Anti-metastatic effects of viral and non-viral mediated Nk4 delivery to tumours.
Anti-metastatic effects of viral and non-viral mediated Nk4 delivery to tumours.
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DOI：
10.1186/1479-0556-7-5
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发表时间：
2009-03-09
期刊：
影响因子：
--
通讯作者：
Tangney M
中科院分区：
文献类型：
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作者：
Buhles A;Collins SA;van Pijkeren JP;Rajendran S;Miles M;O'Sullivan GC;O'Hanlon DM;Tangney M
癌症患者最常见的死亡原因是转移的发生。肿瘤细胞的转移行为受到细胞外生长因子的调节，例如肝细胞生长因子（HGF），c-Met受体酪氨酸激酶的配体，并且c-Met受体的异常表达/激活与转移进展密切相关。 Nk4（也称为白介素 (IL)32b）是 HGF c-Met 系统的竞争性拮抗剂，可抑制 c-Met 信号传导和肿瘤转移。 Nk4 具有额外的抗血管生成活性，与其 HGF 拮抗剂功能无关。血管生成抑制以及癌症特异性细胞凋亡诱导作用使 Nk4 序列成为癌症基因治疗的有吸引力的候选者。本研究探讨基因治疗介导原发肿瘤产生 Nk4 对肿瘤转移的抑制作用。为了实现最高的治疗反应，抗癌基因的最佳传递至关重要。非病毒质粒递送方法具有安全性和易于生产的优点，可提供即时的转基因表达，尽管在大多数肿瘤中持续时间较短。抗血管生成分子的持续存在对于抗血管生成治疗来说是优选的，并且由腺相关病毒（AAV）介导的长期表达可能代表在这方面更合适的递送。然而，AAV 载体达到适当基因表达水平所需的孵育时间阻碍了许多快速生长的小鼠肿瘤模型的功效。在这里，我们描述了评估 Nk4 通过质粒脂转染或 AAV2 载体递送至原发肿瘤时对自发转移性 Lewis 肺癌 (LLC) 模型的影响的小鼠试验。肿瘤内 AAV-Nk4 给药产生了最高的治疗反应，显着降低了原发肿瘤的生长和肺转移的发生率。质粒介导的治疗也显着减少了转移性生长，但适度减少了原发性皮下肿瘤的生长。总体而言，这项研究证明了通过 AAV 或非病毒方法进行 Nk4 基因治疗转移性肿瘤的潜力。
The most common cause of death of cancer sufferers is through the occurrence of metastases. The metastatic behaviour of tumour cells is regulated by extracellular growth factors such as hepatocyte growth factor (HGF), a ligand for the c-Met receptor tyrosine kinase, and aberrant expression/activation of the c-Met receptor is closely associated with metastatic progression. Nk4 (also known as Interleukin (IL)32b) is a competitive antagonist of the HGF c-Met system and inhibits c-Met signalling and tumour metastasis. Nk4 has an additional anti-angiogenic activity independent of its HGF-antagonist function. Angiogenesis-inhibitory as well as cancer-specific apoptosis inducing effects make the Nk4 sequence an attractive candidate for gene therapy of cancer. This study investigates the inhibition of tumour metasasis by gene therapy mediated production of Nk4 by the primary tumour. Optimal delivery of anti-cancer genes is vital in order to achieve the highest therapeutic responses. Non-viral plasmid delivery methods have the advantage of safety and ease of production, providing immediate transgene expression, albeit short-lived in most tumours. Sustained presence of anti-angiogenic molecules is preferable with anti-angiogenic therapies, and the long-term expression mediated by Adeno-associated Virus (AAV) might represent a more appropriate delivery in this respect. However, the incubation time required by AAV vectors to reach appropriate gene expression levels hampers efficacy in many fast-growing murine tumour models. Here, we describe murine trials assessing the effects of Nk4 on the spontaneously metastatic Lewis Lung Carcinoma (LLC) model when delivered to primary tumour via plasmid lipofection or AAV2 vector. Intratumoural AAV-Nk4 administration produced the highest therapeutic response with significant reduction in both primary tumour growth and incidence of lung metastases. Plasmid-mediated therapy also significantly reduced metastatic growth, but with moderate reduction in primary subcutaneous tumour growth. Overall, this study demonstrates the potential for Nk4 gene therapy of metastatic tumours, when delivered by AAV or non-viral methods.