Angiogenesis in acute promyelocytic leukemia:: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid
Angiogenesis in acute promyelocytic leukemia:: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid
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DOI：
10.1182/blood.v97.12.3919
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发表时间：
2001-06-15
期刊：
影响因子：
20.3
通讯作者：
Lingen, MW
中科院分区：
文献类型：
--
作者：
Kini, AR;Peterson, LC;Lingen, MW
最近的研究表明，血管生成除了在实体瘤中的作用外，在白血病的发病机制中也很重要。本研究探讨了血管生成在急性早幼粒细胞白血病（APL）中的可能作用。APL患者骨髓环钻活检显示微血管密度和热点密度明显高于正常对照骨髓活检。为了鉴定APL中血管生成的介质，我们以NB4 APL细胞系为模型系统进行了定量和功能分析。来自NB4细胞的条件培养基（CM）强烈刺激内皮细胞迁移。来自NB4细胞的CM含有高水平的血管内皮生长因子（VEGF），但不含碱性成纤维细胞生长因子（bFGF），最重要的是，加入中和性VEGF抗体完全抑制了NB4 CM刺激内皮细胞迁移的能力，提示APL血管生成是由VEGF介导的。研究全反式维甲酸（ATRA）对APL血管生成的影响。ATRA治疗导致骨髓微血管密度和热点密度降低。经atra处理的APL细胞的CM不刺激内皮细胞迁移。最后，定量分析表明，ATRA处理导致NB4细胞的VEGF生成消失。这些结果表明APL中血管生成和VEGF生成增加，ATRA治疗抑制VEGF生成和抑制血管生成，应探索在分化治疗或化疗中添加特异性抗血管生成药物。
Recent studies indicate that angiogenesis is important in the pathogenesis of leukemias, apart from its well-established role in solid tumors. In this study, the possible role of angiogenesis in acute promyelocytic leukemia (APL) was explored. Bone marrow trephine biopsies from patients with APL showed significantly increased microvessel density and hot spot density compared with normal control bone marrow biopsies. To identify the mediators of angiogenesis in APL, quantitative and functional assays were performed using the NB4 APL cell line as a model system. Conditioned media (CM) from the NB4 cells strongly stimulated endothelial cell migration. CM from the NB4 cells contained high levels of vascular endothelial growth factor (VEGF) but not basic fibroblast growth factor (bFGF), Most important, the addition of neutralizing VEGF antibodies completely inhibited the ability of NB4 CM to stimulate endothelial cell migration, suggesting that APL angiogenesis is mediated by VEGF. The effect of all-trans retinoic acid (ATRA) on APL angiogenesis was then studied. ATRA therapy resulted in a decrease in bone marrow microvessel density and hot spot density. CM from ATRA-treated APL cells did not stimulate endothelial cell migration. Finally, quantitative assays showed that ATRA treatment resulted in the abrogation of VEGF production by the NB4 cells. These results show that there is increased angiogenesis and VEGF production in APL and that ATRA therapy inhibits VEGF production and suppresses angiogenesis, The addition of specific antiangiogenic agents to differentiation therapy or chemotherapy should be explored.