Microenvironment-mediated regulation of cancer growth by the human RNASET2 oncosuppressor gene

The secreted, extracellular human RNASET2 protein belongs to an ancient ribonuclease family which is extremely conserved in evolutionary terms. Of note, secretion of human RNASET2 protein by cancer cells in the tumor microenvironment (TME) has been consistently involved in tumor suppression. Indeed, in both xenograft-based and syngeneic in vivo experimental mouse models, high tumor cell-derived RNASET2 expression was associated with a marked suppression of tumorigenic potential in vivo. Moreover, histological survey of RNASET2-suppressed tumors revealed a marked inflammatory infiltration represented by murine stromal cells belonging to the M1 oncosuppressive subclass of macrophages, thus suggesting a RNASET2-mediated non cell-autonomous role in cancer growth suppression. According to these data, early-stage tumor cells actively secreting RNASET2 would provide an “alarmin-like” danger signal within the microenvinonment, mainly (but likely non exclusively) addressed to cells belonging to the monocyte/macrophage lineage in order to trigger an effective oncosuppressive host immune response. To validate in vitro the role of RNASET2 in macrophage differentiation and polarization previously observed in vivo, we present preliminary data on the functional interaction between the human promyelocytic THP-1 cell line and 22Rv1 human prostate cancer cells that were previously engineered to modulate their expression level of endogenous RNASET2 protein. Though preliminary, our data provide a further confirmation of the ability of human RNASET2 to affect human macrophage’s differentiation and polarization pattern in in vitro experimental settings.