SDF-1, DC1/DC2, and Tumor Angiogenesis
Annual rept. 10 Mar 2004-9 Mar 2005
TULANE UNIV NEW ORLEANS LA
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To examine tumor angiogenesis in the tumor microenvironment, we studied malignant ascites and tumors of patients with untreated ovarian carcinoma. We observed that malignant ascites fluid induced potent in vivo neovascularization in Matrigel assay. We detected sizable amount of VEGF in malignant ascites. However, pathological concentration of VEGF is insufficient to induce in vivo angiogenesis. Ovarian tumors SDF-1CXCL12 is released into malignant ascites. High concentration of CXCL12, but not the pathological concentration of CXCL12 induces in vivo angiogenesis. Strikingly, pathological concentrations of VEGF and CXCL12 efficiently and synergistically induce in vivo angiogenesis. We show that VEGF upregulates the receptor for CXCL12, CXCR4 expression on vascular endothelial cells VECs, and synergizes CXCL12-mediated migration of VECs. Further, CXCL12 synergizes VEGF-mediated VEC expansion, and synergistically protects VECs from sera starvation-induced apoptosis with VEGF. Finally, we show that hypoxia synchronously induces CXCL12 and VEGF production. Therefore, hypoxia-induced signal would be the important factor for initiating and maintaining an active synergistic angiogeneic pathway mediated by CXCL12 and VEGF. Altogether, these results demonstrate that hypoxia triggered tumor CXCL12 and VEGF form a synergistic angiogenic axis in vivo. Interrupting this synergistic axis, rather than VEGF alone, will be a novel efficient anti-angiogenesis strategy to treat cancer.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research