Tsinghua University, Beijing, China.
Cancer Biother Radiopharm. 2010 Dec;25(6):713-21. doi: 10.1089/cbr.2010.0821.
Glioblastoma (GBM) is a highly malignant tumor with poor prognosis. Two hallmarks of this disease are a high expression of vascular endothelial growth factor (VEGF) and a depletion of the phosphatase and tensin homolog (PTEN). In the present study, combined gene therapy using wild-type PTEN reconstruction and VEGF siRNA was examined for its effectiveness in inhibiting tumor growth and tumorigenicity of PTEN-null GBM cells. In U251 GBM cells, PTEN restoration reduced proliferation, arrested the cell cycle at G0/G1 stage, and promoted apoptosis via inhibition of PIK/AKT signaling pathway. Unexpectedly, anchorage-dependent and -independent colony formation ability and the capacity for wound-healing migration of U251 cells with stable expression of VEGF siRNA were significantly inhibited, suggesting that VEGF also appeared to function as an autocrine growth factor in addition to its well-known pro-angiogenic paracrine function. Further, a combined treatment of PTEN restoration and VEGF siRNA had the best tumor suppression effect. In a xenograft study in null mice, both the restoration of PTEN and the expression of VEGF siRNA could significantly inhibit the growth of U251 GBMs, whereas tumor growth was entirely suppressed by a combination of the two treatments. Therefore, the combination of PTEN expression and VEGF knockdown represents an effective gene therapy strategy for malignant gliomas.
胶质母细胞瘤（GBM）是一种预后不良的高度恶性肿瘤。这种疾病的两个特征是血管内皮生长因子（VEGF）的高表达和磷酸酶和张力蛋白同源物（PTEN）的耗竭。在本研究中，研究了野生型 PTEN 重建和 VEGF siRNA 的联合基因治疗对抑制 PTEN 缺失 GBM 细胞肿瘤生长和致瘤性的有效性。在 U251 GBM 细胞中，PTEN 恢复降低了增殖，通过抑制 PIK/AKT 信号通路将细胞周期阻滞在 G0/G1 期，并促进细胞凋亡。出乎意料的是，稳定表达 VEGF siRNA 的 U251 细胞的锚定依赖性和非依赖性集落形成能力以及伤口愈合迁移能力均受到显著抑制，表明 VEGF 除了其众所周知的促血管生成旁分泌功能外，似乎还作为自分泌生长因子发挥作用。此外，PTEN 恢复和 VEGF siRNA 的联合治疗具有最佳的肿瘤抑制作用。在 null 小鼠的异种移植研究中，PTEN 的恢复和 VEGF siRNA 的表达均能显著抑制 U251 GBM 的生长，而两种治疗联合则完全抑制了肿瘤的生长。因此，PTEN 表达和 VEGF 敲低的联合代表了恶性神经胶质瘤的一种有效的基因治疗策略。
