Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin.
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.
Michl
P
P
Department of Internal Medicine I, University Medical Center, University of Ulm, Ulm, Germany.
Buchholz
M
M
Rolke
M
M
Kunsch
S
S
Löhr
M
M
McClane
B
B
Tsukita
S
S
Leder
G
G
Adler
G
G
Gress
T M
TM
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
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