title: Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin.
abstract: OBJECTIVE
  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 (86)Rb-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.
authors.affiliation: Department of Internal Medicine I, University Medical Center, University of Ulm, Ulm, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Michl
authors.forename: M
authors.initials: M
authors.lastname: Buchholz
authors.forename: M
authors.initials: M
authors.lastname: Rolke
authors.forename: S
authors.initials: S
authors.lastname: Kunsch
authors.forename: M
authors.initials: M
authors.lastname: Löhr
authors.forename: B
authors.initials: B
authors.lastname: McClane
authors.forename: S
authors.initials: S
authors.lastname: Tsukita
authors.forename: G
authors.initials: G
authors.lastname: Leder
authors.forename: G
authors.initials: G
authors.lastname: Adler
authors.forename: T M
authors.initials: TM
authors.lastname: Gress
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000503:physiopathology; D062506:Claudin-4; D004305:Dose-Response Relationship, Drug; D004768:Enterotoxins / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D019108:Tight Junctions / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C568157:CLDN4 protein, human; D062506:Claudin-4; C568158:Cldn4 protein, mouse; D004768:Enterotoxins; D008565:Membrane Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C035598:enterotoxin, Clostridium