Analysis of interleukin-13 receptor alpha 2 expression in human pediatric brain tumors

Fujita Health University, Nagoya, Aichi, Japan
Cancer (Impact Factor: 4.9). 09/2004; 101(5):1036-42. DOI: 10.1002/cncr.20470
Source: PubMed

ABSTRACT Compared with normal brain tissue cells, human malignant glioma cells express higher levels of interleukin-13 receptor (IL-13R). However, whether this receptor is expressed in situ has not been carefully examined. With IL-13R-targeted cytotoxin (IL13-PE38QQR, comprising IL-13 and a mutated form of Pseudomonas exotoxin [PE]) being tested in three Phase I/II clinical trials for the treatment of adult human glioma, and with pediatric studies being planned, the authors set out to analyze pediatric brain tumor tissue specimens for the expression of IL-13R.
Using in situ hybridization and immunohistochemical staining, the authors examined 58 pediatric brain tumor specimens for expression of the predominant IL-13 binding and internalizing protein (IL-13Ralpha2) chain at the mRNA and protein levels.
Overall, approximately 83% of pediatric brain tumor samples expressed IL-13Ralpha2. One hundred percent (11 of 11) high-grade astrocytoma, 79% (26 of 33) low-grade astrocytoma, 67% (4 of 6) medulloblastoma, and 67% (2 of 3) ependymoma samples were positive for IL-13Ralpha2. Among IL-13Ralpha2-positive samples, 88% (42 of 48 samples) had positive expression in > or = 50% of all tumor fields. The results obtained using both assays were consistent with each other.
The current study established that pediatric brain tumor specimens expressed the IL-13Ralpha2 chain. Because the IL-13Ralpha2 chain is a major binding component of the IL-13R complex, these results suggest that the targeting of IL-13R may represent a useful approach for the treatment of pediatric brain tumors.

Download full-text


Available from: Satoru Takahashi, Oct 09, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: The interleukin-13 receptor alpha2 (IL-13R alpha2) chain is a primary IL-13 binding and internalization component of the IL-13R system. Previous studies have shown that human brain tumors, including glioblastoma multiforme (GBM), overexpress IL-13R alpha2 chain, while normal brain cells do not express this protein or express very low levels of it. To target IL-13R on brain tumor cells, the authors have developed an IL-13R-directed cytotoxin termed IL13-PE38QQR to induce specific cancer cell killing. To investigate the role of IL-13R alpha2 chain in GBM, cells were treated with antisense oligonucleotide or siRNA to IL-13R alpha2 chain, and cellular IL-13 binding and sensitivity to IL-13 cytotoxin were assessed. IL-13R alpha2 gene interference in GBM cells showed decreased ligand binding, and consequently IL-13 cytotoxin exhibited less cytotoxicity to these cells. The authors next evaluated the antitumor activity of IL-13 cytotoxin in native IL-13R-expressing tumors and after gene transfer of IL-13R alpha2 by injecting plasmid in U87MG tumors subcutaneously implanted in nude mice. These mice were then treated with IL-13 cytotoxin. Mean tumor size in mice receiving intraperitoneal or intratumoral IL-13 cytotoxin was significantly smaller in control tumors; however, tumor sizes were much smaller in IL-13R alpha2-transfected tumors. Furthermore, convection-enhanced delivery of IL-13R alpha2 cDNA in intracranially established U87MG glioma followed by IL-13 cytotoxin administration by the same route mediated tumor regression and prolonged survival of animals by 164% compared with control. These results indicate that IL-13R alpha2 chain in GBM cells is essential for IL-13 cytotoxin-induced cytotoxicity and that IL-13R alpha2 chain plays a critical biologic role in IL-13 cytotoxin-mediated therapy for GBM.
    Journla of Immunotherapy 28(3):193-202. · 3.35 Impact Factor
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The prognosis for most patients with primary brain tumors remains poor. Recent advances in molecular and cell biology have led to a greater understanding of molecular alterations in brain tumors. These advances are being translated into new therapies that will hopefully improve the prognosis for patients with brain tumors. We reviewed the literature on small molecule targeted agents and monoclonal antibodies used in brain tumor research and brain tumor clinical trials for the past 20 years. Brain tumors commonly express molecular abnormalities. These alterations can lead to the activation of cell pathways involved in cell proliferation. This knowledge has led to interest in novel anti-brain-tumor therapies targeting key components of these pathways. Many drugs and monoclonal antibodies have been developed that modulate these pathways and are in various stages of testing. The use of targeted therapies against brain tumors promises to improve the prognosis for patients with brain tumors. However, as the molecular pathogenesis of brain tumors has not been linked to a single genetic defect or target, molecular agents may need to be used in combinations or in tandem with cytotoxic agents. Further study of these agents in well-designed cooperative clinical trials is needed.
    Cancer control: journal of the Moffitt Cancer Center 05/2005; 12(2):116-24. · 2.66 Impact Factor