Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark.
Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark; Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, BGI-Shenzhen, 518083 Shenzhen, China.
J Control Release. 2020 Jun 10;322:53-63. doi: 10.1016/j.jconrel.2020.03.004. Epub 2020 Mar 4.
Albumin accumulation in tumours could reflect a role of albumin in transport of endogenous nutrient cargos required for cellular growth and not just a suggested source of amino acids; a role driven by albumin engagement with its cognate cellular recycling neonatal Fc receptor. We investigate the hypothesis that albumin cellular recruitment is increased by higher human FcRn (hFcRn) expression in human cancer tissue that provides the mechanistic basis for exploitation in albumin-based drug designs engineered to optimise this process. Eight out of ten different human cancer tissue types screened for hFcRn expression by immunohistochemistry (310 samples) exhibited significantly higher hFcRn expression compared to healthy tissues. Accelerated tumour growth over 28 days in mice inoculated with hFcRn-expressing HT-29 human colorectal cancer cell xenografts, compared to CRISPR/Cas9 hFcRn-knockout HT-29, suggests a hFcRn-mediated tumour growth effect. Direct correlation between hFcRn expression and albumin recycling supports hFcRn-mediated diversion of albumin from lysosomal degradation. Two-fold increase in accumulation of fluorescent labelled high-binding hFcRn albumin, compared to wild type albumin, in luciferase MDA-MB-231-Luc-D3H2LN breast cancer xenografts was shown. This work identifies overexpression of hFcRn in several human cancer types with mechanistic data suggesting hFcRn-driven albumin recruitment for increased cellular growth that has the potential to be exploited with high hFcRn-binding albumin variants for targeted therapies.
肿瘤中白蛋白的积累可能反映了白蛋白在运输细胞生长所需的内源性营养货物中的作用，而不仅仅是氨基酸的来源；这种作用是由白蛋白与其同源细胞再循环新生 Fc 受体的结合驱动的。我们研究了这样一个假设，即更高的人 FcRn（hFcRn）在人癌组织中的表达会增加白蛋白的细胞募集，这为人白蛋白为基础的药物设计提供了机制基础，旨在优化这一过程。通过免疫组织化学（310 个样本）对十种不同的人类癌组织类型进行 hFcRn 表达筛选，发现其表达明显高于健康组织。与 CRISPR/Cas9 hFcRn 敲除 HT-29 相比，在 hFcRn 表达 HT-29 人结直肠癌细胞异种移植的小鼠中，28 天内肿瘤生长加速，表明 hFcRn 介导的肿瘤生长效应。hFcRn 表达与白蛋白再循环之间的直接相关性支持 hFcRn 介导的白蛋白从溶酶体降解中的转移。与野生型白蛋白相比，在荧光标记的高结合 hFcRn 白蛋白在 luciferase MDA-MB-231-Luc-D3H2LN 乳腺癌异种移植中的积累增加了两倍。这项工作鉴定了几种人类癌症类型中 hFcRn 的过表达，并提供了机制数据，表明 hFcRn 驱动的白蛋白募集增加了细胞生长，这有可能通过高 hFcRn 结合白蛋白变体来进行靶向治疗。
