Claudin-4:: A new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin
Claudin-4:: A new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin
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DOI：
10.1053/gast.2001.27124
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发表时间：
2001-09-01
期刊：
影响因子：
29.4
通讯作者：
Gress, TM
中科院分区：
文献类型：
--
作者：
Michl, P;Buchholz, M;Gress, TM
背景和目标。最近，claudin家族的几个成员已被确定为紧密连接的组成部分。使用表达谱，我们以前发现claudin-4在胰腺癌中过表达。由于claudin-4已被描述为细胞毒性产气荚膜梭菌肠毒素（CPE）的受体，我们研究了CPE对胰腺癌细胞的影响。方法：采用北方印迹法分析claudin-4的表达。锥虫蓝拒染法和Rb-86释放法测定CPE的体外毒性。在表达紧密连接蛋白-4的Panc-1细胞系的裸鼠异种移植物中研究CPE的体内作用。结果如下：表达分析表明，claudin-4在大多数胰腺癌组织和细胞系以及其他几种胃肠道肿瘤中过表达。CPE导致急性剂量依赖性细胞毒性效应，仅限于表达紧密连接蛋白-4的细胞，并依赖于紧密连接蛋白-4的表达水平。此外，转化生长因子β被鉴定为封闭蛋白-4表达和CPE易感性的负调节剂。在体内，肿瘤内注射Panc-1中的CPE。异种移植导致大面积的肿瘤细胞坏死和肿瘤生长的显著减少。结论：我们的研究结果表明，用CPE靶向表达claudin-4的肿瘤代表了胰腺癌和其他实体瘤的一种有前途的新治疗方式。
Background & Aims. Recently, several members of the claudin family have been identified as integral constituents of tight junctions. Using expression profiling, we previously found claudin-4 to be overexpressed in pancreatic cancer. Because claudin-4 has been described as a receptor for the cytotoxic Clostridium perfringens enterotoxin (CPE), we investigated the effect of CPE on pancreatic cancer cells. Methods: Expression of claudin-4 was analyzed by Northern blots. In vitro toxicity of CPE was determined by trypan blue exclusion and the Rb-86-release assay. The in vivo effect of CPE was studied in claudin-4-expressing nude mouse xenografts of the Panc-1 cell line. Results: Expression analyses showed that claudin-4 was overexpressed in most pancreatic cancer tissues and cell lines and several other gastrointestinal tumors. CPE led to an acute dose-dependent cytotoxic effect, restricted to claudin-4-expressing cells and dependent on claudin-4 expression levels. Furthermore, transforming growth factor beta was identified as a negative modulator of both claudin-4 expression and susceptibility to CPE. In vivo, intratumoral injections of CPE in Panc-1. xenografts led to large areas of tumor cell necrosis and significant reduction of tumor growth. Conclusions: Our findings suggest that targeting claudin-4-expressing tumors with CPE represents a promising new treatment modality for pancreatic cancer and other solid tumors.