Abstract Background: Ewing's sarcoma (ES) is the second most common bone tumor in children. Still, despite multimodal therapy, lung metastasis are the most common cause of demise. Older age has been found to portend a poorer survival in ES. Here we identify differences in the pulmonary micro-environment comparing pediatric to adult lung tissue. Purpose: To identify molecular differences in the pediatric and adult lung micro-environment. Methods: To evaluate whether adult lungs provide a more permissive metastatic environment compared to pediatric lungs, we measured the migration and invasion of ES cells in a modified Boyden chamber assay. ES TC-71 cells, know to have moderate metastatic potential and ES LM-7 cells which are highly metastatic, were compared normal lung epithelial cells (CRL2300). Lungs from 4 week old adolescent and 9 week old adult nude mice, were morselated and placed in a modified Boyden chamber. To compare expression of metastatic genes in pediatric compared to adult lung, RNA was extracted from 4 week and 9 week nude mouse lung and a focused microarray of 128 genes were evaluated for differential expression. Results: The TC-71 cell line and the CRL2300 cells had equal area of migration to adolescent and adult lung. Whereas, LM-7 had a significantly larger area of cell migration to the adult lung compared to the adolescent lung.(p=0.033) The focused gene expression profile demonstrated significant differential expression of 2 genes, Interleukin 1-beta (IL1-B), and Integrin beta-3 (ItgB3). IL1-B was significantly under-expressed and ItgB3 was significantly over-expressed in adolescent lung tissue compared to adult lung tissue. Conclusions: Highly metastatic ES LM-7 cells have a significantly decreased migration to the adolescent/pediatric lung compared to adult lung tissue. This implies a different microenvironment in adolescent lung which does not have the same affinity for metastatic Ewing's sarcoma cells as the adult lung. Furthermore, differential gene expression of IL1-B and ItgB3 and may contribute to the cause of this difference since ItgB3 regulates cell adhesion, invasion and low doses of IL1-B can cause tumor cell eradication. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1440.