F25P preproinsulin abrogates the secretion of pro-growth factors from EGFRvIII cells and suppresses tumor growth in an EGFRvIII/wt heterogenic model
F25P preproinsulin abrogates the secretion of pro-growth factors from EGFRvIII cells and suppresses tumor growth in an EGFRvIII/wt heterogenic model
复制标题
F25P 前胰岛素原消除 EGFRvIII 细胞促生长因子的分泌，并在 EGFRvIII/wt 异源模型中抑制肿瘤生长。
DOI：
10.1016/j.canlet.2016.06.006
复制
发表时间：
2016
期刊：
影响因子：
9.7
通讯作者：
Kang Chun-sheng
中科院分区：
文献类型：
--
作者：
Wei Jian-wei;Cui Jing-qiu;Zhou Xuan;Fang Chuan;Tan Yan-li;Chen Lu-yue;Yang Chao;Liu Ming;Kang Chun-sheng
广泛的异质性是细胞和分子水平上多形性胶质母细胞瘤（GBM）的一个明确标志。 EGFRvIII 是最常见的 EGFR 突变体，在 24-67% 的病例中表达，强烈表明生存预后较差。通过共表达EGFRvIII和EGFRwt，我们建立了EGFRvIII/wt异源模型。利用这种方法，我们证实，与EGFRwt细胞相比，EGFRvIII和EGFRwt以一定比例的混合物可以明显增强体外和体内肿瘤生长，从而表明EGFRvIII细胞促进肿瘤生长。此外，我们证明EGFRvIII细胞可以通过分泌生长因子支持EGFRwt细胞的生长，从而充当维持肿瘤存活的主要来源。 F25P前胰岛素原通过竞争性抑制内质网信号肽酶，有效降低荷瘤小鼠血液中EGF、VEGF和MMP-9的浓度，并提高原位模型的总生存率。综上所述，我们的结果为 EGFRvIII/wt 异基因模型中的 F25P 前胰岛素原提供了有效的治疗方法。
Extensive heterogeneity is a defining hallmark of glioblastoma multiforme (GBM) at the cellular and molecular levels. EGFRvIII, the most common EGFR mutant, is expressed in 24–67% of cases and strongly indicates a poor survival prognosis. By co-expressing EGFRvIII and EGFRwt, we established an EGFRvIII/wt heterogenic model. Using this approach, we confirmed that a mixture of EGFRvIII and EGFRwt at a certain ratio could clearly enhance tumor growth in vitro and in vivo compared with EGFRwt cells, thereby indicating that EGFRvIII cells promote tumor growth. Furthermore, we demonstrated that the EGFRvIII cells could support the growth of EGFRwt cells by secreting growth factors, thus acting as the principal source for maintaining tumor survival. F25P preproinsulin effectively reduced the concentrations of EGF, VEGF, and MMP-9 in the blood of tumor-bearing mice by competitively inhibiting the endoplasmic reticulum signal peptidase and increased the overall survival in orthotopic models. Taken together, our results provided an effective therapy of F25P preproinsulin in the EGFRvIII/wt heterogenic model.