Extracellular RNA Liberates Tumor Necrosis Factor-a to Promote Tumor Cell Trafficking and Progression

Extracellular RNA (eRNA) released from injured cells promotes tissue permeability, thrombosis and inflammation in vitro and in vivo, and RNase1 pretreatment can reduce all these effects. In this study, we investigated the role of the eRNA/RNase1 system in tumor progression and metastasis. Under quiescent and stimulatory conditions, tumor cells released much higher levels of eRNA than non-tumor cells. In glioblastomas, eRNA was detected at higher levels in tumors than non-tumor tissue. eRNA induced tumor cells to adhere to and migrate through human cerebral microvascular endothelial cells (HCMEC/D3), in a manner requiring activation of Vascular Endothelial Growth Factor (VEGF) signaling. Additionally, eRNA liberated tumor necrosis factor- α (TNF-α) from macrophages in a manner requiring activation of the TNF-α-converting enzyme TACE. Accordingly, supernatants derived from eRNA-treated macrophages enhanced tumor cell adhesion to HCMEC/D3. TNF-α release evoked by eRNA relied upon signaling activation of MAP kinases and the NF-κB pathway. In subcutaneous xenograft models of human cancer, administration of RNase1 but not DNase decreased tumor volume and weight. Taken together, these results suggest that eRNA released from tumor cells has the capacity to promote tumor cell invasion through endothelial barriers by both direct and indirect mechanisms, including through a mechanism involving TNF-α release from tumor-infiltrating monocytes/macrophages. Our findings establish a crucial role for eRNA in driving tumor progression, and they suggest applications for extracellular RNase1 as an anti-invasive regimen for cancer treatment.