Inhibition of Soluble Tumor Necrosis Factor Prevents Chemically Induced Carcinogenesis in Mice
| Autor: | Lazar Vujanovic, Nikola L. Vujanovic, Albert B. DeLeo, Fernando Concha-Benavente, Andrea Sobo-Vujanovic, Yan Lin, Robert L. Ferris |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
STAT3 Transcription Factor Cancer Research Carcinogenesis Immunology Drug Evaluation Preclinical Spleen Antineoplastic Agents Mice SCID medicine.disease_cause Article Immune tolerance 03 medical and health sciences chemistry.chemical_compound medicine Immune Tolerance Animals Molecular Targeted Therapy STAT3 biology Tumor Necrosis Factor-alpha Dendritic Cells Neoplasms Experimental Fusion protein Killer Cells Natural Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure chemistry Solubility Receptors Tumor Necrosis Factor Type I Methylcholanthrene Cancer research biology.protein Phosphorylation Cytokines Tumor necrosis factor alpha Female Gene Deletion |
| Zdroj: | Cancer immunology research. 4(5) |
| ISSN: | 2326-6074 |
| Popis: | TNF is a potent promoter of carcinogenesis and potentially important target for cancer prevention. TNF is produced as functionally distinct transmembrane and soluble molecules (tmTNF and sTNF, respectively), but their individual roles in carcinogenesis are unexplored. We investigated the participation of tmTNF and sTNF in chemically induced carcinogenesis in mice. We found that injection of XPro1595, a dominant-negative TNF biologic (DN-TNF) and specific antagonist of sTNF, decreased tumor incidence and growth, and prolonged survival of 3-methylcholanthrene (MCA)–injected mice. Similar results were obtained following the exclusion of both TNF forms by either TNF-receptor 2–Fc fusion protein (TNFR2-Fc) treatment or TNF gene deletion. In addition, gene deletion of TNFR1, which is preferentially triggered by sTNF, was temporarily blocked, whereas gene deletion of TNFR2, which is preferentially triggered by tmTNF, enhanced MCA-induced carcinogenesis. Concomitantly with carcinogenesis induction, MCA increased circulating IL1α, accumulation of myeloid-derived suppressor cells (MDSC), STAT3 phosphorylation, and immunosuppression in the spleen. In sharp contrast, DN-TNF treatment dramatically decreased IL1α and increased the essential immunoregulatory cytokines IL1β, IL12p70, and IL17 in the peripheral blood of MCA-injected mice. In addition, MDSC accumulation, STAT3 phosphorylation, and immunosuppression in MCA-injected mice were prevented by DN-TNF treatment, TNFR2-Fc treatment, and/or gene deletion of TNF or TNFR1, but not deletion of TNFR2. These findings reveal that sTNF is both an essential promoter of carcinogenesis and a pivotal regulator of MDSCs, and indicate that sTNF could be a significant target for cancer prevention and therapy. Cancer Immunol Res; 4(5); 441–51. ©2016 AACR. |
| Databáze: | OpenAIRE |
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