Publication Date:
2013-02-05
Description:
Cancer control by adaptive immunity involves a number of defined death and clearance mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-gamma (IFN-gamma) requires additional undefined mechanisms that arrest cancer cell proliferation. Here we show that the combined action of the T-helper-1-cell cytokines IFN-gamma and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence, we used a mouse model in which the Simian virus 40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumours by attenuating p53- and Rb-mediated cell cycle control. When combined, IFN-gamma and TNF drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16INK4a (also known as CDKN2A), and downstream Rb hypophosphorylation at serine 795. This cytokine-induced senescence strictly requires STAT1 and TNFR1 (also known as TNFRSF1A) signalling in addition to p16INK4a. In vivo, Tag-specific T-helper 1 cells permanently arrest Tag-expressing cancers by inducing IFN-gamma- and TNFR1-dependent senescence. Conversely, Tnfr1(-/-)Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-gamma and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Braumuller, Heidi -- Wieder, Thomas -- Brenner, Ellen -- Assmann, Sonja -- Hahn, Matthias -- Alkhaled, Mohammed -- Schilbach, Karin -- Essmann, Frank -- Kneilling, Manfred -- Griessinger, Christoph -- Ranta, Felicia -- Ullrich, Susanne -- Mocikat, Ralph -- Braungart, Kilian -- Mehra, Tarun -- Fehrenbacher, Birgit -- Berdel, Julia -- Niessner, Heike -- Meier, Friedegund -- van den Broek, Maries -- Haring, Hans-Ulrich -- Handgretinger, Rupert -- Quintanilla-Martinez, Leticia -- Fend, Falko -- Pesic, Marina -- Bauer, Jurgen -- Zender, Lars -- Schaller, Martin -- Schulze-Osthoff, Klaus -- Rocken, Martin -- England -- Nature. 2013 Feb 21;494(7437):361-5. doi: 10.1038/nature11824. Epub 2013 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Dermatology, Eberhard Karls University, Liebermeister Strasse 25, 72076 Tubingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23376950" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigens, Polyomavirus Transforming/genetics/metabolism
;
Cell Aging/*immunology
;
Cell Cycle
;
Cell Proliferation
;
Cyclin-Dependent Kinase Inhibitor p16/deficiency/genetics/metabolism
;
Cytokines/*immunology
;
Disease Models, Animal
;
Disease Progression
;
Female
;
Humans
;
Interferon-gamma/immunology
;
Male
;
Mice
;
Mice, Inbred NOD
;
Mice, SCID
;
Mice, Transgenic
;
Neoplasms/*immunology/*pathology
;
Oncogenes/genetics
;
Phosphoserine/metabolism
;
Receptors, Tumor Necrosis Factor, Type I/metabolism
;
Retinoblastoma Protein/chemistry/metabolism
;
STAT1 Transcription Factor/metabolism
;
Th1 Cells/*immunology
;
Time Factors
;
Tumor Cells, Cultured
;
Tumor Necrosis Factor-alpha/immunology
;
Tumor Suppressor Protein p53/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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