Colitis-associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy
Colitis-associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy
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DOI：
10.1111/his.14358
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发表时间：
2021-04-21
期刊：
影响因子：
6.4
通讯作者：
Ota, Hiroyoshi
中科院分区：
文献类型：
--
作者：
Iwaya, Mai;Hayashi, Hiroyuki;Ota, Hiroyoshi
Claudin 18（CLDN 18）是细胞表面蛋白claudin家族的成员，广泛表达于上皮细胞中，在细胞间粘附中发挥作用。CLDN 18同种型2（CLDN18.2）在胃上皮细胞中特异性表达，并且在胃腺癌中经常以高水平表达。在此基础上，针对CLDN18.2阳性胃食管腺癌患者开发了靶向单克隆抗体唑贝妥昔单抗。结肠炎相关的结直肠腺癌（CAC）往往失去肠道标志物，并显示异常的胃粘蛋白表达。此外，人表皮生长因子受体2（HER 2）抑制剂治疗结直肠癌的临床试验正在进行中。然而，CLDN18.2和HER 2的表达谱还没有被描述在一系列的人类CACs.Methods和结果，我们进行了免疫组化CLDN 18和HER 2对56个连续的CACs从55炎性肠病患者，并比较了56散发性结直肠腺癌（CRC）的对照组的表达谱。CLDN18.1和CLDN18.2的表达通过逆转录聚合酶链反应（PCR）在石蜡包埋的CRC组织中验证。CLDN 18在27%（15/56）的CAC和5%（3/56）的散发性CRC中呈阳性（P = 0.004），并且CLDN 18阳性的CAC比CLDN 18阴性的CAC更可能具有淋巴结转移（67%对36%; P = 0.017）。CLDN 18的表达与MUC 5AC的表达（P < 0.001）和CACs中富含AT的序列结合蛋白2表达的缺失（P = 0.005）显著相关。CLDN18.2在对CLDN 18具有免疫反应性的CRC中表达。只有4%的CAC的免疫反应性HER 2，并没有差异被确定在散发CRCs.Conclusions这些研究结果表明，某些CAC的情况下，可能是候选人有针对性的zolbetuximab治疗。
Aims Claudin 18 (CLDN18) is a member of the claudin family of cell surface proteins, which are widely expressed in epithelial cells and play a role in cell-cell adhesion. CLDN18 isoform 2 (CLDN18.2) is specifically expressed in gastric epithelial cells, and is frequently expressed at high levels in gastric adenocarcinoma. On the basis of this, zolbetuximab, a targeted monoclonal antibody, has been developed for patients with CLDN18.2-positive gastro-oesophageal adenocarcinoma. Colitis-associated colorectal adenocarcinomas (CACs) tend to lose intestinal markers and show aberrant gastric mucin expression. Furthermore, clinical trials of human epidermal growth factor receptor 2 (HER2) inhibitor therapy for colorectal carcinoma are ongoing. However, the expression profile of CLDN18.2 and HER2 has not been described in a series of human CACs.Methods and results We performed immunohistochemistry for CLDN18 and HER2 on 56 consecutive CACs from 55 inflammatory bowel disease patients, and compared the expression profile with that of a control group of 56 sporadic colorectal adenocarcinomas (CRCs). CLDN18.1 expression and CLDN18.2 expression were validated by reverse transcription polymerase chain reaction (PCR) in paraffin-embedded CRC tissues. CLDN18 was positive in 27% (15/56) of CACs and in 5% (3/56) of sporadic CRCs (P = 0.004), and CLDN18-positive CACs were more likely to have lymph node metastasis than CLDN18-negative CACs (67% versus 36%; P = 0.017). CLDN18 expression was significantly associated with MUC5AC expression (P < 0.001) and loss of special AT-rich sequence-binding protein 2 expression (P = 0.005) in CACs. CLDN18.2 was expressed in CRCs that were immunoreactive for CLDN18. Only 4% of CACs were immunoreactive for HER2, and no differences were identified in sporadic CRCs.Conclusions These findings suggest that certain CAC cases may be candidates for targeted zolbetuximab therapy.