title: High neuropeptide Y release associates with Ewing sarcoma bone dissemination - in vivo model of site-specific metastases.
abstract: Ewing sarcoma (ES) develops in bones or soft tissues of children and adolescents. The presence of bone metastases is one of the most adverse prognostic factors, yet the mechanisms governing their formation remain unclear. As a transcriptional target of EWS-FLI1, the fusion protein driving ES transformation, neuropeptide Y (NPY) is highly expressed and released from ES tumors. Hypoxia up-regulates NPY and activates its pro-metastatic functions. To test the impact of NPY on ES metastatic pattern, ES cell lines, SK-ES1 and TC71, with high and low peptide release, respectively, were used in an orthotopic xenograft model. ES cells were injected into gastrocnemius muscles of SCID/beige mice, the primary tumors excised, and mice monitored for the presence of metastases. SK-ES1 xenografts resulted in thoracic extra-osseous metastases (67%) and dissemination to bone (50%) and brain (25%), while TC71 tumors metastasized to the lungs (70%). Bone dissemination in SK-ES1 xenografts associated with increased NPY expression in bone metastases and its accumulation in bone invasion areas. The genetic silencing of NPY in SK-ES1 cells reduced bone degradation. Our study supports the role for NPY in ES bone invasion and provides new models for identifying pathways driving ES metastases to specific niches and testing anti-metastatic therapeutics.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Georgetown University, Washington DC, USA.
authors.forename: Sung-Hyeok
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Department of Nursing, School of Nursing and Health Studies, Georgetown University, Washington DC, USA.|Department of Human Science, School of Nursing and Health Studies, Georgetown University, Washington DC, USA.
authors.forename: Jason U
authors.initials: JU
authors.lastname: Tilan
authors.affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Georgetown University, Washington DC, USA.
authors.forename: Susana
authors.initials: S
authors.lastname: Galli
authors.affiliation: Department of Pathology and Neuropathology, Medical University of GdaÅsk, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Izycka-Swieszewska
authors.affiliation: Department of Human Science, School of Nursing and Health Studies, Georgetown University, Washington DC, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Polk
authors.affiliation: Department of Human Science, School of Nursing and Health Studies, Georgetown University, Washington DC, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Horton
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Georgetown University, Washington DC, USA.|Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Georgetown University, Washington DC, USA.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Mahajan
authors.affiliation: Department of Human Science, School of Nursing and Health Studies, Georgetown University, Washington DC, USA.
authors.forename: David
authors.initials: D
authors.lastname: Christian
authors.affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Georgetown University, Washington DC, USA.
authors.forename: Shari
authors.initials: S
authors.lastname: Jenkins
authors.affiliation: Department of Human Science, School of Nursing and Health Studies, Georgetown University, Washington DC, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Acree
authors.affiliation: Department of Human Science, School of Nursing and Health Studies, Georgetown University, Washington DC, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Connors
authors.affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Georgetown University, Washington DC, USA.
authors.forename: Phuong
authors.initials: P
authors.lastname: Ledo
authors.affiliation: McGovern Institute, Massachusetts Institute of Technology, Boston, MA, USA.
authors.forename: Congyi
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Georgetown University, Washington DC, USA.
authors.forename: Yi-Chien
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Georgetown University, Washington DC, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Rodriguez
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Georgetown University, Washington DC, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Toretsky
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Georgetown University, Washington DC, USA.|Department of Pathology, Georgetown University Medical Center, Georgetown University, Washington DC, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Albanese
authors.affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Georgetown University, Washington DC, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kitlinska
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D017077:Culture Media, Conditioned; D004195:Disease Models, Animal; D005260:Female; D020868:Gene Silencing; D006801:Humans; D000860:Hypoxia; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009478:Neuropeptide Y / Q000737:chemistry*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010641:Phenotype; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000378:metabolism* / Q000473:pathology
chemical_list: D017077:Culture Media, Conditioned; C106031:EWS-FLI fusion protein; D009478:Neuropeptide Y; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS
keywords: Ewing sarcoma; animal model; bone invasion; neuropeptide Y