Veiga J Pedro, Costa Lara F, Sallan Stephen E, Nadler Lee M, Cardoso Angelo A
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Exp Hematol. 2006 May;34(5):610-21. doi: 10.1016/j.exphem.2006.01.013.
Extensive endothelial cell proliferation and marked neovascularization are the most pronounced microenvironmental changes consistently observed in the bone marrow (BM) of patients with acute lymphoblastic leukemia (ALL). It is not known whether ALL cells induce this phenotype and whether they receive critical signals from the tumor-associated BM endothelium. Here, we show that leukemia cells actively stimulate BM endothelium, promote de novo angiogenesis, and induce neovascularization in the leukemic BM. Soluble factors, present in the leukemic BM microenvironment, promote the proliferation, migration, and morphogenesis of BM endothelial cells, which are critical processes in tumor angiogenesis. We also show in vitro that leukemia cells display directional motion towards assembled BM endothelium and following adherence exhibit cell polarization, pseudopodia, and ultrastructural features that suggest the existence of leukemia-endothelium cross-talk. Finally, we show that BM endothelium promotes leukemia cell survival through a mechanism mediated through the anti-apoptotic molecule bcl-2. These studies indicate that ALL cells actively recruit BM endothelium and mediate the leukemia-associated neovascularization observed in ALL. Therefore, disruption of interactions between leukemia cells and BM endothelium may constitute a valid therapeutic strategy.
广泛的内皮细胞增殖和显著的新生血管形成是急性淋巴细胞白血病（ALL）患者骨髓（BM）中始终观察到的最明显的微环境变化。目前尚不清楚ALL细胞是否诱导了这种表型，以及它们是否从肿瘤相关的BM内皮细胞接收关键信号。在这里，我们表明白血病细胞积极刺激BM内皮细胞，促进新生血管生成，并在白血病BM中诱导新生血管形成。白血病BM微环境中存在的可溶性因子促进BM内皮细胞的增殖、迁移和形态发生，这些是肿瘤血管生成中的关键过程。我们还在体外表明，白血病细胞向组装好的BM内皮细胞表现出定向运动，并且在粘附后表现出细胞极化、伪足和超微结构特征，这表明存在白血病-内皮细胞相互作用。最后，我们表明BM内皮细胞通过抗凋亡分子bcl-2介导的机制促进白血病细胞存活。这些研究表明ALL细胞积极募集BM内皮细胞并介导ALL中观察到的白血病相关新生血管形成。因此，破坏白血病细胞与BM内皮细胞之间的相互作用可能构成一种有效的治疗策略。
