Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias
Inhibition of both paracrine and autocrine VEGF/VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias
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DOI：
10.1073/pnas.191117498
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发表时间：
2001-09-11
影响因子：
11.1
通讯作者：
Rafii, S
中科院分区：
文献类型：
--
作者：
Dias, S;Hattori, K;Rafii, S
抗血管生成药物可阻断肿瘤源性血管生成因子（旁分泌因子），例如血管内皮生长因子（VEGF）对内皮细胞（EC）的影响，从而抑制实体瘤的生长。然而，血管生成的抑制是否也可能在液体肿瘤中发挥作用尚未明确。我们最近发现，某些白血病不仅产生 VEGF，还选择性表达功能性 VEGF 受体 (VEGFR)，例如 VEGFR-2 (Flk-1、KDR) 和 VEGFR1 (Flt1)，从而导致自分泌环的产生。在这里，我们通过使用人类白血病模型检查了旁分泌（EC依赖性）和自分泌（EC非依赖性）VEGF/VEGFR信号通路的相对贡献，其中自分泌和旁分泌VEGF/VEGFR环可以通过中和小鼠EC（旁分泌通路）或人类肿瘤（自分泌）VEGFR特异性的单克隆抗体来选择性抑制。阻断旁分泌或自分泌 VEGF/VEGFR-2 途径可延迟白血病的生长和体内植入，但无法治愈接种的小鼠。只有用针对鼠和人 VEGFR-2 的 mAb 治疗小鼠，才能实现没有疾病证据的长期缓解，而针对人或鼠 VEGFR-1 的 mAb 对小鼠的存活没有影响。因此，治疗产生 VEGF、表达 VEGFR 的白血病的有效抗血管生成疗法可能需要阻断旁分泌和自分泌 VEGF/VEGFR-2 血管生成环，以实现缓解和长期治愈。
Antiangiogenic agents block the effects of tumor-derived angiogenic factors (paracrine factors), such as vascular endothelial growth factor (VEGF), on endothelial cells (EC), inhibiting the growth of solid tumors. However, whether inhibition of angiogenesis also may play a role in liquid tumors is not well established. We recently have shown that certain leukemias not only produce VEGF but also selectively express functional VEGF receptors (VEGFRs), such as VEGFR-2 (Flk-1, KDR) and VEGFR1 (Flt1), resulting in the generation of an autocrine loop. Here, we examined the relative contribution of paracrine (EC-dependent) and autocrine (EC-independent) VEGF/VEGFR signaling pathways, by using a human leukemia model, where autocrine and paracrine VEGF/VEGFR loops could be selectively inhibited by neutralizing mAbs specific for murine EC (paracrine pathway) or human tumor (autocrine) VEGFRs. Blocking either the paracrine or the autocrine VEGF/VEGFR-2 pathway delayed leukemic growth and engraftment in vivo, but failed to cure inoculated mice. Long-term remission with no evidence of disease was achieved only if mice were treated with mAbs against both murine and human VEGFR-2, whereas mAbs against human or murine VEGFR-1 had no eff ect on mice survival. Therefore, effective antiangiogenic therapies to treat VEGF-producing, VEGFR-expressing leukemias may require blocking both paracrine and autocrine VEGF/VEGFR-2 angiogenic loops to achieve remission and long-term cure.