Lentiviral transfer of an inducible transgene expressing a soluble form of Gas1 causes glioma cell arrest, apoptosis and inhibits tumor growth
Lentiviral transfer of an inducible transgene expressing a soluble form of Gas1 causes glioma cell arrest, apoptosis and inhibits tumor growth
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DOI：
10.1038/cgt.2010.54
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发表时间：
2011-02-01
影响因子：
6.4
通讯作者：
Segovia, J.
中科院分区：
文献类型：
--
作者：
Lopez-Ornelas, A.;Mejia-Castillo, T.;Segovia, J.
神经胶质瘤是中枢神经系统最常见的原发性肿瘤，其临床预后一直很差。由于神经胶质瘤的特点，基因治疗似乎是一个潜在的相关战略，他们的治疗。然而，由于病毒载体有限的扩散和分布，其不能将治疗基因转移到显著高数量的肿瘤细胞，这仍然是其应用于治疗神经胶质瘤的关键障碍。我们已经证明，过度表达生长停滞特异性1（Gas 1）诱导细胞停滞和凋亡，并消除胶质瘤细胞在体外和植入小鼠。为了提高Gas 1的治疗范围，我们产生了编码可溶形式Gas 1的慢病毒载体。在这里，我们表明，感染这种病毒的细胞产生突变蛋白，以自分泌和旁分泌方式起作用，导致感染细胞和邻近细胞死亡，从而重要地增强了Gas 1的作用。此外，该载体或表达该载体的细胞的施用抑制小鼠中接种的肿瘤的生长。我们提出了一种基因治疗策略，通过消除不仅表达Gas 1的感染细胞，而且邻近的未感染细胞来增加治疗分子的效果。Cancer Gene Therapy（2011）18，87-99; doi：10.1038/cgt.2010.54; 2010年10月1日在线发表
Gliomas are the most frequent primary tumors of the central nervous system, and their clinical prognosis remains very poor. Because of the characteristics of gliomas, gene therapy appears as a potentially relevant strategy for their treatment. However, the inability of viral vectors to transfer the therapeutic genes to a significantly high number of tumor cells, due to their limited diffusion and distribution, remains a critical obstacle for their application treating gliomas. We have demonstrated that the overexpression of growth arrest specific1 (Gas1) induces cell arrest and apoptosis and eliminates glioma cells in vitro and when implanted in mice. To improve the therapeutic range of Gas1, we generated lentiviral vectors coding for a soluble form of Gas1. Here, we show that cells infected with this virus produce the mutant protein, that acting both in autocrine and paracrine manners, causes death of infected and neighbor cells, thus importantly enhancing the effect of Gas1. Furthermore, the administration of this vector, or cells expressing it, inhibit the growth of tumors inoculated in mice. We present a gene therapy strategy that increases the effect of the therapeutic molecule by eliminating not just the infected cells that express Gas1, but neighbor non-infected cells. Cancer Gene Therapy (2011) 18, 87-99; doi: 10.1038/cgt.2010.54; published online 1 October 2010