期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 12, 页码 5351-5360出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI70559
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资金
- Sarcoma Foundation of America
- National Health and Medical Research Council (NHMRC)
- Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH
- Victorian Cancer Agency
- NHMRC Senior Research Fellowship
- NHMRC Australia Fellowship
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 RBI-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.
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