Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan; Department of Oral and Maxillofacial Radiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan; Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Oral Oncol. 2018 Nov;86:251-257. doi: 10.1016/j.oraloncology.2018.09.030. Epub 2018 Oct 5.
Overexpression and increased signaling from the epidermal growth factor receptor (EGFR) often changes oral squamous cell carcinoma (OSCC) and thus EGFR is frequently targeted molecularly by the therapeutic antibody cetuximab. We assessed the roles of OSCC-derived extracellular vesicles (EVs), including exosomes in the trafficking of cetuximab and in epithelial-mesenchymal transition (EMT) of epithelial cells. OSCC cells abundantly expressed EGFR, which was secreted from cells with OSCC-EVs upon EGF stimulations. The OSCC-EGFR-EVs were then able to enter into and transform epithelial cells leading to increased mesenchymal traits with increased vimentin and spindle-like shapes. EGF priming of OSCC cells further increased this EMT-initiating effect of the OSCC-EVs. The internalization and pro-EMT effects of the OSCC-EVs were largely blocked by cetuximab. Thus, OSCC-derived EVs transform normal epithelial cells into a mesenchymal phenotype and anti-EGFR therapeutic antibody cetuximab inhibits such a carcinogenic effect of the OSCC-EVs.
表皮生长因子受体 (EGFR) 的过度表达和信号转导增加通常会改变口腔鳞状细胞癌 (OSCC)，因此 EGFR 经常被治疗性抗体西妥昔单抗靶向进行分子治疗。我们评估了 OSCC 衍生的细胞外囊泡 (EVs)，包括外泌体在西妥昔单抗转运和上皮-间充质转化 (EMT)中的作用。OSCC 细胞大量表达 EGFR，在 EGF 刺激下，OSCC-EVs 从 OSCC 细胞中分泌出来。然后，OSCC-EGFR-EVs 能够进入并转化上皮细胞，导致间充质特征增加，波形蛋白增加，呈纺锤形。EGF 对 OSCC 细胞的预刺激进一步增加了 OSCC-EVs 的 EMT 起始效应。OSCC-EVs 的内化和促 EMT 效应主要被西妥昔单抗阻断。因此，OSCC 衍生的 EVs 将正常上皮细胞转化为间充质表型，而抗 EGFR 治疗性抗体西妥昔单抗抑制 OSCC-EVs 的这种致癌作用。
