Poulos Michael G, Gars Eric J, Gutkin Michael C, Kloss Christopher C, Ginsberg Michael, Scandura Joseph M, Rafii Shahin, Butler Jason M
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
Angiocrine Bioscience, New York, NY 10065, USA.
Exp Hematol. 2014 Nov;42(11):976-986.e3. doi: 10.1016/j.exphem.2014.08.003. Epub 2014 Aug 29.
Understanding the intricate cellular components of the bone marrow microenvironment can lead to the discovery of novel extrinsic factors that are responsible for the initiation and progression of leukemic disease. We have shown that endothelial cells (ECs) provide a fertile niche that allows for the propagation of primitive and aggressive leukemic clones. Activation of the ECs by vascular endothelial growth factor (VEGF)-A provides cues that enable leukemic cells to proliferate at higher rates and also increases the adhesion of leukemia to ECs. Vascular endothelial growth factor A-activated ECs decrease the efficacy of chemotherapeutic agents to target leukemic cells. Inhibiting VEGF-dependent activation of ECs by blocking their signaling through VEGF receptor 2 increases the susceptibility of leukemic cells to chemotherapy. Therefore, the development of drugs that target the activation state of the vascular niche could prove to be an effective adjuvant therapy in combination with chemotherapeutic agents.
了解骨髓微环境复杂的细胞成分有助于发现导致白血病发生和发展的新的外在因素。我们已经表明，内皮细胞（ECs）提供了一个适宜的生态位，使原始和侵袭性白血病克隆得以增殖。血管内皮生长因子（VEGF）-A激活内皮细胞，提供信号使白血病细胞以更高的速率增殖，并增加白血病细胞与内皮细胞的黏附。VEGF-A激活的内皮细胞降低了化疗药物靶向白血病细胞的疗效。通过阻断内皮细胞通过VEGF受体2的信号传导来抑制VEGF依赖性激活，可增加白血病细胞对化疗的敏感性。因此，开发针对血管生态位激活状态的药物可能被证明是与化疗药物联合使用的有效辅助治疗方法。
