Ewing's sarcoma family of tumors (ESFT) is a group of highly aggressive malignancies, the treatment of which remains an unsolved clinical problem. The presence of metastases is the single most powerful adverse prognostic factor for ESFT, with event-free survival at 72% and 27% for patients with localized and metastatic disease, respectively. The most unfavorable prognosis is associated with the presence of bone metastases. Thus, the treatment of metastatic ESFT and preventing disease dissemination is a crucial problem in ESFT clinical management. Despite that, however, the mechanisms governing the metastases formation in ESFT are poorly understood. Hypoxia has been implicated in ESFT progression by clinical and experimental data. In ESFT patients, the presence of unperfused areas within tumor tissue associates with an unfavorable metastatic pattern (multiple metastases with bone involvement), while the lack of such areas with better prognosis. In cell culture, hypoxia has been shown to up-regulate EWS-FLI1, an aberrant transcription factor triggering ESFT development, and shift its transcriptional activity toward pro metastatic and pro-survival genes. On functional levels, low oxygen augments ESFT cell invasiveness and tumorigenic potential. We have also shown hypoxia-induced enrichment in ESFT cells with a high activity of aldehyde dehydrogenase (ALDH), characterized as cancer stem cells, as well as identified neuropeptide Y (NPY), an EWS-FLI1 target gene, as a candidate hypoxia-induced pro-metastatic factor in ESFT. NPY has also been implicated in the regulation of bone homeostasis, suggesting its potential role in bone invasion. Based on these data, we hypothesize that hypoxia in primary tumor promotes ESFT metastases formation and changes their pattern by favoring bone invasion. To provide a direct proof for this notion, we propose developing a novel animal model by performing femoral artery ligation (FAL) in mice bearing orthotopic ESFT xenografts in their gastrocnemius muscles, followed by excision of the primary tumor and long-term monitoring of metastases formation. This approach will allow us to create transient hypoxia in growing ESFT tumor and test its effect on disease dissemination.
The aims of our study are: 1) to establish a model of hypoxia in ESFT primary tumor by testing the impact of FAL on the oxygen level within tumor tissue;2) to determine the effect of hypoxia on metastases formation by comparing number, sizes, latency and localization of metastases in animals with or without hypoxic challenge. Our study will provide direct proof for the role of hypoxia in ESFT metastases formation and disease progression. It will also establish a model that allows for testing factors already implicated in hypoxia-induced metastases formation, such as NPY, and identifying novel molecules involved in this process. This, in turn, will significantl improve our understanding of the metastatic processes in ESFT and address one of the most critical, yet understudied problems in its biology. In the future, this may result in the development of novel therapeutic strategies and prognostic factors, directly benefitting ESFT patients.
Ewing's sarcoma is one of the most aggressive pediatric solid tumors. The presence of metastases at diagnosis is associated with poor clinical outcome of the disease, as manifested by dramatic difference in event-free survival for patients with localized and metastatic tumors (72% and 27%, respectively). Here, we propose a study designed to elucidate mechanisms underlying Ewing's sarcoma metastases formation, the understanding of which is vital for designing therapies targeting the metastatic disease and preventing its further dissemination.
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