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EGFR Downregulation after Anti-EGFR Therapy Predicts the Antitumor Effect in Colorectal Cancer

西妥昔单抗 内化 癌症研究 结直肠癌 表皮生长因子受体 下调和上调 细胞 流式细胞术 单克隆抗体 吉非替尼 癌症 医学 受体 生物 内科学 免疫学 抗体 遗传学 基因 生物化学
作者
Yasuyuki Okada,Tooru Kimura,Tadahiko Nakagawa,Koichi Okamoto,Akira Fukuya,Takahiro Goji,Shota Fujimoto,Masamichi Sogabe,Hiroshi Miyamoto,Naoki Muguruma,Yasushi Tsuji,Toshiya Okahisa,Tetsuji Takayama
出处
期刊:Molecular Cancer Research [American Association for Cancer Research]
卷期号:15 (10): 1445-1454 被引量:38
标识
DOI:10.1158/1541-7786.mcr-16-0383
摘要

Abstract Anti-EGFR mAb is reported to induce EGFR internalization in colorectal cancer cells. However, the biological relevance of EGFR internalization with anti-EGFR mAb is unknown. Therefore, the relevance of EGFR downregulation with anti-EGFR mAb to antitumor activity in colorectal cancer cells was investigated. Quantification of EGFR on the cell surface before cetuximab treatment was assessed by flow cytometry, and its growth-inhibitory effects were measured by Trypan blue exclusion, in 10 RAS, BRAF wild-type colorectal cancer cell lines, but there was no significant correlation between EGFR number and its growth-inhibitory effect. However, a significant correlation existed between the percentage decrease in the number of EGFRs after cetuximab treatment and its growth-inhibitory effect in those cell lines. Treatment with TGFα, a ligand for EGFR, induced EGFR internalization in colorectal cancer cells, but most EGFRs subsequently recycled to the cell surface, consistent with previous studies. While cetuximab treatment induced EGFR internalization, most receptors subsequently translocated into the late endosome, leading to lysosomal degradation, as revealed by immunoblotting and double immunofluorescence. Cetuximab-sensitive colorectal cancer cells showed greater EGFR internalization, stronger cell growth inhibition, and more augmented apoptotic signals than nonsensitive cells. IHC for EGFR, performed using an EGFR pharmDx Kit (mouse anti-human EGFR mAb clone 2-18C9), in clinical specimens before and after anti-EGFR mAb therapy in 13 colorectal cancer patients showed a significant correlation between the response to anti-EGFR mAb and decreased staining after therapy. Implications: This report clearly demonstrates that anti-EGFR mAb facilitates internalization and subsequent degradation of EGFRs in lysosomes, which is an important determinant of the efficacy of anti-EGFR mAb treatment for colorectal cancer. Mol Cancer Res; 15(10); 1445–54. ©2017 AACR.
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