Liu B, Lee K-W, Anzo M, Zhang B, Zi X, Tao Y, Shiry L, Pollak M, Lin S, Cohen P
Division of Pediatric Endocrinology, Department of Pediatrics, Mattel Children's Hospital, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
Oncogene. 2007 Mar 15;26(12):1811-9. doi: 10.1038/sj.onc.1209977. Epub 2006 Sep 18.
Insulin-like growth factor-binding protein-3 (IGFBP-3) is a multifunctional protein that induces apoptosis utilizing both insulin-like growth factor receptor (IGF)-dependent and -independent mechanisms. We investigated the effects of IGFBP-3 on tumor growth and angiogenesis utilizing a human CaP xenograft model in severe-combined immunodeficiency mice. A 16-day course of IGFBP-3 injections reduced tumor size and increased apoptosis and also led to a reduction in the number of vessels stained with CD31. In vitro, IGFBP-3 inhibited both vascular endothelial growth factor- and IGF-stimulated human umbilical vein endothelial cells vascular network formation in a matrigel assay. This action is primarily IGF independent as shown by studies utilizing the non-IGFBP-binding IGF-1 analog Long-R3. Additionally, we used a fibroblast growth factor-enriched matrigel-plug assay and chick allantoic membrane assays to show that IGFBP-3 has potent antiangiogenic actions in vivo. Finally, overexpression of IGFBP-3 or the non-IGF-binding GGG-IGFBP-3 mutant in Zebrafish embryos confirmed that both IGFBP-3 and the non-IGF-binding mutant inhibited vessel formation in vivo, indicating that the antiangiogenic effect of IGFBP-3 is an IGF-independent phenomenon. Together, these studies provide the first evidence that IGFBP-3 has direct, IGF-independent inhibitory effects on angiogenesis providing an additional mechanism by which it exerts its tumor suppressive effects and further supporting its development for clinical use in the therapy of patients with prostate cancer.
胰岛素样生长因子结合蛋白-3（IGFBP-3）是一种多功能蛋白，可利用胰岛素样生长因子受体（IGF）依赖性和非依赖性机制诱导细胞凋亡。我们利用严重联合免疫缺陷小鼠的人CaP异种移植模型研究了IGFBP-3对肿瘤生长和血管生成的影响。为期16天的IGFBP-3注射疗程可减小肿瘤大小、增加细胞凋亡，还可减少CD31染色的血管数量。在体外，在基质胶试验中，IGFBP-3可抑制血管内皮生长因子和IGF刺激的人脐静脉内皮细胞血管网络形成。如使用非IGFBP结合的IGF-1类似物Long-R3的研究所表明的，这一作用主要不依赖于IGF。此外，我们使用富含成纤维细胞生长因子的基质胶栓试验和鸡胚尿囊膜试验表明，IGFBP-3在体内具有强大的抗血管生成作用。最后，在斑马鱼胚胎中过表达IGFBP-3或非IGF结合的GGG-IGFBP-3突变体证实，IGFBP-3和非IGF结合突变体均在体内抑制血管形成，表明IGFBP-3的抗血管生成作用是一种不依赖于IGF的现象。总之，这些研究提供了首个证据，即IGFBP-3对血管生成具有直接的、不依赖于IGF的抑制作用，为其发挥肿瘤抑制作用提供了另一种机制，并进一步支持其在前列腺癌患者治疗中的临床应用开发。
