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Immune response to rb1-regulated senescence limits radiation-Induced osteosarcoma formation
Kansara, Maya Leong, Huei San Lin, Dan Mei Popkiss, Sophie Pang, Puiyi Garsed, Dale W. Walkley, Carl R. Cullinane, Carleen Ellul, Jason Haynes, Nicole M.
Kansara, Maya
Leong, Huei San
Lin, Dan Mei
Popkiss, Sophie
Pang, Puiyi
Garsed, Dale W.
Walkley, Carl R.
Cullinane, Carleen
Ellul, Jason
Haynes, Nicole M.
Abstract
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.
Keywords
Date
2013
Type
Journal article
Journal
Journal of Clinical Investigation
Book
Volume
123
Issue
12
Page Range
5351-5360
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
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DOI
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Open Access Status
License
File Access
Controlled