文章：

血管和造血干细胞：抗血管生成治疗的新靶点？

Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy?

原文发布日期：2002-11-01

DOI: 10.1038/nrc925

类型: Review Article

开放获取: 否

要点：

1. The growth and metastasis of the majority of tumours depends on the formation of new blood vessels. Angiogenic factors that are released by tumour cells promote activation, proliferation and migration of endothelial cells to the tumour tissue, allowing for rapid formation of functional neo-vessels.
2. Endothelial cells contribute to tumour angiogenesis, and can originate from sprouting or co-option of neighbouring pre-existing vessels. Emerging evidence indicates that bone-marrow-derived circulating endothelial progenitor cells (CEPs) can contribute to the angiogenesis and growth of certain tumours.
3. The introduction of wild-type bone marrow CEPs, which express the VEGF receptor (VEGFR)-2, restores tumour angiogenesis and growth in tumour-resistant mice, indicating that bone-marrow-derived cells are essential for the angiogenesis and growth of certain tumours. Co-mobilization of VEGFR1⁺ haematopoietic stem and progenitor cells facilitate the incorporation of CEPs into functional tumour neo-vessels.
4. Mobilization of CEPs and pro-angiogenic haematopoietic cells from bone marrow is a dynamic process that requires angiogenic-factor-mediated activation of metalloproteinases (MMPs), specifically MMP-9, which lead to the release of soluble KIT ligand (sKitL). sKitL promotes the proliferation and motility of CEPs and haematopoietic cells within the bone-marrow microenvironment, thereby laying the framework for their mobilization to the peripheral circulation.
5. Inhibition of either VEGFR1 or VEGFR2 signalling can only partially block tumour angiogenesis and growth. Conversely, simultaneous inhibition of VEGFR1 and VEGFR2 signalling results in impaired mobilization and recruitment of VEGFR1⁺ haematopoietic cells and VEGFR2⁺ CEPs to the tumour vasculature, and is highly effective in retarding the growth of certain tumours.
6. Characterization and quantification of VEGFR2⁺CEPs and VEGFR1⁺ haematopoietic cells in the peripheral blood, and plasma levels of VEGF, sKitL, MMP-9 and placental growth factor might lead to their use as surrogate markers for assessing the response to therapy or progression of certain malignancies. Moreover, factors that are involved in the mobilization and incorporation of CEPs and pro-angiogenic haematopoietic cells provide new targets to block tumour angiogenesis and growth.

要点翻译：

1. 大多数肿瘤的生长和转移依赖于新血管的形成。肿瘤细胞释放的血管生成因子促进内皮细胞的活化、增殖和迁移至肿瘤组织，从而快速形成功能性新生血管。
2. 内皮细胞通过出芽或套叠方式来源于邻近已存在的血管，参与肿瘤血管生成。新近证据表明，骨髓来源的循环内皮祖细胞（CEPs）对某些肿瘤的血管生成和生长具有促进作用。
3. 将表达血管内皮生长因子受体（VEGFR）-2的野生型骨髓CEPs植入抗肿瘤小鼠体内，可恢复其肿瘤血管生成和生长能力，这表明骨髓来源细胞对某些肿瘤的血管生成和生长至关重要。VEGFR1+造血干细胞和祖细胞的协同动员促进了CEPs整合到功能性肿瘤新生血管中。
4. CEPs和促血管生成造血细胞从骨髓中的动员是一个动态过程，需要血管生成因子介导的金属蛋白酶（特别是MMP-9）的激活，从而释放可溶性KIT配体（sKitL）。sKitL促进骨髓微环境中CEPs和造血细胞的增殖与运动，为其向外周循环动员奠定基础。
5. 单独抑制VEGFR1或VEGFR2信号传导只能部分阻断肿瘤血管生成和生长。相反，同时抑制VEGFR1和VEGFR2信号传导会损害VEGFR1+造血细胞和VEGFR2+ CEPs向肿瘤血管系统的动员和募集，从而有效延缓某些肿瘤的生长。
6. 通过检测外周血中VEGFR2+CEPs和VEGFR1+造血细胞的数量特征，以及血浆中VEGF、sKitL、MMP-9和胎盘生长因子水平，可能将这些指标作为评估特定恶性肿瘤治疗反应或疾病进展的替代标志物。此外，参与CEPs和促血管生成造血细胞动员与整合的因子为阻断肿瘤血管生成和生长提供了新的靶点。

英文摘要：

Tumours recruit neighbouring blood vessels and vascular endothelial cells to support their own blood supply. Recent evidence has indicated, however, that tumours are also capable of mobilizing bone-marrow-derived endothelial precursor cells, inducing them to migrate to the tumour and become incorporated into the developing vasculature. Tumour-derived angiogenic factors promote the recruitment of these cells, which include circulating endothelial progenitor cells and haematopoietic stem and progenitor cells. As clinical trials with anti-angiogenic agents have been confronted with therapeutic hurdles, inhibiting the recruitment of these vascular precursors might provide a novel approach to blocking tumour angiogenesis.

摘要翻译： 

肿瘤会招募邻近的血管和血管内皮细胞以支持自身的血液供应。然而，最新证据表明，肿瘤还能够动员骨髓来源的内皮前体细胞，诱导其迁移至肿瘤并整合进正在发育的血管系统中。肿瘤来源的促血管生成因子促进这些细胞的募集，其中包括循环内皮祖细胞以及造血干/祖细胞。由于抗血管生成药物的临床试验面临治疗障碍，抑制这些血管前体细胞的募集可能为阻断肿瘤血管生成提供一种新策略。

原文链接：

Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy?