Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization
Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization
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DOI：
10.1101/gad.436307
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发表时间：
2007-06-15
影响因子：
10.5
通讯作者：
Mittal, Vivek
中科院分区：
文献类型：
--
作者：
Nolan, Daniel J.;Ciarrocchi, Alessia;Mittal, Vivek
肿瘤通过预先存在的脉管系统的共选择和骨髓（BM）衍生的内皮祖细胞（EPC）的从头募集来构建血管。然而，EPCs在肿瘤血管生成中的作用和功能仍存在争议。因此，通过使用基因标记的骨髓祖细胞，我们证明了精确的空间和时间的贡献，EPCs的新血管的三个移植和一个自发性乳腺肿瘤在体内使用高分辨率显微镜和流式细胞术。我们发现，早期肿瘤招募骨髓来源的EPCs分化成成熟的骨髓来源的内皮细胞（EC）和管腔纳入一个子集的萌芽肿瘤新血管。值得注意的是，在晚期肿瘤中，这些BM衍生的血管被来自外周的非BM衍生的血管稀释，这解释了先前发表的报告中声称的差异。此外，我们表明，特定的消融BM衍生的EPCs与α粒子发射抗VE钙粘蛋白抗体显着损害肿瘤生长与血管化减少。我们的研究结果表明，骨髓来源的内皮祖细胞是肿瘤新生血管形成的最早阶段的关键组成部分。
Tumors build vessels by cooption of pre-existing vasculature and de novo recruitment of bone marrow (BM)-derived endothelial progenitor cells (EPCs). However, the contribution and the functional role of EPCs in tumor neoangiogenesis are controversial. Therefore, by using genetically marked BM progenitor cells, we demonstrate the precise spatial and temporal contribution of EPCs to the neovascularization of three transplanted and one spontaneous breast tumor in vivo using high-resolution microscopy and flow cytometry. We show that early tumors recruit BM-derived EPCs that differentiate into mature BM-derived endothelial cells (ECs) and luminally incorporate into a subset of sprouting tumor neovessels. Notably, in later tumors, these BM-derived vessels are diluted with non-BM-derived vessels from the periphery, which accounts for purported differences in previously published reports. Furthermore, we show that specific ablation of BM-derived EPCs with alpha-particle-emitting anti-VE-cadherin antibody markedly impaired tumor growth associated with reduced vascularization. Our results demonstrate that BM-derived EPCs are critical components of the earliest phases of tumor neoangiogenesis.