Document Detail

IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma.
MedLine Citation:
PMID:  21536546     Owner:  NLM     Status:  MEDLINE    
PURPOSE: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. The alveolar subtype of rhabdomyosarcoma (ARMS) is a paradigm for refractory and incurable solid tumors because more than half of the children at diagnosis have either regional lymph node or distant metastases. These studies follow our previous observation that Interleukin-4 receptor α (IL-4Rα) is upregulated in both human and murine ARMS, and that the IL-4R signaling pathway may be a target for abrogating tumor progression.
EXPERIMENTAL DESIGN: By in vitro biochemical and cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of IL-4 and IL-13 in IL-4R-mediated mitogenesis, myodifferentiation, and tumor progression.
RESULTS: IL-4 and IL-13 ligands accelerated tumor cell growth and activated STAT6, Akt, or MAPK signaling pathways in the human RMS cell lines, RD and Rh30, as well as in mouse primary ARMS cell cultures. IL-4 and IL-13 treatment also decreased protein expression of myogenic differentiation factors MyoD and Myogenin, indicating a loss of muscle differentiation. Using a genetically engineered mouse model of ARMS, we have shown that inhibition of IL-4R signaling pathway with a neutralizing antibody has a profound effect on the frequency of lymph node and pulmonary metastases, resulting in significant survival extension in vivo.
CONCLUSIONS: Our results indicate that an IL-4R-dependent signaling pathway regulates tumor cell progression in RMS, and inhibition of this pathway could be a promising adjuvant therapeutic approach.
Tohru Hosoyama; Mohammed Imran Aslam; Jinu Abraham; Suresh I Prajapati; Koichi Nishijo; Joel E Michalek; Lee Ann Zarzabal; Laura D Nelon; Denis C Guttridge; Brian P Rubin; Charles Keller
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  17     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-03     Completed Date:  2011-09-15     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2757-66     Citation Subset:  IM    
Copyright Information:
©2011 AACR.
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MeSH Terms
Cell Dedifferentiation / genetics*
Cell Transformation, Neoplastic / chemically induced,  genetics*
Cells, Cultured
Disease Models, Animal
Genes, p53
Mice, Transgenic
Muscle Neoplasms / genetics*,  pathology
Myogenic Regulatory Factors / genetics
Neoplasm Metastasis
Paired Box Transcription Factors / genetics
Receptors, Interleukin-4 / genetics,  physiology*
Rhabdomyosarcoma / genetics*,  pathology
Signal Transduction / genetics,  physiology
Grant Support
5R01CA133229-03/CA/NCI NIH HHS; R01 CA133229/CA/NCI NIH HHS; R01 CA133229-03/CA/NCI NIH HHS; R01 CA143082/CA/NCI NIH HHS
Reg. No./Substance:
0/Mitogens; 0/Myogenic Regulatory Factors; 0/Paired Box Transcription Factors; 0/Receptors, Interleukin-4; 0/myogenic factor 6; 138016-91-8/Pax3 protein, mouse

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