Title: Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation
Authors: Kansara, M
Leong, HS
Lin, DM
Popkiss, S
Pang, PY
Garsed, DW
Walkley, CR
Cullinane, C
Ellul, J
Haynes, NM
Hicks, R
Kuijjer, ML
Cleton-Jansen, AM
Hinds, PW
Smyth, MJ
Thomas, DM
Issue Year: 2013
Publisher AMER SOC CLINICAL INVESTIGATION INC
Series JOURNAL OF CLINICAL INVESTIGATION: 123(12): 5351-5360
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 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.
URI: https://publications.svi.edu.au/publications/1702
ISSN 0021-9738
Other Identifiers 10.1172/JCI70559
Publication type Article
Grant ID GNT0559016; GNT0559019
Find it online http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859382/