3598

IL13RA2

interleukin 13 receptor, alpha 2;IL13RA2;interleukin 13 receptor, alpha 2

IL-13 receptor subunit alpha-2|IL-13R subunit alpha-2|IL-13R-alpha-2|IL-13RA2|cancer/testis antigen 19|interleukin 13 binding protein|interleukin 13 receptor alpha 2 chain|interleukin-13 receptor subunit alpha-2|interleukin-13-binding protein

Xq23

protein-coding

Previously, we have demonstrated that a variety of human cancers including the ovarian cancer express IL-13Ralpha2, a high affinity receptor for IL-13. Herein, we have examined if IL-13 regulates invasion and metastasis of ovarian cancer through IL-13Ralpha2 in vitro and in vivo in animal models of human ovarian cancer. We tested cell invasion and protease activity in IL-13Ralpha2-overexpressing and IL-13Ralpha2-negative ovarian tumor cell lines. IL-13 treatment significantly augmented both cell invasion and enzyme activities in only IL-13Ralpha2-positive cells but not in IL-13Ralpha2-negative cells in vitro. Mechanistically, IL-13 enhanced ERK1/2, AP-1 and MMP activities only in IL-13Ralpha2-positive cells but not in IL-13Ralpha2-negative cells. In contrast, other signaling pathways such as IRS1/2, PI3K and AKT do not seem to be involved in IL-13 induced signaling in ovarian cancer cell lines. Highly specific inhibitors for MMP and AP-1 efficiently inhibited both invasion and protease activities without impacting the basal level invasion and protease activities in vitro. In orthotopic animal model of human ovarian cancer, IL-13Ralpha2-positive tumors metastasized to lymph nodes and peritoneum earlier than IL-13Ralpha2-negative tumors. Interestingly, the IL-13Ralpha2-positive tumor bearing mice died earlier than mice with IL-13Ralpha2-negative tumor. Intraperitoneal injection of IL-13 further shortened survival of IL-13Ralpha2-positive tumor bearing mice compared to IL-13Ralpha2-negative tumor mice. IL-13Ralpha2-positive tumors and lymph node metastasis expressed higher levels of MMPs and higher ERK1/2 activation compared to IL-13Ralpha2-negative tumors. Taken together, IL-13Ralpha2 is involved in cancer metastasis through activation of ERK/AP-1 and that targeting IL-13Ralpha2 might not only directly kill primary tumors but also prevent cancer metastasis.

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.

CONTEXT: Pheochromocytomas and paragangliomas are rare catecholamine-secreting neuroendocrine tumors arising from the adrenal medulla and sympathetic tissues. When complete surgical resection is not an option, the treatment of pheochromocytoma is limited. OBJECTIVE: The objective of the study was to identify and characterize overexpression of IL-13 receptor-alpha2 (IL-13Ralpha2) gene expression in human and murine tumors and verify xenograft mouse pheochromocytoma cell (MPC)-derived tumor's response to a selective cytotoxin. DESIGN/SETTING/PATIENTS: expression of IL-13Ralpha2 was evaluated in a panel of 25 human pheochromocytoma clinical samples by RT-PCR and eight MPC tumors by indirect immunofluorescence assay and RT-PCR. INTERVENTION: The function of IL-13Ralpha2 in these tumor cells was examined by evaluating tumor sensitivity to a recombinant IL-13-Pseudomonas exotoxin (IL-13PE). Subcutaneous small and large MPC tumors in athymic nude mice (n = 10) were treated intratumorally with IL-13PE (100 m icrog/kg). MAIN OUTCOME MEASURES: IC(50) and tumor size were measured. RESULTS: IL-13PE immunotoxin was highly cytotoxic to IL-13Ralpha2-overexpressing MPC cells (IC(50) <2.5 ng/ml) in vitro. Furthermore, IL-13PE was highly cytotoxic to sc tumors. Our results showed a statistically significant decrease in tumor size as early as 3 d after initial treatment and further suppressed growth of MPC tumors. All tumors displayed a histological evidence of necrosis in response to IL-13 immunotoxin without any adverse effects in host at this dose. CONCLUSIONS: Human and murine neuroendocrine pheochromocytoma overexpress the IL-13Ralpha2 chain, and an IL-13PE-based receptor-directed anticancer approach may prove useful in treatment for metastatic pheochromocytoma patients.