Interleukin 13 Mediates Signal Transduction through Interleukin 13 Receptor α2 in Pancreatic Ductal Adenocarcinoma: Role of IL-13 Pseudomonas Exotoxin in Pancreatic Cancer Therapy

Purpose: Interleukin-13 receptor alpha 2 (IL-13R alpha 2) is a tumor antigen that is overexpressed in certain human tumors. However, its significance and expression in pancreatic cancer is not known. It is also not known whether IL-13 can signal through IL-13R alpha 2 in cancer. Experimental Design: The expression of IL-13R alpha 2 was assessed in pancreatic cancer samples by immunohistochemistry and in cell lines by flow cytometry and reverse transcription-PCR. The role of IL-13R alpha 2 was examined by IL-13-induced signaling in pancreatic cancer cell lines. IL-13R alpha 2-positive tumors were targeted by IL-13PE cytotoxin in vitro and in vivo in an orthotopic murine model of human pancreatic cancer. Results: Of the pancreatic tumor samples 71% overexpressed moderate to high-density IL-13R alpha 2 chain compared with normal pancreatic samples. IL-13 induced transforming growth factor-beta 1 promoter activity in IL-13R alpha 2-positive tumor cells and in cells engineered to express IL-13R alpha 2 but not in IL-13R alpha 2-negative or RNA interference knockdown cells. c-Jun and c-Fos of the AP-1 family of nuclear factors were activated by IL-13 only in IL-13R alpha 2-positive cells. In the orthotopic mouse model, IL13-PE significantly decreased tumor growth when assessed by whole-body imaging and prolonged the mean survival time. Similar results were observed in mice xenografted with a surgically resected human pancreatic tumor sample. Conclusions: These results indicate that IL-13R alpha 2 is a functional receptor as IL-13 mediates signaling in human pancreatic cancer cell lines. IL-13 causes transforming growth factor-beta activation via AP-1 pathway, which may cause tumor induced immunosuppression in the host. In addition, IL13-PE cytotoxin may be an effective therapeutic agent for the treatment of pancreatic cancer. Clin Cancer Res; 16(2); 577-86. (C)2010 AACR.