title: IL6 secreted by Ewing sarcoma tumor microenvironment confers anti-apoptotic and cell-disseminating paracrine responses in Ewing sarcoma cells.
abstract: BACKGROUND
  The prognosis of patients with Ewing sarcoma (ES) has improved over the course of the last decades. However, those patients suffering from metastatic and recurrent ES still have only poor chances of survival and require new therapeutic approaches. Interleukin-6 (IL6) is a pleiotropic cytokine expressed by immune cells and a great variety of cancer cells. It induces inflammatory responses, enhances proliferation and inhibits apoptosis in cancer cells, thereby promoting chemoresistance.
  
  
  METHODS
  We investigated expression of IL6, its receptors and the IL6 signal transduction pathway in ES tumor samples and cell lines applying reverse transcriptase PCR, immunoblot and immunohistochemistry. The impact of IL6 on cell viability and apoptosis in ES cell lines was analyzed by MTT and propidium iodide staining, migration assessed by chorioallantoic membrane (CAM) assay.
  
  
  RESULTS
  Immunohistochemistry proved IL6 expression in the stroma of ES tumor samples. IL6 receptor subunits IL6R and IL6ST were expressed on the surface of ES cells. Treatment of ES cells with rhIL6 resulted in phosphorylation of STAT3. rhIL6 protected ES cells from serum starvation-induced apoptosis and promoted migration. IL6 blood serum levels were elevated in a subgroup of ES patients with poor prognosis.
  
  
  CONCLUSIONS
  These data suggest that IL6 contributes to ES tumor progression by increasing resistance to apoptosis in conditions of cellular stress, such as serum starvation, and by promotion of metastasis.
authors.affiliation: Division of Pediatric Hematology and Oncology, Charité - University Medical Center, Berlin, Germany. andrej.lissat@charite.de.
authors.forename: Andrej
authors.initials: A
authors.lastname: Lissat
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany. mandy.joerschke@uniklinik-freiburg.de.
authors.forename: Mandy
authors.initials: M
authors.lastname: Joerschke
authors.affiliation: Dheeraj Shinde, Institute of Oncology Research, Via Vincenzo Vela, Bellinzona, 66500, Switzerland. dheeraj.shinde@ior.iosi.ch.
authors.forename: Dheeraj A
authors.initials: DA
authors.lastname: Shinde
authors.affiliation: Institute of Pathology, RWTH Aachen University, Aachen, Germany. tbraunschweig@ukaachen.de.
authors.forename: Till
authors.initials: T
authors.lastname: Braunschweig
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany. angelina.meier@uniklinik-freiburg.de.
authors.forename: Angelina
authors.initials: A
authors.lastname: Meier
authors.affiliation: Division of Pediatric Hematology and Oncology, University Medical Center Aachen, Pauwelsstraße 30, Aachen, 52074, Germany. amakowska@ukaachen.de.
authors.forename: Anna
authors.initials: A
authors.lastname: Makowska
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany. rachel.bortnick@uniklinik-freiburg.de.
authors.forename: Rachel
authors.initials: R
authors.lastname: Bortnick
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany. philipp.henneke@uniklinik-freiburg.de.
authors.forename: Philipp
authors.initials: P
authors.lastname: Henneke
authors.affiliation: Department of Traumatology and Orthopaedics, University Medical Center Freiburg, Freiburg, Germany. georg.herget@uniklinik-freiburg.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Herget
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany. tgorr@access.uzh.ch.|Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland. tgorr@access.uzh.ch.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gorr
authors.affiliation: Division of Pediatric Hematology and Oncology, University Medical Center Aachen, Pauwelsstraße 30, Aachen, 52074, Germany. ukontny@ukaachen.de.
authors.forename: Udo
authors.initials: U
authors.lastname: Kontny
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D018450:Disease Progression; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D019899:Paracrine Communication; D010766:Phosphorylation; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: C508600:IL6 protein, human; C508603:IL6R protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human