The influence of the extracellular RNA/RNase system on humoral and cellular reactions at the tumor-vessel interface
Final Report Abstract
Extracellular RNA (eRNA), released from cells under pathological conditions, has been shown to act as prothrombotic and proangiogenic factor and further to induce vascular endothelial growth factor (VEGF)-dependent hyperpermeability and proinflammatory activities in vivo and in vitro. Human pancreatic-type RNase1, constitutively expressed in endothelial cells and also stored in Weibel-Palade bodies, served as natural counterpart of eRNA in the vascular system, and pretreatment with exogenous RNase1 reduced the (pathological) activities of eRNA, thereby exhibiting a prominent vessel-protective function. Tumor cells released larger amounts of eRNA (mostly microparticle-associated ribosomal RNA) into the cell supernatants as compared to non-tumor cells, and eRNA induced the adhesion of tumor cells to the endothelium via activation of the VEGF/VEGF-R2. Accordingly, application of RNase1 in an experimental mouse tumor model reduced tumor growth and weight as well as vessel density. In vitro studies further demonstrated that eRNA induced the release of TNF-α from monocytes and macrophages, which involved activation of the sheddase TNF-α-converting enzyme (TACE). These results indicate that eRNA released from tumor cells or damaged tissue might induce tumor growth and metastatic invasion of tumor cells directly in a VEGF-dependent manner and additionally by the mobilization of cytokines from monocytes and/or macrophages by a new proteolytic mechanism. Thus, therapeutic intervention with RNase1 could provide a novel protective regimen against tumor spread.
