P. Michl et al., Claudin-4: A new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin, GASTROENTY, 121(3), 2001, pp. 678-684
Background & Aims. Recently, several members of the claudin family have bee
n 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 cytotoxi
c Clostridium perfringens enterotoxin (CPE), we investigated the effect of
CPE on pancreatic cancer cells. Methods: Expression of claudin-4 was analyz
ed by Northern blots. In vitro toxicity of CPE was determined by trypan blu
e exclusion and the Rb-86-release assay. The in vivo effect of CPE was stud
ied in claudin-4-expressing nude mouse xenografts of the Panc-1 cell line.
Results: Expression analyses showed that claudin-4 was overexpressed in mos
t pancreatic cancer tissues and cell lines and several other gastrointestin
al 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 r
epresents a promising new treatment modality for pancreatic cancer and othe
r solid tumors.