Microenvironmental control of malignancy exerted by RNASET2, a widely conserved extracellular RNase

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 3; pp. 1104 - 1109
• Main Authors: Acquati, Francesco, Bertilaccio, Sabrina, Grimaldi, Annalisa, Monti, Laura, Cinquetti, Raffaella, Bonetti, Paolo, Lualdi, Marta, Vidalino, Laura, Fabbri, Marco, Sacco, Maria Grazia, van Rooijen, Nico, Campomenosi, Paola, Vigetti, Davide, Passi, Alberto, Riva, Cristina, Capella, Carlo, Sanvito, Francesca, Doglioni, Claudio, Gribaldo, Laura, Macchi, Paolo, Sica, Antonio, Noonan, Douglas M., Ghia, Paolo, Taramelli, Roberto, Klein, George
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.01.2011; National Acad Sciences
• Subjects: Analysis of Variance; animal ovaries; Animals; Antibodies; Biological Sciences; Cancer; carcinogenesis; Cell growth; Cell Line, Tumor; Cell lines; cellular microenvironment; Chromosomes; Data processing; Epithelial cells; Female; gene expression regulation; Genes; Genotype & phenotype; Human subjects; Humans; Immunohistochemistry; In Situ Hybridization; in vitro studies; In Vitro Techniques; lymphocytes; Macrophages; Macrophages - immunology; Malignancy; Melanoma; Mice; Mice, Nude; Microenvironments; Monocytes; Natural killer cells; Neoplasia; Oncology; Ovarian cancer; ovarian neoplasms; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; phenotype; Ribonuclease; ribonucleases; Ribonucleases - genetics; Ribonucleases - immunology; Ribonucleic acid; RNA; suppressor genes; Transcription; Tumor cell line; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - immunology; Tumorigenesis; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1013746108

A recent body of evidence indicates an active role for stromal (mis)-regulation in the progression of neoplasias. Within this conceptual framework, genes belonging to the growing but still poorly characterized class of tumor antagonizing/malignancy suppressor genes (TAG/MSG) seem to play a crucial role in the regulation of the cross-talk between stromal and epithelial cells by controlling malignant growth in vivo without affecting any cancer-related phenotype in vitro. Here, we have functionally characterized the human RNASET2 gene, which encodes the first human member of the widespread Rh/T2/S family of extracellular RNases and was recently found to be down-regulated at the transcript level in several primary ovarian tumors or cell lines and in melanoma cell lines. Although we could not detect any activity for RNASET2 in several functional in vitro assays, a remarkable control of ovarian tumorigenesis could be detected in vivo. Moreover, the control of ovarian tumorigenesis mediated by this unique tumor suppressor gene occurs through modification of the cellular microenvironment and the induction of immunocompetent cells of the monocyte/macrophage lineage. Taken together, the data presented in this work strongly indicate RNASET2 as a previously unexplored member of the growing family of tumor-antagonizing genes.