Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit, De Boelelaan 1108, Amsterdam, 1081 HZ, The Netherlands.
Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands.
Oncogene. 2018 Jul;37(30):4110-4121. doi: 10.1038/s41388-018-0255-7. Epub 2018 Apr 30.
Glioblastoma (GBM) is the most aggressive and an incurable type of brain cancer. Human cytomegalovirus (HCMV) DNA and encoded proteins, including the chemokine receptor US28, have been detected in GBM tumors. US28 displays constitutive activity and is able to bind several human chemokines, leading to the activation of various proliferative and inflammatory signaling pathways. Here we show that HCMV, through the expression of US28, significantly enhanced the growth of 3D spheroids of U251- and neurospheres of primary glioblastoma cells. Moreover, US28 expression accelerated the growth of glioblastoma cells in an orthotopic intracranial GBM-model in mice. We developed highly potent and selective US28-targeting nanobodies, which bind to the extracellular domain of US28 and detect US28 in GBM tissue. The nanobodies inhibited chemokine binding and reduced the constitutive US28-mediated signaling with nanomolar potencies and significantly impaired HCMV/US28-mediated tumor growth in vitro and in vivo. This study emphasizes the oncomodulatory role of HCMV-encoded US28 and provides a potential therapeutic approach for HCMV-positive tumors using the nanobody technology.
胶质母细胞瘤（GBM）是最具侵袭性和无法治愈的脑癌类型。人巨细胞病毒（HCMV）的 DNA 和编码蛋白，包括趋化因子受体 US28，已在 GBM 肿瘤中被检测到。US28 显示组成性活性，能够结合几种人类趋化因子，导致各种增殖和炎症信号通路的激活。在这里，我们表明 HCMV 通过表达 US28 显著增强了 U251 三维球体和原代脑胶质瘤细胞神经球的生长。此外，US28 表达加速了小鼠原位颅内 GBM 模型中脑胶质瘤细胞的生长。我们开发了高度有效和选择性的针对 US28 的纳米抗体，其与 US28 的细胞外结构域结合，并在 GBM 组织中检测到 US28。纳米抗体抑制趋化因子结合，并以纳摩尔效力降低组成性 US28 介导的信号，显著损害体外和体内 HCMV/US28 介导的肿瘤生长。这项研究强调了 HCMV 编码的 US28 的致癌调节作用，并为使用纳米抗体技术治疗 HCMV 阳性肿瘤提供了一种潜在的治疗方法。
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