骨髓来源内皮祖细胞(EPCs)有助于小鼠和人肿瘤组织内血管生成现象依赖性生长。内皮祖细胞通过旁分泌促血管生成因子以及促进管腔直接进入发芽状态的新生血管来调节血管生成开关。
微小RNA(miRNA)是参与多种细胞生物学过程的关键调节因子包括血管生成。然而, miRNA 是否对骨髓来源内皮祖细胞介导的血管生成有作用仍然不明。
近日,一项最新研究表明遗传消融微小RNA加工Dicer酶后,导致循环内皮祖细胞数量下降,引发血管生成抑制,肿瘤生长受损。
此外,微小RNA的全基因组深度测序揭示其中miR-10b和miR-196b是肿瘤EPC内在的miRNA,miR-10b和miR-196b先前已确定是HOX信号和成人干细胞分化的关键调节因子。
值得注意的是,科研人员发现miR-10b和miR-196b对血管内皮生长因子(VEGF)刺激有反应,并且两者在人乳腺肿瘤血管中的表达是升高的。
引人注目的是,作用于miR-10B和miR-196b后导致血管生成介导的小鼠肿瘤生长显著被抑制。针对这些miRNAs可能是一种新的抑制肿瘤血管生成的策略。(生物谷:Bioon.com)
doi:10.1158/0008-5472.CAN-12-0271
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MicroRNAs regulate tumor angiogenesis modulated by endothelial progenitor cells.
Prue N Plummer1, Ruth Freeman1, Ryan Taft2, Jelena Vider1, Michael Sax1, s et al.
Bone marrow (BM)-derived endothelial progenitor cells (EPCs), contribute to the angiogenesis dependent growth of tumors in mice and humans. EPCs regulate the angiogenic switch via paracrine secretion of proangiogenic growth factors, and by direct luminal incorporation into sprouting nascent vessels. MicroRNAs (miRNAs) have emerged as key regulators of several cellular processes including angiogenesis; however, whether miRNAs contribute to BM-mediated angiogenesis has remained unknown. Here, we show that genetic ablation of microRNA processing enzyme Dicer, specifically in the BM, decreased the number of circulating EPCs, resulting in angiogenesis suppression and impaired tumor growth. Furthermore, genome-wide deep sequencing of small RNAs revealed tumor EPC-intrinsic miRNAs including miR-10b and miR-196b; which have been previously identified as key regulators of HOX signaling and adult stem cell differentiation. Notably, we found that both miR-10b and miR-196b, are responsive to vascular endothelial growth factor (VEGF) stimulation, and show elevated expression in human high-grade breast tumor vasculature. Strikingly, targeting miR-10b and miR-196b led to significant defects in angiogenesis-mediated tumor growth in mice. Targeting these miRNAs may constitute a novel strategy for inhibiting tumor angiogenesis.