The oncopathic potency of Clostridium perfringens is independent of its alpha-toxin gene.
The oncopathic potency of Clostridium perfringens is independent of its alpha-toxin gene.
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产气荚膜梭菌的致癌效力与其α毒素基因无关。
DOI：
10.1089/hum.2008.145
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发表时间：
2009
影响因子：
4.2
通讯作者：
Woo,SavioLC
中科院分区：
文献类型：
--
作者：
Li,Zhiyu;Fallon,John;Mandeli,John;Wetmur,James;Woo,SavioLC
实体瘤中的缺氧是常规治疗中的主要障碍，因为治疗剂向病变的递送效率低，但提供了可能导致肿瘤破坏的厌氧菌定植的可能性。我们之前已经报道了一种重组产气荚膜梭菌（Cp）菌株，该菌株通过缺失超氧化物歧化酶（sod）基因并插入Panton-Valentine杀白细胞素（PVL）基因构建，Cp/sod−/PVL，在免疫活性和同源小鼠的原位胰腺癌模型中显示出较高的氧敏感性，肿瘤选择性和致瘤效力，并导致动物生存期大幅延长。Cp/sod−/PVL在临床应用中的一个主要限制是它表达磷脂酶C（plc），这是Cp中的α毒素和主要毒力决定簇，是气性坏疽发展的原因。在这项研究中，Cp/sod−/PVL中的plc基因被敲除，以产生Cp/plc−/sod−/PVL，这被证明不能诱导小鼠气性坏疽。静脉注射Cp/plc−/sod−/PVL孢子在荷瘤小鼠中具有显著的生存优势，其疗效与Cp/sod−/PVL相同，表明Cp的致瘤效力不依赖于功能性plc基因。该处理也没有导致对随后的病原体攻击的减弱的免疫应答，表明宿主中不存在全身性免疫抑制作用。因此，Cp/plc−/sod−/PVL是一种新的肿瘤致病性细菌制剂，可有效治疗胰腺癌和其他血管化不良的肿瘤，具有显著增强的安全性，这对未来的转化研究至关重要。
Hypoxia in solid tumors is a major obstacle in conventional treatment because of inefficient delivery of therapeutic agents to the lesions, but offers the potential for anaerobic bacterial colonization that can lead to tumor destruction. We have previously reported a recombinant Clostridium perfringens (Cp) strain constructed by deletion of the superoxide dismutase (sod) gene and insertion of the Panton–Valentine leukocidin (PVL) gene, Cp/sod−/PVL, which showed elevated oxygen sensitivity, tumor selectivity, and oncopathic potency in an orthotopic model of pancreatic cancer in immune-competent and syngeneic mice, and that led to substantial prolongation of animal survival. A major limitation to Cp/sod−/PVL in clinical applications is that it expresses phospholipase C (plc), the α-toxin and the major virulence determinant in Cp that is causative in the development of gas gangrene. In this study, the plc gene in Cp/sod−/PVL was knocked out to create Cp/plc−/sod−/PVL, which was shown to be incapable of inducing gas gangrene in mice. Intravenous injection of Cp/plc−/sod−/PVL spores led to a significant survival advantage in tumor-bearing mice with the same efficacy as Cp/sod−/PVL, indicating that the oncopathic potency of Cp is independent of a functional plc gene. The treatment also did not lead to an attenuated immune response to a subsequent pathogen challenge, indicating that a systemic immune-suppressive effect in the host is absent. Consequently, Cp/plc−/sod−/PVL is a novel oncopathic bacterial agent for the effective treatment of pancreatic cancer and other poorly vascularized tumors, with a substantially enhanced safety profile, which is essential for the development of translational studies in the future.