Ciarrocchi Alessia, Jankovic Vladimir, Shaked Yuval, Nolan Daniel J, Mittal Vivek, Kerbel Robert S, Nimer Stephen D, Benezra Robert
Program of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
PLoS One. 2007 Dec 19;2(12):e1338. doi: 10.1371/journal.pone.0001338.
Loss of Id1 in the bone marrow (BM) severely impairs tumor angiogenesis resulting in significant inhibition of tumor growth. This phenotype has been associated with the absence of circulating endothelial progenitor cells (EPCs) in the peripheral blood of Id1 mutant mice. However, the manner in which Id1 loss in the BM controls EPC generation or mobilization is largely unknown. Using genetically modified mouse models we demonstrate here that the generation of EPCs in the BM depends on the ability of Id1 to restrain the expression of its target gene p21. Through a series of cellular and functional studies we show that the increased myeloid commitment of BM stem cells and the absence of EPCs in Id1 knockout mice are associated with elevated p21 expression. Genetic ablation of p21 rescues the EPC population in the Id1 null animals, re-establishing functional BM-derived angiogenesis and restoring normal tumor growth. These results demonstrate that the restraint of p21 expression by Id1 is one key element of its activity in facilitating the generation of EPCs in the BM and highlight the critical role these cells play in tumor angiogenesis.
骨髓（BM）中Id1的缺失严重损害肿瘤血管生成，导致肿瘤生长受到显著抑制。这种表型与Id1突变小鼠外周血中循环内皮祖细胞（EPCs）的缺失有关。然而，BM中Id1缺失控制EPC生成或动员的方式在很大程度上尚不清楚。在此，我们使用基因改造小鼠模型证明，BM中EPC的生成取决于Id1抑制其靶基因p21表达的能力。通过一系列细胞和功能研究，我们表明BM干细胞髓系定向增加以及Id1基因敲除小鼠中EPC的缺失与p21表达升高有关。p21的基因消融挽救了Id1基因缺失动物中的EPC群体，重建了功能性BM来源的血管生成并恢复了正常肿瘤生长。这些结果表明，Id1对p21表达的抑制是其在促进BM中EPC生成活动中的一个关键要素，并突出了这些细胞在肿瘤血管生成中所起的关键作用。
