磁共振分子影像学检测口腔癌外显子 B 型纤连蛋白的有效性的临床前评估
Preclinical Assessment of the Effectiveness of Magnetic Resonance Molecular Imaging of Extradomain-B Fibronectin for Detection and Characterization of Oral Cancer.
机构信息
Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USA.
Department of Endodontics, Case Western Reserve University, Cleveland, OH, 44106, USA.
出版信息
Mol Imaging Biol. 2020 Dec;22(6):1532-1542. doi: 10.1007/s11307-020-01524-6. Epub 2020 Aug 12.
PURPOSE
Oral squamous cell carcinoma (OSCC) has not seen a substantial improvement in patient survival despite therapeutic advances, making accurate detection and characterization of the disease a clinical priority. Here, we aim to demonstrate the effectiveness of magnetic resonance imaging (MRI) with the targeted MRI contrast agent MT218 specific to extradomain-B fibronectin (EDB-FN) in the tumor microenvironment for detection and characterization of aggressive OSCC tumors.
PROCEDURES
EDB-FN expression was evaluated in human normal tongue and OSCC specimens with immunohistochemistry. Invasiveness of human CAL27, HSC3, and SCC4 OSCC cells was analyzed with spheroid formation and transwell assays. EDB-FN expression in the cells was analyzed with semiquantitative real-time PCR, western blotting, and a peptide binding study with confocal microscopy. Contrast-enhanced MRI with MT218 was performed on subcutaneous OSCC mouse models at a dose of 0.04 mmol/kg, using gadoteridol (0.1 mmol/kg) as a control.
RESULTS
Strong EDB-FN expression was observed in human untreated primary and metastatic OSCC, reduced expression in treated OSCC, and little expression in normal tongue tissue. SCC4 and HSC3 cell lines demonstrated high invasive potential with high and moderate-EDB-FN expression, respectively, while CAL27 showed little invasive potential and low-EDB-FN expression. In T-weighted MRI, MT218 produced differential contrast enhancement in the subcutaneous tumor models in correlation with EDB-FN expression in the cancer cells. Enhancement in the high-EDB-FN tumors was greater with MT218 at 0.04 mmol/kg than gadoteridol at 0.1 mmol/kg.
CONCLUSIONS
The results suggest EDB-FN has strong potential as an imageable biomarker for aggressive OSCC. MRMI results demonstrate the effectiveness of MT218 and the potential for differential diagnostic imaging of oral cancer for improving the management of the disease.
目的
尽管治疗方法有所进步，但口腔鳞状细胞癌（OSCC）患者的生存率并未显著提高，因此准确检测和描述疾病成为临床重点。本研究旨在证明针对细胞外结构域 B 型纤连蛋白（EDB-FN）的靶向 MRI 对比剂 MT218 在肿瘤微环境中检测和描述侵袭性 OSCC 肿瘤的有效性。
方法
通过免疫组织化学评估人正常舌组织和 OSCC 标本中的 EDB-FN 表达。通过球体形成和 Transwell 分析评估人 CAL27、HSC3 和 SCC4 OSCC 细胞的侵袭性。通过半定量实时 PCR、Western blot 和共聚焦显微镜的肽结合研究分析细胞中的 EDB-FN 表达。在皮下 OSCC 小鼠模型中以 0.04mmol/kg 的剂量进行 MT218 对比增强 MRI，以钆特醇（0.1mmol/kg）作为对照。
结果
在未经治疗的原发性和转移性 OSCC 中观察到强烈的 EDB-FN 表达，在治疗后的 OSCC 中表达降低，在正常舌组织中表达较少。SCC4 和 HSC3 细胞系表现出高侵袭潜能，分别具有高和中 EDB-FN 表达，而 CAL27 表现出低侵袭潜能和低 EDB-FN 表达。在 T1 加权 MRI 中，MT218 在与癌细胞中 EDB-FN 表达相关的皮下肿瘤模型中产生了差异对比增强。在 0.04mmol/kg 的 MT218 中，高 EDB-FN 肿瘤的增强程度大于 0.1mmol/kg 的钆特醇。
结论
结果表明 EDB-FN 具有作为侵袭性 OSCC 可成像生物标志物的强大潜力。MRMI 结果证明了 MT218 的有效性以及对口腔癌进行差异化诊断成像的潜力，以改善疾病的管理。
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