title: The role of CD95 and CD95 ligand in cancer.
abstract: CD95 (Fas/APO-1) and its ligand, CD95L, have long been viewed as a death receptor/death ligand system that mediates apoptosis induction to maintain immune homeostasis. In addition, these molecules are important in the immune elimination of virus-infected cells and cancer cells. CD95L was, therefore, considered to be useful for cancer therapy. However, major side effects have precluded its systemic use. During the last 10 years, it has been recognized that CD95 and CD95L have multiple cancer-relevant nonapoptotic and tumor-promoting activities. CD95 and CD95L were discovered to be critical survival factors for cancer cells, and were found to protect and promote cancer stem cells. We now discuss five different ways in which inhibiting or eliminating CD95L, rather than augmenting, may be beneficial for cancer therapy alone or in combination with standard chemotherapy or immune therapy.
authors: Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors: M E
authors: ME
authors: Peter
authors: Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors: A
authors: A
authors: Hadji
authors: Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors: A E
authors: AE
authors: Murmann
authors: Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors: S
authors: S
authors: Brockway
authors: Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors: W
authors: W
authors: Putzbach
authors: Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors: A
authors: 0000000158226430
authors: A
authors: Pattanayak
authors: Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors: P
authors: P
authors: Ceppi
mesh_terms: D017209:Apoptosis; D053222:Fas Ligand Protein / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D007107:Immune System / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D034622:RNA Interference; D015398:Signal Transduction; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; D019014:fas Receptor
references: Cell. 2009 Aug 7;138(3):592-603
references: 19665978
references: Nat Med. 2009 Sep;15(9):1010-2
references: 19734877
references: Cell. 2007 May 4;129(3):447-50
references: 17482535
references: Clin Cancer Res. 2000 Sep;6(9):3576-80
references: 10999747
references: Immunity. 2009 Feb 20;30(2):180-92
references: 19239902
references: J Immunol. 2004 Feb 15;172(4):2118-25
references: 14764677
references: Cancer Gene Ther. 2003 Dec;10(12):870-8
references: 14712313
references: Cell Rep. 2014 Apr 10;7(1):208-22
references: 24656822
references: Gastroenterology. 2009 Sep;137(3):934-44, 944.e1-4
references: 19524576
references: Urol Int. 2013;91(4):456-61
references: 23948854
references: Nat Med. 2000 Aug;6(8):920-3
references: 10932231
references: World J Gastroenterol. 2005 Jun 21;11(23):3632-5
references: 15962391
references: Nature. 1997 Jul 10;388(6638):190-5
references: 9217161
references: Eur J Haematol. 2001 May;66(5):342-6
references: 11422415
references: J Exp Med. 1999 Dec 20;190(12):1879-90
references: 10601362
references: Asian Pac J Cancer Prev. 2013;14(1):281-5
references: 23534738
references: Int Immunol. 2000 Apr;12(4):555-62
references: 10744657
references: Cancer. 2001 Jul 15;92(2):287-93
references: 11466681
references: Int J Cancer. 2000 Mar 20;89(2):127-32
references: 10754489
references: Gynecol Oncol. 2002 Mar;84(3):443-8
references: 11855885
references: Adv Exp Med Biol. 1999;457:251-8
references: 10500800
references: Oncogene. 2013 Feb 28;32(9):1183-92
references: 22508480
references: World J Gastroenterol. 2003 Jul;9(7):1415-20
references: 12854132
references: Nat Med. 2005 Jan;11(1):63-70
references: 15619626
references: J Clin Invest. 2001 Jul;108(1):51-62
references: 11435457
references: Clin Cancer Res. 2006 Jun 15;12(12):3705-12
references: 16778096
references: Int Immunol. 1996 Mar;8(3):423-31
references: 8671629
references: Cancer Biother Radiopharm. 2002 Oct;17(5):563-7
references: 12470426
references: J Pathol. 1999 Nov;189(3):378-86
references: 10547600
references: Science. 2000 Jun 30;288(5475):2354-7
references: 10875918
references: Cell Death Differ. 2003 Jan;10(1):26-35
references: 12655293
references: Cancer. 2002 May 15;94(10):2552-60
references: 12173320
references: Nature. 1994 Aug 25;370(6491):650-2
references: 7520535
references: Oncogene. 2003 May 8;22(18):2795-804
references: 12743602
references: Gastroenterology. 2008 May;134(5):1494-506
references: 18471522
references: J Clin Virol. 2005 Oct;34(2):140-6
references: 16157266
references: N Engl J Med. 2012 Jun 28;366(26):2443-54
references: 22658127
references: Cell Death Differ. 2015 Jul;22(7):1192-202
references: 25613377
references: EMBO Rep. 2004 Nov;5(11):1084-9
references: 15514680
references: Stem Cells. 2004;22(1):51-64
references: 14688391
references: Clin Cancer Res. 2013 Jan 15;19(2):462-8
references: 23169436
references: Nature. 2011 Mar 24;471(7339):523-6
references: 21430781
references: Int J Oncol. 2001 Jun;18(6):1157-62
references: 11351245
references: FASEB J. 2005 Apr;19(6):620-2
references: 15670977
references: Nat Med. 2000 May;6(5):529-35
references: 10802708
references: PLoS One. 2013;8(7):e69024
references: 23894399
references: Inflamm Bowel Dis. 2010 Jun;16(6):1063-70
references: 20049944
references: Cancer Res. 2000 Feb 15;60(4):822-8
references: 10706087
references: Nat Rev Cancer. 2002 Apr;2(4):277-88
references: 12001989
references: Nature. 1992 Mar 26;356(6367):314-7
references: 1372394
references: PLoS One. 2012;7(11):e49636
references: 23166734
references: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11400-5
references: 17600087
references: J Exp Med. 1991 Mar 1;173(3):647-58
references: 1900079
references: Cell Cycle. 2014;13(9):1373-8
references: 24690893
references: J Immunol. 1999 Oct 15;163(8):4462-72
references: 10510388
references: Ann Hematol. 2010 Sep;89(9):889-96
references: 20352431
references: Cell. 1994 Mar 25;76(6):969-76
references: 7511063
references: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13820-5
references: 19666588
references: Apoptosis. 2003 Mar;8(2):151-60
references: 12766475
references: Medscape J Med. 2008;10(6):130
references: 18679533
references: Clin Cancer Res. 2000 Jun;6(6):2448-55
references: 10873098
references: Nat Immunol. 2000 Dec;1(6):489-95
references: 11101870
references: J Exp Med. 1996 Feb 1;183(2):657-61
references: 8627178
references: J Biol Chem. 2014 Apr 18;289(16):11522-35
references: 24627480
references: J Clin Invest. 2010 Jan;120(1):41-50
references: 20051635
references: Clin Cancer Res. 2002 Jun;8(6):1843-8
references: 12060626
references: Int J Cancer. 2008 Apr 15;122(8):1716-21
references: 18092329
references: Int J Androl. 2009 Apr;32(2):123-30
references: 17916181
references: Clin Cancer Res. 1999 Sep;5(9):2464-9
references: 10499620
references: Cell. 1997 Feb 7;88(3):355-65
references: 9039262
references: Oncol Rep. 2001 Mar-Apr;8(2):311-4
references: 11182046
references: Cell. 2007 Dec 14;131(6):1109-23
references: 18083101
references: Eur Rev Med Pharmacol Sci. 2012 Dec;16(15):2044-50
references: 23280017
references: Genes Dev. 2008 Apr 1;22(7):894-907
references: 18381893
references: EMBO J. 1997 May 15;16(10):2794-804
references: 9184224
references: J Immunol. 1998 Jul 15;161(2):897-908
references: 9670968
references: Cancer. 2000 Dec 15;89(12):2560-4
references: 11135216
references: Nature. 2009 Oct 1;461(7264):659-63
references: 19794494
references: Cell Death Differ. 2006 Jan;13(1):31-40
references: 16003386
references: Cancer Immunol Immunother. 1998 Oct;47(2):65-71
references: 9769114
references: J Exp Med. 1993 Jan 1;177(1):195-200
references: 7678113
references: Eur J Cancer. 2013 Aug;49(12):2734-46
references: 23582741
references: J Exp Med. 1998 Apr 20;187(8):1205-13
references: 9547332
references: Int J Oral Maxillofac Surg. 2000 Oct;29(5):360-5
references: 11071240
references: J Neurooncol. 2003 Aug-Sep;64(1-2):55-61
references: 12952286
references: Carcinogenesis. 2014 Jan;35(1):173-83
references: 23929433
references: Immunity. 1994 Aug;1(5):357-64
references: 7533644
references: Eur J Immunol. 2000 Mar;30(3):725-31
references: 10741386
references: Mol Cell. 2010 Jun 25;38(6):908-15
references: 20620960
references: J Exp Med. 1996 Sep 1;184(3):1075-82
references: 9064324
references: Folia Histochem Cytobiol. 2007;45(2):87-91
references: 17597021
references: Breast Cancer Res Treat. 1999 Apr;54(3):245-53
references: 10445423
references: Urology. 2001 Sep;58(3):471-6
references: 11549508
references: Am J Hematol. 2006 May;81(5):307-14
references: 16628716
references: Oncogene. 2001 Sep 13;20(41):5865-77
references: 11593392
references: Exp Cell Res. 2000 Apr 10;256(1):42-9
references: 10739650
references: Eur J Surg Oncol. 2002 Mar;28(2):120-5
references: 11884046
references: Cell Stem Cell. 2012 Jun 14;10(6):717-28
references: 22704512
references: Med Oncol. 2012 Sep;29(3):2046-52
references: 21528407
references: Cell. 2008 May 16;133(4):704-15
references: 18485877
references: J Exp Med. 1993 Dec 1;178(6):2231-5
references: 7504062
references: Cancer. 2013 Apr 15;119(8):1503-11
references: 23340930
references: N Engl J Med. 2013 Jul 11;369(2):134-44
references: 23724846
references: PLoS Biol. 2011 Jun;9(6):e1001090
references: 21713032
references: Nat Genet. 1995 Nov;11(3):294-300
references: 7581453
references: Br J Cancer. 2000 Apr;82(8):1446-52
references: 10780525
references: Nature. 1993 Aug 26;364(6440):806-9
references: 7689176
references: J Exp Med. 1999 Dec 20;190(12):1891-6
references: 10601363
references: Apoptosis. 2008 Jan;13(1):41-51
references: 17955374
references: Cancer Lett. 2011 Feb 28;301(2):203-11
references: 21196076
references: Science. 1994 Jul 22;265(5171):528-30
references: 7518614
references: Am J Pathol. 2003 Apr;162(4):1139-49
references: 12651606
references: Gastric Cancer. 2001;4(4):198-205
references: 11846063
references: Eur J Cancer. 1999 Oct;35(10):1462-5
references: 10673978
references: J Immunol. 2009 Mar 15;182(6):3801-8
references: 19265159
references: Anticancer Res. 2007 Nov-Dec;27(6B):4083-6
references: 18225575
references: Am J Clin Pathol. 2005 Jun;123(6):879-85
references: 15899779
references: Lung Cancer. 2006 May;52(2):241-7
references: 16529843
references: Nat Med. 1996 Mar;2(3):317-22
references: 8612231
references: Nat Cell Biol. 2003 Feb;5(2):118-25
references: 12545171
references: J Hematother Stem Cell Res. 2001 Dec;10(6):759-68
references: 11798502
references: Cancer Res. 2013 Nov 15;73(22):6711-21
references: 24072745
references: Int J Immunopathol Pharmacol. 2005 Jan-Mar;18(1):59-64
references: 15698511
references: Cytokine Growth Factor Rev. 2003 Feb;14(1):53-66
references: 12485619
references: J Biol Chem. 2011 Jul 15;286(28):24776-84
references: 21613217
references: J Immunol. 2012 Jun 15;188(12):5954-61
references: 22573809
references: Int Rev Immunol. 1994;11(3):193-210
references: 7930845
references: Br J Cancer. 2005 Sep 5;93(5):544-51
references: 16091761
references: J Biol Chem. 2004 Nov 5;279(45):46742-7
references: 15345718
references: EMBO Rep. 2011 Sep;12(9):931-7
references: 21760611
references: Nature. 2001 Nov 1;414(6859):105-11
references: 11689955
references: J Biol Chem. 2006 Jan 20;281(3):1840-52
references: 16306044
references: Proc Natl Acad Sci U S A. 1994 May 10;91(10):4185-9
references: 7514297
references: Annu Rev Genet. 1999;33:29-55
references: 10690403
references: J Biol Chem. 2012 Jun 8;287(24):20664-73
references: 22535954
references: Pediatr Hematol Oncol. 2005 Apr-May;22(3):247-56
references: 16020109
references: Br J Cancer. 1999 Mar;79(7-8):1262-9
references: 10098769
references: Nat Med. 2014 Jun;20(6):607-15
references: 24793239
references: J Clin Pathol. 2006 Jan;59(1):101-4
references: 16394289
references: Cell Stem Cell. 2009 Aug 7;5(2):178-90
references: 19664992
references: Gastroenterology. 2010 Jun;138(7):2357-67
references: 20188103
references: Nature. 1994 May 5;369(6475):31-7
references: 8164737
references: J Biol Chem. 2002 Dec 6;277(49):47826-33
references: 12324452
references: Eur J Haematol. 2006 Jun;76(6):465-72
references: 16494623
references: Cancer Res. 2003 Sep 1;63(17):5573-81
references: 14500397
references: Br J Cancer. 2001 Sep 28;85(7):1047-54
references: 11592778
references: BMC Cancer. 2009;9:202
references: 19555472
references: Cancer Res. 2003 Jul 15;63(14):4095-100
references: 12874012
references: J Pathol. 2000 Jan;190(1):20-30
references: 10640988
references: Leukemia. 1999 Nov;13(11):1854-8
references: 10557062
references: Oncology. 2003;65(1):83-8
references: 12837986
references: Nature. 2000 Oct 12;407(6805):789-95
references: 11048730
references: Biochim Biophys Acta. 2005 May 25;1755(1):25-36
references: 15907590
references: Cancer Cell. 2008 Mar;13(3):235-48
references: 18328427
references: Nat Commun. 2014;5:5238
references: 25366259
references: EMBO J. 2004 Aug 4;23(15):3175-85
references: 15272306
references: Cell Death Dis. 2014;5:e1444
references: 25299769
references: Mol Clin Oncol. 2015 Jan;3(1):151-156
references: 25469286
references: Gut. 2005 May;54(5):661-5
references: 15831912
references: J Exp Med. 2002 Oct 21;196(8):1105-11
references: 12391022
references: Cancer Cell. 2008 Oct 7;14(4):324-34
references: 18835034
references: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11445-50
references: 14504390
references: J Immunol. 1994 Feb 1;152(3):1127-33
references: 7507960
references: Int J Oncol. 2002 Feb;20(2):291-7
references: 11788891
references: J Hepatol. 2010 Dec;53(6):1069-77
references: 20832890
references: Nature. 2010 May 27;465(7297):492-6
references: 20505730
references: Urol Int. 2012;88(3):263-70
references: 22398398
references: Cancer Immunol Immunother. 2005 Nov;54(11):1127-36
references: 15889255
references: Anticancer Res. 2011 Dec;31(12):4507-12
references: 22199323
references: J Gastrointest Cancer. 2012 Jun;43(2):224-8
references: 21271302
references: J Immunol. 2000 Apr 1;164(7):3645-51
references: 10725721
references: Cell Cycle. 2004 Oct;3(10):1235-9
references: 15467462
references: Int J Cancer. 1999 Jun 21;84(3):239-43
references: 10371340
references: Mol Cell Biol. 2002 Jan;22(1):207-20
references: 11739735
references: Virchows Arch. 2008 Jan;452(1):65-74
references: 18000680
references: Trends Mol Med. 2013 Jun;19(6):329-35
references: 23540716
references: N Engl J Med. 2012 Jun 28;366(26):2455-65
references: 22658128
references: Nat Med. 1998 Jan;4(1):31-6
references: 9427603
references: Mol Cell Biol. 2003 May;23(10):3623-35
references: 12724420
references: Mol Cancer. 2010;9:161
references: 20573240
references: Annu Rev Immunol. 2006;24:321-52
references: 16551252