title: Non-cell-autonomous tumor suppression: oncogene-provoked apoptosis promotes tumor cell senescence via stromal crosstalk.
abstract: Activated oncogenes evoke cellular fail-safe programs such as apoptosis, senescence, or autophagy to protect the organism from the expansion of damaged and potentially harmful cells. Non-cell-autonomous interactions between tumor cells and nonmalignant bystander cells add to cell-autonomous modes of tumor suppression during tumor development and progression. In particular, the role of stroma or host immune cells converting tumor-generated signals into a response that feeds back to the tumor cell population has been experimentally underappreciated. Using the Eμ-myc transgenic mouse lymphoma model, we elucidated how constitutive Myc signaling indirectly promotes cellular senescence via cytokines that were released by nonmalignant cells in response to oncogene-evoked cell-autonomous effects. Specifically, Myc primarily promotes apoptosis in a subset of the tumor cell population, leading to the attraction of macrophages, which subsequently engulf the apoptotic remainders. Phagocytosis-activated macrophages, in turn, exhibit strongly increased secretion of various cytokines, among them transforming growth factor beta to an extent that is capable of inducing cellular senescence in surrounding malignant cells. Our findings, recapitulated in human aggressive B-cell lymphomas, unveil that apoptosis and senescence are not simply two context-dependent cell-autonomous choices of stress responses, but rather cooperate via extracellular mediators-namely cells of the innate immune system-to profoundly limit tumorigenesis in vivo. A deeper mechanistic understanding of the organismic interconnection between different fail-safe programs will help to identify cellular components of the tumor stroma and their signal mediators that are readily available to impose a second line of host defense against cancer cells. This will open new perspectives for the development of antineoplastic therapies, whose targets not only encompass tumor but also stroma cell populations.
authors: Charité-Universitätsmedizin Berlin/Molekulares Krebsforschungszentrum der Charité-MKFZ, 13353 Berlin, Germany.
authors: Maurice
authors: M
authors: Reimann
authors: Clemens A
authors: CA
authors: Schmitt
authors: Soyoung
authors: S
authors: Lee
references: J Cell Sci. 2005 Feb 1;118(Pt 3):485-96
references: 15657080
references: Oncogene. 2008 Oct 6;27(45):5932-43
references: 18836474
references: J Leukoc Biol. 2002 Sep;72(3):417-28
references: 12223508
references: Nat Rev Immunol. 2006 Nov;6(11):836-48
references: 17063185
references: Nat Rev Immunol. 2003 Jan;3(1):23-35
references: 12511873
references: Nat Rev Cancer. 2003 Apr;3(4):286-95
references: 12671667
references: Genes Dev. 2009 Apr 1;23(7):798-803
references: 19279323
references: Cancer Cell. 2010 Mar 16;17(3):262-72
references: 20227040
references: Nat Cell Biol. 2006 Oct;8(10):1124-32
references: 16998475
references: Gene Ther. 2000 Feb;7(3):255-62
references: 10694803
references: Cell. 2009 Jul 23;138(2):286-99
references: 19632179
references: J Biol Chem. 2006 Oct 6;281(40):29568-74
references: 16880208
references: J Exp Med. 2008 Jun 9;205(6):1261-8
references: 18490490
references: J Immunol. 2001 May 1;166(9):5374-80
references: 11313373
references: Annu Rev Pathol. 2010;5:99-118
references: 20078217
references: Blood. 2007 Oct 15;110(8):2996-3004
references: 17562874
references: Eur J Cancer. 2006 Apr;42(6):717-27
references: 16520032
references: Br Med J. 1957 Apr 6;1(5022):779-86
references: 13404306
references: Immunity. 2003 Jan;18(1):1-6
references: 12530970
references: J Biol Chem. 1999 Dec 3;274(49):35053-8
references: 10574984
references: Nature. 2009 Oct 1;461(7264):659-63
references: 19794494
references: Cell. 1997 Mar 7;88(5):593-602
references: 9054499
references: Cancer Cell. 2005 Nov;8(5):369-80
references: 16286245
references: Nature. 2001 Apr 26;410(6832):1107-11
references: 11323675
references: N Engl J Med. 2004 Nov 18;351(21):2159-69
references: 15548776
references: Cell. 2003 Jun 13;113(6):717-30
references: 12809603
references: N Engl J Med. 2008 Nov 27;359(22):2313-23
references: 19038878
references: Trends Immunol. 2004 Dec;25(12):677-86
references: 15530839
references: Immunity. 2005 Mar;22(3):371-83
references: 15780993
references: J Immunol. 2007 Feb 15;178(4):1975-9
references: 17277099
references: Genes Dev. 2010 Jun 15;24(12):1281-94
references: 20551174
references: Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12072-7
references: 11593017
references: Cell. 2008 Jun 13;133(6):1019-31
references: 18555778
references: Biochem Soc Trans. 2004 Nov;32(Pt 5):785-8
references: 15494015
references: Cell. 2008 Jul 25;134(2):215-30
references: 18662538
references: Nat Rev Mol Cell Biol. 2007 Sep;8(9):741-52
references: 17717517
references: Cell. 2008 Jun 13;133(6):1006-18
references: 18555777
references: J Immunol. 2005 Jan 15;174(2):636-45
references: 15634881
references: Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15231-6
references: 15477587
references: Nature. 2005 Aug 4;436(7051):660-5
references: 16079837
references: Pathol Int. 2008 Aug;58(8):529-32
references: 18705775
references: Cancer Cell. 2005 Mar;7(3):211-7
references: 15766659
references: Cell. 2004 Apr 16;117(2):211-23
references: 15084259
references: Cancer Res. 2005 Apr 15;65(8):3437-46
references: 15833879
references: Cell. 2008 Feb 8;132(3):363-74
references: 18267069
references: Cell. 2000 Jan 7;100(1):57-70
references: 10647931
references: Br J Cancer. 2006 Aug 7;95(3):272-81
references: 16832418
references: Nature. 2007 Feb 8;445(7128):656-60
references: 17251933
references: Science. 1992 Jul 10;257(5067):212-4
references: 1378649
references: Curr Opin Immunol. 2007 Apr;19(2):203-8
references: 17292599
references: Cell Death Differ. 2010 Apr;17(4):616-23
references: 20075940
references: Cell. 1992 Apr 3;69(1):119-28
references: 1555236
references: Cell. 2007 Mar 9;128(5):931-46
references: 17350577
references: Cancer Cell. 2010 Nov 16;18(5):485-98
references: 21035406