Department of Surgical Oncology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
Oncol Rep. 2012 Jul;28(1):49-54. doi: 10.3892/or.2012.1803. Epub 2012 May 4.
The ERBB proteins are cell membrane tyrosine kinase receptors. Among these receptors, ERBB1 (EGFR or HER1) and ERBB2 (HER2/Neu) have been reported to be the most important in terms of the development and progression of squamous cell carcinoma of the esophagus (SCC). Thus, targeting of ERBB1 and ERBB2 may become a promising strategy to treat SCC. In the present study, we examined ERBB1 and ERBB2 expression of SCC cell lines (TT, TE2, TE6 and TE10) and tumor samples. In addition, we evaluated the effect of the anti-ERBB1 antibody cetuximab and the anti-ERBB2 antibody trastuzumab for SCC in vitro and in vivo. Biological activities (receptor downregulation, the phosphorylation of MAPK and AKT) induced by the two agents were also investigated. Immunohistochemistry of SCC samples showed that ERBB1 was detected in 84%, while ERBB2 was detected in 30%. RT-PCR analysis revealed that ERBB1 and ERBB2 mRNA were detectable in all four cell lines. MTT cell proliferation analysis showed that cetuximab, but not trastuzumab, inhibited growth in each of the SCC cell lines in a dose-dependent manner. Further, cetuximab and trastuzumab used together produced stronger inhibition of growth compared to cetuximab alone. Cetuximab downregulated ERBB1, but not ERBB2, at the TE6 cell surface. However, neither ERBB1 nor ERBB2 showed any downregulation by trastuzumab at the TE6 cell surface. Cetuximab, not but trastuzumab, inhibited the phosphorylation of MAPK and Akt. When administered in combination, the two agents inhibited Akt phosphorylation to a greater degree compared to treatment with cetuximab alone. In the in vivo study, cetuximab, but not trastuzumab, significantly inhibited the TT tumors. Additionally, the combination of cetuximab with trastuzumab induced a synergistic inhibitory antitumor effect in the TT tumors. In conclusion, combination of cetuximab and trastuzumab revealed a synergistic antitumor effect for SCC in vitro and in vivo. The antitumor effect may be induced by the inhibition of the phosphorylation of Akt. These findings suggest that combination therapy including cetuximab and trastuzumab may be a promising strategy to treat SCC.
ERBB 蛋白是细胞膜酪氨酸激酶受体。在这些受体中，ERBB1（EGFR 或 HER1）和 ERBB2（HER2/Neu）在食管鳞状细胞癌（SCC）的发展和进展方面被认为是最重要的。因此，针对 ERBB1 和 ERBB2 可能成为治疗 SCC 的一种有前途的策略。在本研究中，我们检测了 SCC 细胞系（TT、TE2、TE6 和 TE10）和肿瘤样本中 ERBB1 和 ERBB2 的表达。此外，我们评估了抗 ERBB1 抗体西妥昔单抗和抗 ERBB2 抗体曲妥珠单抗对 SCC 的体内外作用。还研究了这两种药物引起的生物学活性（受体下调、MAPK 和 AKT 的磷酸化）。SCC 样本的免疫组织化学显示 ERBB1 检测到 84%，而 ERBB2 检测到 30%。RT-PCR 分析显示 ERBB1 和 ERBB2 mRNA 可在所有四种细胞系中检测到。MTT 细胞增殖分析表明，西妥昔单抗而非曲妥珠单抗以剂量依赖性方式抑制 SCC 细胞系中的每种细胞生长。此外，西妥昔单抗和曲妥珠单抗联合使用比单独使用西妥昔单抗产生更强的生长抑制作用。西妥昔单抗下调 TE6 细胞表面的 ERBB1，但不下调 ERBB2。然而，曲妥珠单抗在 TE6 细胞表面没有下调 ERBB1 或 ERBB2。西妥昔单抗而非曲妥珠单抗抑制 MAPK 和 Akt 的磷酸化。当联合使用时，两种药物与单独使用西妥昔单抗相比，更能抑制 Akt 磷酸化。在体内研究中，西妥昔单抗而非曲妥珠单抗显著抑制 TT 肿瘤。此外，西妥昔单抗与曲妥珠单抗联合在 TT 肿瘤中诱导协同抑制抗肿瘤作用。总之，西妥昔单抗和曲妥珠单抗联合在体内外对 SCC 显示出协同抗肿瘤作用。抗肿瘤作用可能是通过抑制 Akt 的磷酸化诱导的。这些发现表明，包括西妥昔单抗和曲妥珠单抗在内的联合治疗可能是治疗 SCC 的一种有前途的策略。
