Characterization of a Novel Human Tumor Antigen Interleukin-13 Receptor α2 Chain

Kawakami, Koji; Terabe, Masaki; Kawakami, Mariko; Berzofsky, Jay A.; Puri, Raj K.

doi:10.1158/0008-5472.can-05-1265

Cited by 31 publications

(32 citation statements)

References 35 publications

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“…Since this chain is overexpresed in a variety of human primary as well as metastatic tumors, we predict that IL-13Ra2 targeted agents such as IL-13PE (composed of IL-13 and truncated Pseudomonas exotoxin) will not only target primary tumors but also metastatic lesions. 6,18,32,34 As we have previously shown that IL-13Ra2 is a tumor rejection antigen 35 and a target for receptor directed cancer vaccines, a combination therapy with targeted immunotoxin will be a useful strategy to target primary and metastatic tumors. These studies are currently ongoing in our laboratory.…”

Section: Discussionmentioning

confidence: 99%

IL‐13 regulates cancer invasion and metastasis through IL‐13Rα2 via ERK/AP‐1 pathway in mouse model of human ovarian cancer

Fujisawa

Joshi

Puri

2011

Intl Journal of Cancer

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127

112

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Previously, we have demonstrated that a variety of human cancers including the ovarian cancer express IL-13Ra2, a high affinity receptor for IL-13. Herein, we have examined if IL-13 regulates invasion and metastasis of ovarian cancer through IL-13Ra2 in vitro and in vivo in animal models of human ovarian cancer. We tested cell invasion and protease activity in IL-13Ra2-overexpressing and IL-13Ra2-negative ovarian tumor cell lines. IL-13 treatment significantly augmented both cell invasion and enzyme activities in only IL-13Ra2-positive cells but not in IL-13Ra2-negative cells in vitro. Mechanistically, IL-13 enhanced ERK1/2, AP-1 and MMP activities only in IL-13Ra2-positive cells but not in IL-13Ra2-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-13Ra2-positive tumors metastasized to lymph nodes and peritoneum earlier than IL-13Ra2-negative tumors. Interestingly, the IL-13Ra2-positive tumor bearing mice died earlier than mice with IL-13Ra2-negative tumor. Intraperitoneal injection of IL-13 further shortened survival of IL-13Ra2-positive tumor bearing mice compared to IL-13Ra2-negative tumor mice. IL-13Ra2-positive tumors and lymph node metastasis expressed higher levels of MMPs and higher ERK1/2 activation compared to IL-13Ra2-negative tumors. Taken together, IL-13Ra2 is involved in cancer metastasis through activation of ERK/AP-1 and that targeting IL-13Ra2 might not only directly kill primary tumors but also prevent cancer metastasis.Ovarian cancer is the fifth major cause of cancer related deaths in women. It is estimated that 21,880 women will be diagnosed and 13,850 will die of ovarian cancer in 2010. 1 Severity of the disease is determined by staging, which is based on the distance and extent of cancer spread within the pelvic and peritoneal cavity. The 5-year survival rate of ovarian cancer patients is related to the stage of the disease. 2 Therefore, novel and effective anticancer therapies are needed to prevent cancer cell spread. We have previously reported that IL13Ra2 is a biomarker of disease in ovarian cancer and targeting of this receptor with specific immunotoxin decreases tumor burden and extends survival of animals. 3 Despite its overexpression in a variety of human tumors and its characterization as a potent target for receptor directed anticancer therapy, 4-7 the biology of this receptor is highly complex and not understood completely. IL-13Ra2 is one of two receptor subunits of IL-13R complex. Another key-player of the receptor complex is IL-13Ra1, which forms a productive complex with IL-4Ra upon binding to IL-13 and mediates signal transduction. On the other hand, IL13Ra2 does not seem to require IL-4Ra and by itself binds IL-13 with high af...

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Section: Discussionmentioning

confidence: 99%

IL‐13 regulates cancer invasion and metastasis through IL‐13Rα2 via ERK/AP‐1 pathway in mouse model of human ovarian cancer

Fujisawa

Joshi

Puri

2011

Intl Journal of Cancer

Self Cite

127

112

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“…IL-13 is known to regulate airway hyperresponsiveness and allergic inflammation by binding to heterodimers of IL-13R␣1 and IL-4R␣ (9 -16). Another IL-13 receptor, IL-13R␣2, binds IL-13 with high affinity and, in contrast to IL-13R␣1, is a decoy receptor and a negative regulator of IL-13-induced biological functions (17)(18)(19)(20)(21)(22)(23)(24)(27)(28)(29). In HBEpCs, we found that LPA treatment increased IL-13R␣2 gene expression and protein production without affecting IL-13R␣1 and IL-4R␣ (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its function in a Th2-dominant immune response, IL-13R␣2 is being investigated as a therapeutic target for many human cancers, including prostate tumor, pediatric brain tumor, and breast and pancreatic tumors (22)(23)(24). Although plasma LPA levels are elevated in ovarian and breast cancer (58), no causal relationship has been proposed between LPA and IL-13R␣2 in cancer.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Induces Interleukin-13 (IL-13) Receptor α2 Expression and Inhibits IL-13 Signaling in Primary Human Bronchial Epithelial Cells

Zhao

et al. 2007

Journal of Biological Chemistry

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“…Infected cells were selected with puromycin (1 μg/mL) for 7 days. IL-13Rα2 overexpression in HPAF-II was determined as described previously (27).…”

Section: Methodsmentioning

confidence: 99%

A Novel Role of Interleukin-13 Receptor α2 in Pancreatic Cancer Invasion and Metastasis

et al. 2009

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Whereas interleukin-13 receptor α2 chain (IL-13Rα2) 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-13Rα2-negative HPAF-II and IL-13Rα2-positive HS766T, and generated IL-13Rα2 stably transfected HPAF-II as well as IL-13Rα2 RNA interference knocked-down HS766T cells. Ability of invasion and signal transduction was compared between IL-13Rα2-negative and IL-13Rα2-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-13Rα2-positive cancer cell lines but not in IL-13Rα2-negative cell lines. Furthermore, gene transfer of IL-13Rα2 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-13Rα2-positive cancer metastasized to lymph nodes, liver, and peritoneum at a significantly higher rate compared with IL-13Rα2-negative tumors. The expression of IL-13Rα2 in metastatic lesions was found to be increased compared with primary tumors, and mice with IL-13Rα2-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 signalregulated kinase 1/2 and activator protein-1 nuclear factors in IL-13Rα2-positive pancreatic cancer cell lines but not in IL-13Rα2-negative cell lines. Taken together, our results show for the first time that IL-13 can signal through IL-13Rα2 in pancreatic cancer cells and IL-13Rα2 may serve as a prognostic biomarker of invasion and metastasis in pancreatic cancer.

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Characterization of a Novel Human Tumor Antigen Interleukin-13 Receptor α2 Chain

Cited by 31 publications

References 35 publications

IL‐13 regulates cancer invasion and metastasis through IL‐13Rα2 via ERK/AP‐1 pathway in mouse model of human ovarian cancer

IL‐13 regulates cancer invasion and metastasis through IL‐13Rα2 via ERK/AP‐1 pathway in mouse model of human ovarian cancer

Lysophosphatidic Acid Induces Interleukin-13 (IL-13) Receptor α2 Expression and Inhibits IL-13 Signaling in Primary Human Bronchial Epithelial Cells

A Novel Role of Interleukin-13 Receptor α2 in Pancreatic Cancer Invasion and Metastasis

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