Sentinel Lymph Node-Targeted Therapy by Oncolytic Sendai Virus Suppresses Micrometastasis of Head and Neck Squamous Cell Carcinoma in an orthotopic Nude Mouse Model
Sentinel Lymph Node-Targeted Therapy by Oncolytic Sendai Virus Suppresses Micrometastasis of Head and Neck Squamous Cell Carcinoma in an orthotopic Nude Mouse Model
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DOI：
10.1158/1535-7163.mct-18-1372
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发表时间：
2019-08-01
影响因子：
5.7
通讯作者：
Yamashita, Taku
中科院分区：
文献类型：
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作者：
Tanaka, Yuya;Araki, Koji;Yamashita, Taku
在临床 N0 (cN0) 头颈鳞状细胞癌 (HNSCC) 病例中，治疗选择仍然存在争议：选择性颈清扫术还是观察等待。我们专注于使用尿激酶型纤溶酶原激活剂（uPA）依赖性溶瘤仙台病毒“BioKnife”进行前哨淋巴结（SLN）靶向治疗。本研究的目的是研究 BioKnife 向 SLN 的迁移并阐明其对淋巴结转移 (LNM) 的抗肿瘤作用。我们建立了原位裸鼠 HNSCC 模型，经常诱导 LNM。我们将人高度转移的舌鳞状细胞癌细胞HSC-3-M3接种到裸鼠的舌中，两周后，我们将BioKnife注射到原发肿瘤中。我们通过免疫染色、RT-PCR 和体内成像系统跟踪 BioKnife 迁移到 SLN 中。我们还通过淋巴结的连续切片分析检查了其抗肿瘤作用和机制。 GFP 报告基因表达在病毒组的淋巴结（对应于 SLN）中清晰可见。与对照组相比，病毒组舌和淋巴结相对 GFP mRNA 均显着升高（P < 0.05）。连续切片分析显示，与对照组相比，BioKnife感染癌细胞并对LNM表现出显着的抗肿瘤作用（P < 0.05）。我们检测到 BioKnife 感染的 LNM 中的细胞凋亡。 BioKnife 在注射到原发肿瘤后迁移到 SLN 中，并有效抑制 LNM，这表明使用 BioKnife 进行 SLN 靶向治疗具有巨大的潜力，可以为 cN0 头颈部鳞癌患者的选择性颈清扫术提供一种新颖且有前景的替代方案。
In clinical N0 (cN0) cases with head and neck squamous cell carcinoma (HNSCC), a treatment selection is still controversial: elective neck dissection or watchful waiting. We focused on sentinel lymph node (SLN)-targeted therapy using the urokinase-type plasminogen activator (uPA)-dependent oncolytic Sendai virus "BioKnife." The objectives of this study were to investigate BioKnife migration into SLNs and elucidate its antitumor effect on lymph node metastases (LNM). We established an orthotopic nude mouse model of HNSCC, with LNM being frequently induced. We inoculated HSC-3-M3, human highly metastatic tongue squamous cell carcinoma cells, in the tongue of the nude mice, and after 2 weeks, we injected BioKnife into the primary tumor. We tracked BioKnife migration into the SLNs by immunostaining, RT-PCR, and an in vivo imaging system. We also examined its antitumor effects and mechanisms through serial section analysis of lymph nodes. GFP reporter expression was clearly visible in the lymph nodes of virus groups, which corresponded to SLNs. Relative GFP mRNA was significantly increased in both the tongues and lymph nodes in the virus groups compared with that in the control group (P < 0.05). Serial section analysis showed that BioKnife infected cancer cells and exhibited significant antitumor effect against LNM compared with the control groups (P < 0.05). We detected apoptosis in LNM infected by BioKnife. BioKnife migrated into SLNs after its injection into the primary tumor and effectively suppressed LNM, suggesting that SLN-targeted therapy using BioKnife has great potential to provide a novel and promising alternative to elective neck dissection in cN0 patients with HNSCC.