Details

Autor(en) / Beteiligte

• Michl, Patrick
• Buchholz, Malte
• Rolke, Monika
• Kunsch, Steffen
• Löhr, Matthias
• McClane, Bruce
• Tsukita, Shoichiro
• Leder, Gerhard
• Adler, Guido
• Gress, Thomas M.

Titel

Claudin-4: A new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin

Ist Teil von

• Gastroenterology (New York, N.Y. 1943), 2001-09, Vol.121 (3), p.678-684

Ort / Verlag

New York, NY: Elsevier Inc

Erscheinungsjahr

2001

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 86Rb-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 β 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. GASTROENTEROLOGY 2001;121:678-684