Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy
Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy
复制标题
DOI：
10.1038/gt.2009.142
复制
发表时间：
2010-02-01
期刊：
影响因子：
5.1
通讯作者：
Yun, C-O
中科院分区：
文献类型：
--
作者：
Choi, I-K;Lee, Y-S;Yun, C-O
当代基因治疗面临的紧迫挑战是将足够的治疗基因传递给体内足够的癌细胞。为了改善病毒的分布和肿瘤的渗透，我们探索了使用decorin来促进病毒的传播和肿瘤组织的渗透。我们生成了表达装饰素的复制不能力腺病毒（dl-LacZ-DCNG、dl-LacZ-DCNQ和dl-LacZ-DCNK）和复制能力腺病毒（Ad-Delta E1B-DCNG、Ad-Delta E1B-DCNQ和Ad-Delta E1B-DCNK）。decorin基因（DCNG）的点突变体DCNK和DCNQ分别对i型胶原纤维具有负和中等的结合亲和力。在肿瘤球体和体内已建立的实体瘤中，dl-LacZ- dcng的组织渗透能力都比dl-LacZ、dl-LacZ- dcnq和dl-LacZ- dcnk显著增强，这种增强的组织渗透作用来源于表达decorin的Ad，依赖于decorin与胶原纤维的结合亲和力。DCNG的表达增强了复制Ad的病毒传播，从而提高了肿瘤的减少和生存效益。此外，Ad-Delta E1B-DCNQ和Ad-Delta E1B-DCNK的杀瘤作用减弱，与胶原的结合亲和力降低，表明癌细胞毒性的增加是由decorin作用于细胞外基质（extracellular matrix， ECM）驱动的。此外，Ad-Delta E1B-DCNG显著降低了肿瘤组织内的ECM成分。最后，在原发肿瘤部位瘤内注射Ad-Delta E1B-DCNG可大大减少小鼠B16BL6黑色素瘤细胞肺转移的形成。综上所述，这些数据显示了decorin作为分散剂的效用，并突出了其在提高复制ad介导的癌症基因治疗效果方面的效用和潜力。基因治疗（2010）17,190-201；doi: 10.1038 / gt.2009.142;2009年11月12日在线发布
The pressing challenge for contemporary gene therapy is to deliver enough therapeutic genes to enough cancer cells in vivo. With the aim of improving viral distribution and tumor penetration, we explored the use of decorin to enhance viral spreading and tumor tissue penetration. We generated decorin-expressing replication-incompetent (dl-LacZ-DCNG, dl-LacZ-DCNQ and dl-LacZ-DCNK) and replication-competent (Ad-Delta E1B-DCNG, Ad-Delta E1B-DCNQ and Ad-Delta E1B-DCNK) adenoviruses (Ads). Point mutants of decorin gene (DCNG), DCNK and DCNQ, have a negative and moderate binding affinity to type-I collagen fibril, respectively. In both tumor spheroids and established solid tumors in vivo, tissue penetration potency of dl-LacZ-DCNG was greatly enhanced than those of dl-LacZ, dl-LacZ-DCNQ and dl-LacZ-DCNK, and this enhanced tissue penetration effect derived from decorin-expressing Ad was dependent on the binding affinity of decorin to collagen fibril. Expression of DCNG enhanced viral spread of replicating Ad, leading to improved tumor reduction and survival benefit. Moreover, the tumoricidal effects of Ad-Delta E1B-DCNQ and Ad-Delta E1B-DCNK were lessened, as the binding affinity to collagen was decreased, showing that the increased cancer cell cytotoxicity was driven by the action of decorin on extracellular matrix (ECM). Furthermore, Ad-Delta E1B-DCNG substantially decreased ECM components within the tumor tissue. Finally, intratumoral injection of Ad-Delta E1B-DCNG in primary tumor site greatly reduced the formation of B16BL6 melanoma cell pulmonary metastases in mice. Taken together, these data show the utility of decorin as a dispersion agent and highlight its utility and potential in improving the efficacy of replicating Ad-mediated cancer gene therapy. Gene Therapy (2010) 17, 190-201; doi: 10.1038/gt.2009.142; published online 12 November 2009