Browne Marybeth, Stellmach Veronica, Cornwell Mona, Chung Chuhan, Doll Jennifer A, Lee Eun-Jig, Jameson J Larry, Reynolds Marleta, Superina Riccardo A, Abramson Lisa P, Crawford Susan E
Department of Surgery, Children's Memorial Hospital, Chicago, Illinois 60614, USA.
Pediatr Res. 2006 Sep;60(3):282-7. doi: 10.1203/01.pdr.0000232789.86632.91. Epub 2006 Jul 20.
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-betagal, 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-betagal-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.
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。我们推测PEDF表达降低可能是驱动肝母细胞瘤生长的一种机制，并且PEDF的体内基因转移可抑制新生血管形成并限制肿瘤生长。使用内皮细胞迁移试验在体外测定PEDF功能活性，并使用皮下肿瘤模型在体内测定。用PEDF（Hyb-PEDF，n = 4）或β-半乳糖苷酶（Hyb-betagal，n = 4）的混合腺病毒/腺相关病毒表达载体每天处理HUH-6人肝母细胞瘤肿瘤，持续4天。评估有丝分裂象、微血管密度（MVD）、PEDF和VEGF表达。与Hyb-betagal处理的肿瘤相比，Hyb-PEDF处理抑制体内肿瘤生长（p < 0.008）并降低MVD（p < 0.001）、有丝分裂象数量（p < 0.001）和VEGF表达。当在低氧条件下培养以及在体内生长时，HUH-6细胞中PEDF的表达显著降低，并且添加中和抗PEDF抗体可增加HUH-6细胞分泌物在体外本就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因子。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。强效血管生成抑制剂，如PEDF，可能是肝母细胞瘤患儿的一种有效替代治疗方法。
