Department of Therapeutic Radiology and Oncology, Innsbruck Medical University, Austria.
Radiother Oncol. 2010 Jul;96(1):108-15. doi: 10.1016/j.radonc.2010.04.017. Epub 2010 May 5.
Radiation therapy cures malignant tumors of the head and neck region more effectively when it is combined with application of the anti-EGFR monoclonal antibody cetuximab. Despite the successes achieved, we still do not know how to select patients who will respond to this combination of anti-EGFR monoclonal antibody and radiation. This study was conducted to elucidate possible mechanisms which cause the combined treatment with cetuximab and irradiation to fail in some cases of squamous cell carcinomas.
Mice bearing FaDu and A431 squamous cell carcinoma xenograft tumors were treated with cetuximab (total dose 3 mg, intraperitoneally), irradiation (10 Gy) or their combination at the same doses. Treatment was applied when tumors reached 8mm in size. To collect samples for further protein analysis (two-dimensional differential gel electrophoresis (2-D DIGE), mass spectrometry MALDI-TOF/TOF, Western blot analysis, and ELISA), mice from each group were sacrificed on the 8th day after the first injection of cetuximab. Other mice were subjected to tumor growth delay assay.
In FaDu xenografts, treatment with cetuximab alone was nearly as effective as cetuximab combined with ionizing radiation, whereas A431 tumors responded to the combined treatment with significantly enhanced delay in tumor growth. Tumors extracted from the untreated FaDu and A431 xenografts were analysed for protein expression, and 34 proteins that were differently expressed in the two tumor types were identified. The majority of these proteins are closely related to intratumoral angiogenesis, cell adhesion, motility, differentiation, epithelial-to-mesenchymal transition (EMT), c-myc signaling and DNA repair.
The failure of cetuximab to enhance radiation response in FaDu xenografts was associated with the initiation of the program of EMT and with c-myc up-regulation in the carcinoma cells. For this reason, c-myc and EMT-related proteins (E-cadherin, vimentin) may be considered as potential biomarkers to predict squamous cell carcinoma response after treatment with cetuximab in combination with radiation.
当放射疗法与抗 EGFR 单克隆抗体西妥昔单抗联合应用于头颈部恶性肿瘤时，其治愈率更高。尽管取得了成功，但我们仍不知道如何选择对这种抗 EGFR 单克隆抗体联合放射治疗有反应的患者。本研究旨在阐明导致西妥昔单抗联合放疗在某些情况下对鳞状细胞癌无效的可能机制。
将携带 FaDu 和 A431 鳞状细胞癌异种移植肿瘤的小鼠用西妥昔单抗（总剂量 3mg，腹腔内）、放疗（10Gy）或相同剂量的联合治疗。当肿瘤长到 8mm 时开始治疗。为了收集进一步的蛋白质分析（二维差异凝胶电泳（2-D DIGE）、基质辅助激光解吸电离飞行时间/飞行时间（MALDI-TOF/TOF）质谱、Western blot 分析和 ELISA）的样本，每组小鼠在第一次注射西妥昔单抗后第 8 天处死。其他小鼠进行肿瘤生长延迟试验。
在 FaDu 异种移植瘤中，西妥昔单抗单独治疗的效果几乎与西妥昔单抗联合电离辐射一样有效，而 A431 肿瘤对联合治疗的反应是肿瘤生长延迟明显增强。对未处理的 FaDu 和 A431 异种移植瘤提取的肿瘤进行蛋白质表达分析，鉴定出两种肿瘤类型中表达不同的 34 种蛋白质。这些蛋白质大多数与肿瘤内血管生成、细胞黏附、运动、分化、上皮间质转化（EMT）、c-myc 信号和 DNA 修复密切相关。
西妥昔单抗未能增强 FaDu 异种移植瘤对放射治疗的反应与 EMT 程序的启动和癌细胞中 c-myc 的上调有关。因此，c-myc 和 EMT 相关蛋白（E-钙黏蛋白、波形蛋白）可作为潜在的生物标志物，用于预测西妥昔单抗联合放疗治疗后鳞状细胞癌的反应。
