Article

A Novel Role of Interleukin-13 Receptor 2 in Pancreatic Cancer Invasion and Metastasis

Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Cancer Research (Impact Factor: 9.28). 11/2009; 69(22):8678-85. DOI: 10.1158/0008-5472.CAN-09-2100
Source: PubMed

ABSTRACT Whereas interleukin-13 receptor alpha2 chain (IL-13Ralpha2) is overexpressed in a variety of human solid cancers including pancreatic cancer, we investigated its significance in cancer invasion and metastasis. We used two pancreatic cancer cell lines, IL-13Ralpha2-negative HPAF-II and IL-13Ralpha2-positive HS766T, and generated IL-13Ralpha2 stably transfected HPAF-II as well as IL-13Ralpha2 RNA interference knocked-down HS766T cells. Ability of invasion and signal transduction was compared between IL-13Ralpha2-negative and IL-13Ralpha2-positive cells and tumor metastasis was assessed in murine model for human pancreatic cancer with orthotopic implantation of tumors. IL-13 treatment enhanced cell invasion in IL-13Ralpha2-positive cancer cell lines but not in IL-13Ralpha2-negative cell lines. Furthermore, gene transfer of IL-13Ralpha2 in negative cell lines enhanced invasion, whereas its silencing downmodulated invasion of pancreatic cell lines in a Matrigel invasion assay. In vivo study revealed that IL-13Ralpha2-positive cancer metastasized to lymph nodes, liver, and peritoneum at a significantly higher rate compared with IL-13Ralpha2-negative tumors. The expression of IL-13Ralpha2 in metastatic lesions was found to be increased compared with primary tumors, and mice with IL-13Ralpha2-positive cancer displayed cachexia and poor prognosis. Invasion and metastasis also correlated with increased matrix metalloproteinase protease activity in these cells. Mechanistically, IL-13 activated extracellular signal-regulated kinase 1/2 and activator protein-1 nuclear factors in IL-13Ralpha2-positive pancreatic cancer cell lines but not in IL-13Ralpha2-negative cell lines. Taken together, our results show for the first time that IL-13 can signal through IL-13Ralpha2 in pancreatic cancer cells and IL-13Ralpha2 may serve as a prognostic biomarker of invasion and metastasis in pancreatic cancer.

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    • "An immunohistochemical analysis of human tissues found IL-13Rα2 overexpression in 71% of pancreatic ductal adenocarcinoma samples in comparison to normal pancreas controls (142). Indeed, experiments in an orthotopic mouse model of pancreatic cancer suggest that IL-13Rα2 is an important mediator of the pro-tumor effects of IL-13, including activation of AP-1 growth signals, production of immunomodulatory cytokines such as TGF-β, and promotion of metastasis (58, 142). Similar IL-13Rα2-dependent effects have been demonstrated in other cancer models, including ovarian carcinoma (59), colorectal cancer (57), head and neck squamous cell carcinoma (143), and malignant glioma (144). "
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    • "In our recent study on the role of IL-13Rα2 in pancreatic cancer invasion and metastasis, we demonstrated that IL-13Rα2–positive cancer metastasized to lymph nodes, liver, and peritoneum at a significantly higher rate compared with IL-13Rα2–negative tumors. The level of IL-13Rα2 expression in metastatic lesion was higher compared to the primary tumors [28]. Though we did not investigate the presence of metastasis in this model, the pancreatic tumor cells collected from lymph nodes metastasis were much more sensitive to IL-13-PE in vitro than compared with primary tumor cells indicating higher level of IL-13Rα2 in metastatic lesion. "
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