Targeting claudin-4 in human pancreatic cancer.

INTRODUCTION: Pancreatic cancer is one of the most malignant human diseases and there is an urgent need to develop novel diagnostic and therapeutic strategies. Claudin-4, overexpressed in pancreatic cancer and its precursor lesions, is a receptor for Clostridium perfringens enterotoxin (CPE). The cytotoxic effects of CPE and monoclonal antibodies against claudin-4 are useful as novel therapeutic tools for pancreatic cancer. AREAS COVERED: This review describes and discusses the studies targeting claudin-4 in normal human pancreatic duct epithelial (HPDE) cells and cancer cells. EXPERT OPINION: Claudin-4 is in part regulated via a PKCα signal transduction pathway in pancreatic cancer cell lines. PKCα inhibitors may represent potential therapeutic agents against human pancreatic cancer cells by the use of CPE cytotoxicity via claudin-4. The COOH-terminal half fragment of CPE (C-CPE) enhances the effectiveness of clinically relevant chemotherapies and can be used as a carrier for drugs and other bacterial toxins to claudin-4-positive cancer cells. hTERT-HPDE cells, in which the human telomerase reverse transcriptase (hTERT) gene is introduced into normal HPDE cells, may be a useful model of normal HPDE cells not only for physiological regulation of claudin-4 expression but also for developing safer and more effective therapeutic methods targeting claudin-4 in pancreatic cancer.