CXCL12 AND VEGF SYNERGISTICALLY INDUCE NEOANGIOGENESIS IN HUMAN OVARIAN CANCERS

CXCL12 和 VEGF 协同诱导人类卵巢癌新血管生成

• 批准号: 7349120
• 负责人: I KRYCZEK
• 金额: $ 3.1万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349120
• 关键词: CXCL12; VEGF; SYNERGISTICALLY; INDUCE; NEOANGIOGENESIS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Ovarian carcinomas have a poor prognosis, often associated with multifocal i.p. dissemination accompanied by intense neovascularization. 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 a sizable amount of vascular endothelial cell growth factor (VEGF) in malignant ascites. However, pathologic concentration of VEGF is insufficient to induce in vivo angiogenesis. We show that ovarian tumors strongly express CXC chemokine stromal-derived factor (SDF-1/CXCL12). High concentration of CXCL12, but not the pathologic concentration of CXCL12 induces in vivo angiogenesis. Strikingly, pathologic concentrations of VEGF and CXCL12 efficiently and synergistically induce in vivo angiogenesis. Migration, expansion, and survival of vascular endothelial cells (VEC) form the essential functional network of angiogenesis. We further provide a mechanistic basis for explaining the interaction between CXCL12 and VEGF. We show that VEGF up-regulates the receptor for CXCL12, CXCR4 expression on VECs, and synergizes CXCL12-mediated VEC migration. CXCL12 synergizes VEGF-mediated VEC expansion and synergistically protects VECs from sera starvation-induced apoptosis with VEGF. Finally, we show that hypoxia synchronously induces tumor CXCL12 and VEGF production. Therefore, hypoxia triggered tumor CXCL12 and VEGF form a synergistic angiogenic axis in vivo. Hypoxia-induced signals would be the important factor for initiating and maintaining an active synergistic angiogeneic pathway mediated by CXCL12 and VEGF. Thus, interrupting this synergistic axis, rather than VEGF alone, will be a novel efficient antiangiogenesis strategy to treat cancer.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。卵巢癌预后较差，常伴有多灶性淋巴结播散并伴有强烈的新生血管形成。为了研究肿瘤微环境中的血管生成，我们研究了未经治疗的卵巢癌患者的恶性腹水和肿瘤。我们观察到恶性腹水诱导强有力的体内新生血管的Matrigel试验。我们在恶性腹水中检测到相当数量的血管内皮细胞生长因子（VEGF）。然而，病理浓度的VEGF不足以诱导体内血管生成。我们发现卵巢肿瘤强烈表达CXC趋化因子基质衍生因子（SDF-1/CXCL12）。高浓度CXCL12诱导体内血管生成，而非病理浓度的CXCL12诱导体内血管生成。引人注目的是，病理浓度的VEGF和CXCL12有效地协同诱导体内血管生成。血管内皮细胞（VEC）的迁移、扩张和存活形成了血管生成的基本功能网络。我们进一步为解释CXCL12与VEGF的相互作用提供了机制基础。我们发现VEGF上调了VECs上CXCL12、CXCR4受体的表达，并协同CXCL12介导的VEC迁移。CXCL12协同VEGF介导的VEC扩张，并协同保护VEC免受血清饥饿诱导的凋亡。最后，我们发现缺氧同步诱导肿瘤CXCL12和VEGF的产生。因此，缺氧触发的肿瘤CXCL12和VEGF在体内形成协同的血管生成轴。缺氧诱导的信号可能是启动和维持由CXCL12和VEGF介导的主动协同血管生成途径的重要因素。因此，阻断这种协同轴，而不是单独阻断VEGF，将是一种新的有效的治疗癌症的抗血管生成策略。