title: IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas, USA.
authors.forename: Tohru
authors.initials: T
authors.lastname: Hosoyama
authors.forename: Mohammed Imran
authors.initials: MI
authors.lastname: Aslam
authors.forename: Jinu
authors.initials: J
authors.lastname: Abraham
authors.forename: Suresh I
authors.initials: SI
authors.lastname: Prajapati
authors.forename: Koichi
authors.initials: K
authors.lastname: Nishijo
authors.forename: Joel E
authors.initials: JE
authors.lastname: Michalek
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Zarzabal
authors.forename: Laura D
authors.initials: LD
authors.lastname: Nelon
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.forename: Charles
authors.initials: C
authors.lastname: Keller
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008934:Mitogens; D019042:Muscle Neoplasms / Q000235:genetics* / Q000473:pathology; D018006:Myogenic Regulatory Factors / Q000235:genetics; D009362:Neoplasm Metastasis; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000502:physiology*; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D008934:Mitogens; D018006:Myogenic Regulatory Factors; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D019948:Receptors, Interleukin-4; C063403:myogenic factor 6; C068686:Pax3 protein, mouse