Gene transfer of pigment epithelium-derived factor suppresses tumor growth and angiogenesis in a hepatoblastoma xenograft model
Gene transfer of pigment epithelium-derived factor suppresses tumor growth and angiogenesis in a hepatoblastoma xenograft model
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DOI：
10.1203/01.pdr.0000232789.86632.91
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发表时间：
2006-09-01
影响因子：
3.6
通讯作者：
Crawford, Susan E.
中科院分区：
文献类型：
--
作者：
Browne, Marybeth;Stellmach, Veronica;Crawford, Susan E.
正常肝细胞表达色素上皮衍生因子（PEDF），一种内源性抗血管生成因子。我们假设PEDF表达减少可能是驱动肝母细胞瘤生长的一种机制，PEDF的体内基因转移可以抑制新血管形成并限制肿瘤生长。 PEDF 功能活性在体外使用内皮细胞迁移测定进行测定，在体内使用皮下肿瘤模型进行测定。每天用 PEDF (Hyb-PEDF, n = 4) 或 β-半乳糖苷酶 (Hyb-beta gal, n = 4) 的混合腺病毒/腺相关病毒表达载体治疗 HUH-6 人肝母细胞瘤肿瘤，持续 4 天。评估有丝分裂图、微血管密度 (MVD)、PEDF 和 VEGF 表达。与 Hyb-beta gal 治疗的肿瘤相比，Hyb-PEDF 治疗可抑制体内肿瘤生长 (p < 0.008)，并降低 MVD (p < 0.001)、有丝分裂像数 (p < 0.001) 和 VEGF 表达。在缺氧条件下培养以及体内生长时，PEDF 的 HUH-6 表达显着降低，并且中和性抗 PEDF 抗体的添加增加了体外 HUH-6 细胞分泌物本已较高的基线血管生成活性（p < 0.04）。 PEDF 是肝脏血管系统的重要内源性调节剂。增加肿瘤内 PEDF 水平可通过减少血管生成和 VEGF 表达来抑制肿瘤生长。有效的血管生成抑制剂，例如 PEDF，可能是治疗儿童肝母细胞瘤的有效替代疗法。
Normal hepatocytes express pigment epithelium-derived factor (PEDF), an endogenous antiangiogenic factor. We hypothesized that decreased PEDF expression may be one mechanism driving hepatoblastoma growth, and in vivo gene transfer of PEDF could suppress neovascularization and limit tumor growth. PEDF functional activity was determined in vitro using endothelial cell migration assays and in vivo using a subcutaneous tumor model. HUH-6 human hepatoblastoma tumors were treated with hybrid adenoviral/adeno-associated viral expression vectors for PEDF (Hyb-PEDF, n = 4) or beta-galactosidase (Hyb-beta gal, n = 4) daily for 4 d. Mitotic figures, microvascular density (MVD), PEDF, and VEGF expression were assessed. Hyb-PEDF treatment inhibited in vivo tumor growth (p < 0.008) and decreased MVD (p < 0.001), the number of mitotic figures (p < 0.001), and VEGF expression when compared with Hyb-beta gal-treated tumors. HUH-6 expression of PEDF was dramatically reduced when cultured under hypoxic conditions and also when grown in vivo, and the addition of neutralizing anti-PEDF antibody increased the already high baseline angiogenic activity of the HUH-6 cell secretions in vitro (p < 0.04). PEDF is an important endogenous regulator of the liver vasculature. Augmenting intra-tumoral PEDF levels inhibits tumor growth by reducing angiogenesis and VEGF expression. Potent inhibitors of angiogenesis, such as PEDF, may be an effective alternative treatment for children with hepatoblastoma.