RESUMEN
Osteosarcomas are bone tumors that frequently metastasize to the lung. Aberrant expression of the transcription factor, runt-related transcription factor 2 (RUNX2), is a key pathological feature in osteosarcoma and associated with loss of p53 and miR-34 expression. Elevated RUNX2 may transcriptionally activate genes mediating tumor progression and metastasis, including the RUNX2 target gene osteopontin (OPN/SPP1). This gene encodes a secreted matricellular protein produced by osteoblasts to regulate bone matrix remodeling and tissue calcification. Here we investigated whether and how the RUNX2/OPN axis regulates lung metastasis of osteosarcoma. Importantly, RUNX2 depletion attenuates lung metastasis of osteosarcoma cells in vivo. Using next-generation RNA-sequencing, protein-based assays, as well as the loss- and gain-of-function approaches in selected osteosarcoma cell lines, we show that osteopontin messenger RNA levels closely correlate with RUNX2 expression and that RUNX2 controls the levels of secreted osteopontin. Elevated osteopontin levels promote heterotypic cell-cell adhesion of osteosarcoma cells to human pulmonary microvascular endothelial cells, but not in the presence of neutralizing antibodies. Collectively, these findings indicate that the RUNX2/OPN axis regulates the ability of osteosarcoma cells to attach to pulmonary endothelial cells as a key step in metastasis of osteosarcoma cells to the lung.
Asunto(s)
Neoplasias Óseas/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Invasividad Neoplásica , Osteopontina/metabolismo , Osteosarcoma/metabolismo , Animales , Neoplasias Óseas/patología , Adhesión Celular/fisiología , Línea Celular Tumoral , Células Endoteliales/metabolismo , Xenoinjertos , Humanos , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos NOD , Ratones SCID , Osteosarcoma/secundarioRESUMEN
OBJECTIVE: The aim of this study was to analyze the survival of children with Wilms tumor and other malignant renal tumors treated with the TWPINDA-99 protocol. MATERIALS AND METHODS: Between January 1999 and December 2013, 226 patients were registered on this trial, based on National Wilms Tumor Study-5. Patient characteristics and survival were evaluated. RESULTS: Two hundred seven patients were diagnosed with Wilms tumor, which represented 91.6% of renal tumors. The male to female ratio was 0.7:1. The median age at diagnosis was 3.3 years. Stage III was the most frequent (39.2%). Metastatic disease was present in 16.7% of the cases. Synchronous bilateral disease was observed in 9.3% of the cases. Favorable histology was diagnosed in 93.6% and anaplastic histology in 6.4% of the patients. Median follow-up was 7.5 years. Ten-year event-free survival and overall survival (OS) for assessable patients with Wilms tumor (n=192) were 82.0% and 89.9%, respectively. OS for patients with stage I was 100% (n=36), stage II: 97.1% (n=35), stage III: 88.6% (n=71), stage IV: 77.9% (n=32), and stage V: 80.8% (n=18). OS for favorable histology (n=180) and anaplastic histology tumors (n=12) were 91.0% and 72.9%, respectively. Other malignant renal tumors had a poorer survival. CONCLUSION: Prognosis for patients with Wilms tumor treated on TWPINDA-99 seems to be better than previous national trials and is similar to developed countries.