Harry Perkins Institute of Medical Research, Centre for Medical Research, QEII Medical Centre, The University of Western Australia, Perth, WA, Australia.
Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
EMBO Mol Med. 2019 Dec;11(12):e10923. doi: 10.15252/emmm.201910923. Epub 2019 Nov 11.
High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin-nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα.
实体瘤中细胞外基质（ECM）含量高会损害肿瘤灌注，从而影响成像和治疗药物的摄取。我们设计了一种新的方法来降解肿瘤 ECM，以提高循环化合物的摄取。我们使用一种新发现的肽配体 CSG 将免疫调节细胞因子肿瘤坏死因子 α（TNFα）靶向肿瘤。该肽与小鼠和人癌中的层粘连蛋白-巢蛋白复合物结合，在正常组织中几乎检测不到肽，并且它选择性地将重组 TNFα-CSG 融合蛋白递送到荷瘤小鼠的肿瘤 ECM 中。静脉注射 TNFα-CSG 可引发小鼠肿瘤中强烈的免疫细胞浸润，特别是在 ECM 丰富的区域。免疫细胞的涌入伴随着广泛的 ECM 降解、肿瘤硬度降低、肿瘤血管扩张、灌注改善以及对比剂钆喷酸葡胺和氧化铁纳米颗粒在肿瘤内的摄取增加。观察到抑制肿瘤生长和延长荷瘤小鼠的存活时间。这些效果可以在没有 TNFα 通常严重的毒副作用的情况下实现。
