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 T₁-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.

中文翻译：

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域外-B 纤连蛋白的磁共振分子成像对口腔癌检测和表征的有效性的临床前评估。

目的

尽管治疗取得了进展，但口腔鳞状细胞癌 (OSCC) 的患者存活率并未显着提高，因此准确检测和表征该疾病成为临床优先事项。在这里，我们旨在证明磁共振成像 (MRI) 在肿瘤微环境中特异性针对域外 B 纤连蛋白 (EDB-FN) 的靶向 MRI 造影剂 MT218 的有效性，用于检测和表征侵袭性 OSCC 肿瘤。

程序

EDB-FN 表达在人类正常舌和 OSCC 标本中进行了免疫组织化学评估。人 CAL27、HSC3 和 SCC4 OSCC 细胞的侵袭性通过球体形成和 transwell 测定进行分析。细胞中 EDB-FN 的表达通过半定量实时 PCR、蛋白质印迹和肽结合研究与共聚焦显微镜进行分析。在皮下 OSCC 小鼠模型上以 0.04 mmol/kg 的剂量使用 MT218 进行对比增强 MRI，使用钆特醇 (0.1 mmol/kg) 作为对照。

结果

在人类未治疗的原发性和转移性 OSCC 中观察到强 EDB-FN 表达，在治疗后的 OSCC 中表达降低，在正常舌组织中几乎没有表达。SCC4 和 HSC3 细胞系分别具有高和中度 EDB-FN 表达的高侵袭潜力，而 CAL27 显示低侵袭潜力和低 EDB-FN 表达。在 T ₁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不同的对比度增强。0.04 mmol/kg 的 MT218 比 0.1 mmol/kg 的钆特醇对高 EDB-FN 肿瘤的增强作用更大。

结论

结果表明，EDB-FN 作为侵袭性 OSCC 的可成像生物标志物具有强大的潜力。MRMI 结果证明了 MT218 的有效性和口腔癌鉴别诊断成像改善疾病管理的潜力。