Antiangiogenic antitumor activities of IGFBP-3 are mediated by IGF-independent suppression of Erk1/2 activation and Egr-1-mediated transcriptional events
Antiangiogenic antitumor activities of IGFBP-3 are mediated by IGF-independent suppression of Erk1/2 activation and Egr-1-mediated transcriptional events
复制标题
DOI：
10.1182/blood-2010-08-299784
复制
发表时间：
2011-09-01
期刊：
影响因子：
20.3
通讯作者：
Lee, Ho-Young
中科院分区：
文献类型：
--
作者：
Kim, Jai-Hyun;Choi, Dong Soon;Lee, Ho-Young
目前在临床试验中评估的大多数抗血管生成疗法靶向血管内皮生长因子途径;然而，肿瘤血管系统可以通过转移到其他血管生成机制来获得对血管内皮生长因子靶向疗法的抗性。胰岛素样生长因子结合蛋白-3（IGFBP-3）已被报道通过IGF依赖性和IGF非依赖性机制抑制肿瘤生长和血管生成;然而，对其IGF非依赖性机制的了解有限。我们观察到IGFBP-3在非小细胞肺癌和头颈部鳞状细胞癌中阻断肿瘤血管生成和生长。来自IGFBP-3处理的非小细胞肺癌细胞系的条件培养基显示诱导HUVEC增殖和主动脉出芽的能力显著降低。在癌细胞中，IGFBP-3直接与Erk 1/2相互作用，导致Erk 1/2和Elk-1失活，并抑制早期生长反应蛋白1及其靶基因碱性成纤维细胞生长因子和血小板衍生生长因子的转录。这些数据表明，IGF-非依赖性Erk 1/2失活和IGFBP-3诱导的Egr-1表达降低阻断了血管内皮细胞和癌细胞中血管生成因子的自分泌和旁分泌环。总之，这些发现提供了IGFBP-3的IGF非依赖性抗血管生成抗肿瘤活性的分子框架。IGFBP-3作为一种新的抗血管生成肿瘤药物的开发还需要进一步的研究。（血。2011; 118（9）：2622-2631）
Most antiangiogenic therapies currently being evaluated in clinical trials target the vascular endothelial growth factor pathway; however, the tumor vasculature can acquire resistance to vascular endothelial growth factor-targeted therapy by shifting to other angiogenesis mechanisms. Insulin-like growth factor binding protein-3 (IGFBP-3) has been reported to suppress tumor growth and angiogenesis by both IGF-dependent and IGF-independent mechanisms; however, understanding of its IGF-independent mechanisms is limited. We observed that IGFBP-3 blocked tumor angiogenesis and growth in non-small cell lung cancer and head and neck squamous cell carcinoma. Conditioned media from an IGFBP-3-treated non-small cell lung cancer cell line displayed a significantly decreased capacity to induce HUVEC proliferation and aortic sprouting. In cancer cells, IGFBP-3 directly interacted with Erk1/2, leading to inactivation of Erk1/2 and Elk-1, and suppressed transcription of early growth response protein 1 and its target genes, basic fibroblast growth factor and platelet-derived growth factor. These data suggest that IGF-independent Erk1/2 inactivation and decreased IGFBP-3-induced Egr-1 expression block the autocrine and paracrine loops of angiogenic factors in vascular endothelial and cancer cells. Together, these findings provide a molecular framework of IGFBP-3's IGF-independent antiangiogenic antitumor activities. Future studies are needed for development of IGFBP-3 as a new line of anti-angiogengic cancer drug. (Blood. 2011; 118(9):2622-2631)