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

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

doi:10.18632/oncotarget.3345

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.

Highlights

Ewing sarcoma (ES) is a malignant tumor that arises in bones or soft tissues of children and adolescents
To determine if high neuropeptide Y (NPY) secretion influences the pattern of metastases, we used two ES cell lines, SKES1 and TC71, which express high and low NPY levels, respectively (Fig. 1A)
Even though some factors contributing to their formation, such as Dickkopf-related protein 2 (DKK2), have been identified, the detailed mechanisms promoting their development remain unclear [5, 34]

Summary

Introduction

Ewing sarcoma (ES) is a malignant tumor that arises in bones or soft tissues of children and adolescents. Patients with metastatic ES are treated with the same standard therapy as those with localized disease. This lack of adequate and specific therapies for metastatic ES reflects a poor understanding of the mechanisms governing ES dissemination. Studies aimed at identifying such mechanisms are hindered by the limited availability of clinical material and lack of animal models that accurately recapitulate metastatic processes. The analyses often focus solely on lung metastases, not advancing mechanistic understanding of tumor metastasis to other locations, including bone [5, 9,10,11,12,13]

Methods

Results

Conclusion