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

Abstract

Purpose: Interleukin-13 receptor α2 (IL-13Rα2) 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-13Rα2 in cancer.Experimental Design: The expression of IL-13Rα2 was assessed in pancreatic cancer samples by immunohistochemistry and in cell lines by flow cytometry and reverse transcription-PCR. The role of IL-13Rα2 was examined by IL-13-induced signaling in pancreatic cancer cell lines. IL-13Rα2-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-13Rα2 chain compared with normal pancreatic samples. IL-13 induced transforming growth factor-β1 promoter activity in IL-13Rα2-positive tumor cells and in cells engineered to express IL-13Rα2 but not in IL-13Rα2-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-13Rα2-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-13Rα2 is a functional receptor as IL-13 mediates signaling in human pancreatic cancer cell lines. IL-13 causes transforming growth factor-β 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. ©2010 AACR.

Targeting of IL-4 and IL-13 receptors for cancer therapy

“…Type I IL-13R consist of two chains of IL-13R (IL-13Ra1 and IL-13Ra2) and IL-4Ra chain. This type of configuration is reported on a variety of solid human tumor cells such as glioma, pancreatic cancer, head and neck cancer and ovarian cancer [21,76]. IL-13 binds to IL-13Ra1 and it recruits IL-4Ra to form a functional receptor complex.…”

“…This discovery led to the study of IL-13 receptor structure not only in RCC, but also in malignant glioma and other cancer cell types [71,72] including AIDS-associated Kaposi's Sarcoma tumor cells (AIDS-KS), squamous cell carcinoma of head and neck (SCCHN), pancreatic ductal adenocarcinoma and ovarian cancer [21,[72][73][74][75][76]. IL-13 binds to three different receptor chains in different configurations to generate three different types of IL-13R complexes [42,43] (Fig.…”

Epigenetic Modulation Enhances the Therapeutic Effect of Anti–IL-13Rα2 Antibody in Human Mesothelioma Xenografts

“…IL13Ra2 has, therefore, been studied for its potential in tumor molecule targeted therapy. Cytotoxin or immunotoxin targeting of IL-13Ra2 has been studied both in vitro and in vivo (11). Cintredekin besudotox (IL13-PE38QQR), a synthesized cytotoxin combining human IL-13 and mutated Pseudomonas exotoxin PE38, was shown to have a promising antitumor effect in vitro and in vivo (12,13).…”

Characterization and Immunotherapeutic Implications for a Novel Antibody Targeting Interleukin (IL)-13 Receptor α2

“…However, recent studies have challenged that theory based on studies demonstrating that upon binding of IL-13 to IL13R␣2 downstream signaling occurs in specialized pulmonary macrophages (11) as well as in pancreatic ductal (12) and ovarian carcinoma cells (13). Moreover, overexpression of IL13R␣2 in GBM but not in normal brain tissue (14,15) uniquely positions this receptor as a candidate for targeting tumor cells.…”