Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer
Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer
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DOI：
10.1186/s12943-020-01251-0
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发表时间：
2020-08-26
期刊：
影响因子：
37.3
通讯作者：
Kodera, Yasuhiro
中科院分区：
文献类型：
--
作者：
Kanda, Mitsuro;Shimizu, Dai;Kodera, Yasuhiro
背景控制转移是改善胃癌患者预后的关键。在这里，我们的目的是确定GC转移所需的分子，并研究其作为开发治疗性抗体（Abs）的靶点的潜在效用。方法通过转录组和生物信息学分析，确定神经元正五聚蛋白受体（neuronalpentraxinreceptor，NPTXR）为候选分子，通过调控NPTXR在人胃癌细胞中的表达，并在体外和小鼠异种移植瘤模型中评估其对细胞内信号传导和恶性行为的影响，探讨NPTXR的功能。我们还制备了抗NPTXR抗体和Nptxr（-/-）小鼠，并评估了GC标本中NPTXR表达的临床意义。结果NPTXR mRNA在胃癌组织中的表达与胃癌的进展有关，在有远处转移的胃癌组织中表达明显高于无远处转移的胃癌组织，NPTXR可调控与胃癌转移相关的基因的表达以及PI 3 K-AKT-mTOR、FAK-JNK和雅普信号通路的激活，NPTXR沉默可促进caspase介导的胃癌细胞凋亡，抑制胃癌细胞的增殖、细胞周期进程、迁移、增殖和凋亡。体外实验表明，该基因可明显抑制胃癌细胞的侵袭、粘附、干细胞样特性和对5-氟尿嘧啶的耐药性，体内实验表明，该基因可明显抑制胃癌细胞的致瘤性。Nptxr（-/-）小鼠在生殖、发育、代谢和运动功能方面均无异常。结论NPTXR在体内外调控胃癌细胞恶性行为中起重要作用，NPTXR靶向抗体有望成为胃癌诊断和/或治疗的新工具。
Background Controlling metastasis is essential for improving the prognosis of patients with gastric cancer (GC). Here, we aimed to identify a molecule required for GC metastasis and to investigate its potential utility as a target for the development of therapeutic antibodies (Abs). Methods Transcriptome and bioinformatics analyses of human GC cell lines identified the neuronal pentraxin receptor (NPTXR) as a candidate molecule.NPTXRfunction was probed by modulating its expression in GC cells and assessing the effects on intracellular signaling and malignant behaviors in vitro and in mouse xenograft models. We also generated anti-NPTXR Abs andNptxr(-/-)mice, and assessed the clinical significance ofNPTXRexpression in GC specimens. Results NPTXRmRNA expression in clinical specimens was associated with disease progression and was significantly higher in tissues from GC patients with distant metastasis compared with those without.NPTXRregulated expression of genes involved in metastatic behaviors as well as activation of the PI3K-AKT-mTOR, FAK-JNK, and YAP signaling pathways.NPTXRsilencing promoted caspase-mediated apoptosis and attenuated GC cell proliferation, cell cycle progression, migration, invasion, adhesion, stem cell-like properties, and resistance to 5-fluorouracil in vitro, and also inhibited the tumorigenicity of GC cells in vivo. Anti-NPTXRAbs inhibited GC peritoneal metastasis in mice.Nptxr(-/-)mice showed no abnormalities in reproduction, development, metabolism, or motor function. Conclusions NPTXRplays an essential role in controlling the malignant behavior of GC cells in vitro and in vivo.NPTXR-targeting Abs may thus have utility as novel diagnostic tools and/or treatment modalities for GC.