Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation
Autor: | Marieke L. Kuijjer, Jason Ellul, Dale W. Garsed, Maya Kansara, Huei San Leong, Sophie Popkiss, Carl R. Walkley, Rod Hicks, Puiyi Pang, Mark J. Smyth, Philip W. Hinds, Carleen Cullinane, Anne-Marie Cleton-Jansen, Nicole M. Haynes, Dan Mei Lin, David Thomas |
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Rok vydání: | 2013 |
Předmět: |
Senescence
Neoplasms Radiation-Induced Tumor suppressor gene Bone Neoplasms Retinoblastoma Protein Mice medicine Animals Humans Genes Retinoblastoma Immunologic Surveillance Cellular Senescence Osteosarcoma Osteoblasts biology Interleukin-6 Retinoblastoma Calcium Radioisotopes Retinoblastoma protein General Medicine Prognosis medicine.disease Pediatric cancer eye diseases Neoplasm Proteins Mice Inbred C57BL Immunosurveillance Phenotype Immunology Cancer research biology.protein Cytokines Intercellular Signaling Peptides and Proteins Natural Killer T-Cells RNA Interference Cell aging Neoplasm Transplantation Research Article |
Zdroj: | Journal of Clinical Investigation, 123(12), 5351-5360 |
ISSN: | 0021-9738 |
Popis: | Ionizing radiation (IR) and germline mutations in the retinoblastoma tumor suppressor gene (RB1) are the strongest risk factors for developing osteosarcoma. Recapitulating the human predisposition, we found that Rb1+/- mice exhibited accelerated development of IR-induced osteosarcoma, with a latency of 39 weeks. Initial exposure of osteoblasts to carcinogenic doses of IR in vitro and in vivo induced RB1-dependent senescence and the expression of a panel of proteins known as senescence-associated secretory phenotype (SASP), dominated by IL-6. RB1 expression closely correlated with that of the SASP cassette in human osteosarcomas, and low expression of both RB1 and the SASP genes was associated with poor prognosis. In vivo, IL-6 was required for IR-induced senescence, which elicited NKT cell infiltration and a host inflammatory response. Mice lacking IL-6 or NKT cells had accelerated development of IR-induced osteosarcomas. These data elucidate an important link between senescence, which is a cell-autonomous tumor suppressor response, and the activation of host-dependent cancer immunosurveillance. Our findings indicate that overcoming the immune response to senescence is a rate-limiting step in the formation of IR-induced osteosarcoma. |
Databáze: | OpenAIRE |
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