Cross-talk between Tumor and Endothelial Cells Involving the Notch3-DII4 Interaction Marks Escape from Tumor Dormancy
Cross-talk between Tumor and Endothelial Cells Involving the Notch3-DII4 Interaction Marks Escape from Tumor Dormancy
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DOI：
10.1158/0008-5472.can-08-2791
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发表时间：
2009-02-15
期刊：
影响因子：
11.2
通讯作者：
Amadori, Alberto
中科院分区：
文献类型：
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作者：
Indraccolo, Stefano;Minuzzo, Sonia;Amadori, Alberto
Notch配体DII4在生理性和肿瘤血管生成过程中具有公认的作用，因为它有助于调节内皮细胞(EC)中的Notch活性。然而，DII4对表达Notch受体的肿瘤细胞中的Notch信号的影响仍然很不清楚。在这里，我们报道了人类T细胞急性淋巴细胞白血病(T-ALL)细胞或结直肠癌细胞摆脱休眠与肿瘤微环境中DII4的表达和肿瘤细胞中Notch3信号的增加有关。DII4在新生血管形成过程中的早期时间点即有表达，并在新生血管灌流前表达。血管生成因子诱导共培养的T-ALL细胞表达DII4，增强Notch3活性。DII4的中和大大减少了EC介导的T-ALL细胞中Notch 3信号的激活，并阻止了肿瘤的发生。此外，通过RNA干扰沉默Notch3在体外对T-ALL细胞具有显著的抗增殖和促凋亡作用，并降低了体内的致瘤性。我们的结果阐明了一种新的机制，通过这种机制，内皮细胞和肿瘤细胞之间的直接相互作用可以促进生存和触发肿瘤生长。[癌症资源2009；69(4)：1314-23]
The Notch ligand DII4 has a recognized role during both physiologic and tumor angiogenesis, as it contributes to regulate Notch activity in endothelial cells (EC). The effects of DII4 on Notch signaling in tumor cells expressing Notch receptors remain, however, largely unknown. Here, we report that escape of human T-cell acute lymphoblastic leukemia (T-ALL) cells or colorectal cancer cells from dormancy is associated with DII4 expression in the tumor microenvironment and increased Notch3 signaling in tumor cells. DII4 was expressed at early time points during the angiogenic process, and its expression preceded perfusion of the newly established vessels. Treatment of EC with angiogenic factors induced DII4 expression and increased Notch3 activation in cocultured T-ALL cells. Neutralization of DII4 greatly reduced EC-mediated activation of Notch 3 signaling in T-ALL cells and blocked tumorigenesis. Moreover, silencing Notch3 by RNA interference had marked antiproliferative and proapoptotic effects on T-ALL cells in vitro and reduced tumorigenicity in vivo. Our results elucidate a novel mechanism by which a direct interplay between endothelial and tumor cells promotes survival and triggers tumor growth. [Cancer Res 2009;69(4):1314-23]