Central nervous system (CNS) relapse remains an important cause of morbidity and mortality in acute leukemia, but the mechanisms of CNS infiltration are poorly understood. Some results have shown the blood-brain barrier (BBB) makes CNS become a refugee to leukemic cells and serves as a resource of cells that seed extraneural sites. The authors ask how can leukemic cells disrupt BBB and then successfully enter the CNS in the process of leukemia metastasis. Tight junctions between brain microvessel endothelial cells (BMECs) of BBB possess an intricate complex of transmembrane proteins with cytoplasmic accessory proteins, and hence act as physiological and pharmacological barrier, thereby preventing influx of molecules from the bloodstream into the brain. So the loss of endothelial tight-junction proteins might be an important event related to the disruption of BBB. Vascular endothelial growth factor (VEGF) is one of the potent mediators of vascular permeability and the VEGF secreted by leukemic cells may be implicated in this response. Leukemic cells not only produce VEGF, but also express functional VEGFR, resulting in an autocrine loop for tumor growth and dissemination. It has been observed that forced VEGF over expression triggers proliferation and migration/invasion of some leukemic cells, thereby inducing a more invasive tumor phenotype. It has been identified that VEGF-mediated disruption of endothelial transmembrane tight-junction proteins is contributed to the breakdown of BBB in some CNS inflammation disease. Here, we hypothesize that VEGF secreted by leukemic cells also plays an important role in increasing the permeability of BBB by disrupting endothelial tight-junction proteins and give leukemic cells an entrance to the CNS in CNS leukemia. We propose the key tight-junction proteins claudin-5, occludin, and ZO-1 as targets of VEGF action in promoting BBB breakdown, and in interfering with the VEGF/VEGFR pathway using anti-VEGF or anti-VEGFR antibodies can reduce the permeability of BBB. All these will be tested on the BBB model in vitro and in vivo based on an animal model of CNS leukemia. This hypothesis is useful for exploring the mechanism of leukemic CNS infiltration. If correct, the mechanism put forward here will provide a potent evidence for anti-VEGF strategies in treatment of CNS leukemia.
Copyright © 2011. Published by Elsevier Ltd.