Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration
Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration
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DOI：
10.1172/jci8978
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发表时间：
2000-08-01
影响因子：
15.9
通讯作者：
Rafii, S
中科院分区：
文献类型：
--
作者：
Dias, S;Hattori, K;Rafii, S
新出现的数据表明，内皮细胞和造血干细胞都表达VEGF受体。因此，我们假设功能性VEGF受体也可能在恶性造血干细胞（如白血病）中表达。我们证明，某些白血病不仅在体内和体外产生VEGF，而且还表达功能性的VEGFR-2，从而产生可能支持白血病细胞存活和增殖的自分泌环。大约50%的新分离白血病表达VEGFR-2的mRNA和蛋白。VEGF（165）诱导VEGFR-2磷酸化并增加白血病细胞的增殖，证明这些受体是有功能的。VEGF（165）还诱导白血病细胞表达MMP-9，并促进其通过重组基底膜迁移。针对人VEGFR-2的中和单抗IMC-1C11在体外抑制白血病细胞存活，阻断VEGF（165）介导的白血病细胞增殖和VEGF诱导的白血病细胞迁移。将原发性白血病和白血病细胞系异种移植到免疫功能低下的非肥胖糖尿病小鼠体内，可显著提高人血浆中VEGF水平，并在3周内导致接种小鼠死亡。注射IMC-1C11可抑制异种移植人白血病细胞的增殖，显著提高接种小鼠的存活率。中断VEGFR-2的信号传导，特别是VEGFR-2，可能为抑制白血病细胞增殖提供了一种新的策略。
Emerging data suggest that VEGF receptors are expressed by endothelial cells as well as hematopoietic stem cells. Therefore, we hypothesized that functional VEGF receptors may also be expressed in malignant counterparts of hematopoietic stem cells such as leukemias. We demonstrate that certain leukemias not only produce VEGF but also express functional VEGFR-2 in vivo and in vitro, resulting in the generation of an autocrine loop that may support leukemic cell survival and proliferation. Approximately 50% of freshly isolated leukemias expressed mRNA and protein for VEGFR-2. VEGF(165) induced phosphorylation of VEGFR-2 and increased proliferation of leukemic cells, demonstrating these receptors were functional. VEGF(165) also induced the expression of MMP-9 by leukemic cells and promoted their migration through reconstituted basement membrane. The neutralizing mAb IMC-1C11, specific to human VEGFR-2, inhibited leukemic cell survival in vitro and blocked VEGF(165)-mediated proliferation of leukemic cells and VEGF-induced leukemic cell migration. Xenotransplantation of primary leukemias and leukemic cell lines into immunocompromised nonobese diabetic mice resulted in significant elevation of human, but not murine, VEGF in plasma and death of inoculated mice within 3 weeks. Injection of IMC-1C11 inhibited proliferation of xenotransplanted human leukemias and significantly increased the survival of inoculated mice. Interruption of signaling by VEGFR-2, particularly VEGFR-2, may provide a novel strategy for inhibiting leukemic cell proliferation.