Santarelli Justin G, Udani Vikram, Yung Yun C, Cheshier Sam, Wagers Amy, Brekken Rolf A, Weissman Irving, Tse Victor
Department of Neurosurgery, Stanford University, Stanford, California 94305-5327, USA.
Neurosurgery. 2006 Aug;59(2):374-82; discussion 374-82. doi: 10.1227/01.NEU.0000222658.66878.CC.
Neoangiogenesis is a prerequisite for the full phenotypic expression and growth of a malignant tumor mass. It is believed to be triggered by tissue hypoxia and involves proliferation and sprouting of the preexisting vessels and the recruitment of endothelial progenitor cells from bone marrow.
A chimeric mouse model was used to examine the contribution of these progenitor cells to the neovasculature of brain tumor. T-cell knockout (RAG/KO5.2) mice were irradiated lethally, and their bone marrow was repopulated with T-cell depleted green fluorescent protein (GFP)-expressing bone marrow cells. RAG/RT-2 glioma cells were implanted into the striatum of the animals. Neovascular formation at various times of tumor growth was monitored together with the extent of incorporation of GFP+ bone marrow-derived cells within the vascular tree, in particular, cells carrying the endothelial progenitor markers CD34 and Flk-1.
The recruitment of GFP+ cells to the growing tumor and their incorporation into the vascular network occurred during the period of increasing vascular density and preceded the expansion of the tumor. The number of marrow-derived cells with endothelial morphology and phenotype was small but significant (4% of all endothelial cells at Day 12); 54% of all tumor vessels contained at least one GFP+ cell.
Our results suggest that bone marrow cells are recruited to newly formed and remodeled tumor vessels. Their recruitment may occur in response to signals from a highly proliferating milieu, and their role is to support the neovascular complex and to promote tumor growth.
新生血管生成是恶性肿瘤块完整表型表达和生长的先决条件。据信它由组织缺氧触发，涉及既有血管的增殖和出芽以及骨髓中内皮祖细胞的募集。
使用嵌合小鼠模型来检查这些祖细胞对脑肿瘤新生血管形成的贡献。对T细胞敲除（RAG/KO5.2）小鼠进行致死性照射，并用表达绿色荧光蛋白（GFP）且T细胞耗尽的骨髓细胞重新填充其骨髓。将RAG/RT-2胶质瘤细胞植入动物的纹状体。在肿瘤生长的不同时间监测新生血管形成以及GFP+骨髓来源细胞在血管树中的掺入程度，特别是携带内皮祖细胞标志物CD34和Flk-1的细胞。
在血管密度增加期间，GFP+细胞被募集到生长中的肿瘤并掺入血管网络，且发生在肿瘤扩张之前。具有内皮形态和表型的骨髓来源细胞数量虽少但很显著（第12天时占所有内皮细胞的4%）；所有肿瘤血管中有54%至少含有一个GFP+细胞。
我们的结果表明骨髓细胞被募集到新形成和重塑的肿瘤血管。它们的募集可能是对来自高度增殖环境的信号作出的反应，其作用是支持新生血管复合体并促进肿瘤生长。
