xenograft Model Antitumor Assays Rats Pancreatic Neoplasms Endocrinology Oncology chemistry biology.protein Cancer research Female medicine.symptom Ex vivo Carcinoma Pancreatic Ductal |
| Zdroj: | Cancer research. 64(3) |
| ISSN: | 0008-5472 |
| Popis: | Tumor-associated angiogenesis is critical for tumor growth and metastasis and is controlled by various pro- and antiangiogenic factors. The Eph family of receptor tyrosine kinases has emerged as one of the pivotal regulators of angiogenesis. Here we report that interfering with EphA signaling resulted in a pronounced inhibition of angiogenesis in ex vivo and in vivo model systems. Administration of EphA2/Fc soluble receptors inhibited, in a dose-dependent manner, microvessel formation in rat aortic ring assay, with inhibition reaching 76% at the highest dose of 5000 ng/ml. These results were further confirmed in vivo in a porcine aortic endothelial cell-vascular endothelial growth factor (VEGF)/basic fibroblast growth factor Matrigel plug assay, in which administration of EphA2/Fc soluble receptors resulted in 81% inhibition of neovascularization. The additive effects of simultaneous inhibition of VEGF receptor 2 and EphA signaling pathways in aortic ring assay and antiangiogenic efficacy of EphA2/Fc soluble receptors against VEGF/basic fibroblast growth factor-mediated neovascularization in vivo indicated a critical and nonredundant role for EphA signaling in angiogenesis. Furthermore, in two independent experiments, we demonstrated that EphA2/Fc soluble receptors strongly (by ∼50% versus controls) suppressed growth of ASPC-1 human pancreatic tumor s.c. xenografts. Inhibition of tumor growth was due to decreased proliferation of tumor cells. In an orthotopic pancreatic ductal adenocarcinoma model in mice, suppression of EphA signaling by i.p. administration of EphA2/Fc (30 μg/dose, three times a week for 56 days) profoundly inhibited the growth of primary tumors and the development of peritoneal, lymphatic, and hepatic metastases. These data demonstrate a critical role of EphA signaling in tumor growth and metastasis and provide a strong rationale for targeting EphA2 receptors for anticancer therapies. |
| Databáze: | OpenAIRE |
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