Oncotarget

Research Papers:

High neuropeptide Y release associates with Ewing sarcoma bone dissemination - in vivo model of site-specific metastases

Sung-Hyeok Hong _, Jason U. Tilan, Susana Galli, Ewa Izycka-Swieszewska, Taylor Polk, Meredith Horton, Akanksha Mahajan, David Christian, Shari Jenkins, Rachel Acree, Katherine Connors, Phuong Ledo, Congyi Lu, Yi-Chien Lee, Olga Rodriguez, Jeffrey A. Toretsky, Chris Albanese and Joanna Kitlinska

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Oncotarget. 2015; 6:7151-7165. https://doi.org/10.18632/oncotarget.3345

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Abstract

Sung-Hyeok Hong1, Jason U. Tilan2,3, Susana Galli4, Ewa Izycka-Swieszewska5, Taylor Polk3, Meredith Horton3, Akanksha Mahajan1,4, David Christian3, Shari Jenkins4, Rachel Acree3, Katherine Connors3, Phuong Ledo4, Congyi Lu6, Yi-Chien Lee1, Olga Rodriguez1, Jeffrey A. Toretsky1, Chris Albanese1,7 and Joanna Kitlinska4

1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Georgetown University, Washington DC, USA

2 Department of Nursing, School of Nursing and Health Studies, Georgetown University, Washington DC, USA

3 Department of Human Science, School of Nursing and Health Studies, Georgetown University, Washington DC, USA

4 Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Georgetown University, Washington DC, USA

5 Department of Pathology and Neuropathology, Medical University of Gdańsk, Poland

6 McGovern Institute, Massachusetts Institute of Technology, Boston, MA, USA

7 Department of Pathology, Georgetown University Medical Center, Georgetown University, Washington DC, USA

Correspondence to:

Joanna Kitlinska, email:

Keywords: Ewing sarcoma, neuropeptide Y, bone invasion, animal model

Received: January 08, 2015 Accepted: January 13, 2015 Published: January 30, 2015

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.


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