How Do Cytotoxic Lymphocytes Kill Cancer Cells?

Clinical Cancer Research

Volumn 21, Issue 22, 2015, Pages 5047-5056

  Martínez Lostao, Luis ^a   Anel, Alberto ^a   Pardo, Julián ^a,b  

^a UNIVERSITY OF ZARAGOZA   (Spain)

^b Aragon ID Foundation   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

DEATH RECEPTOR; GRANZYME; PERFORIN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; PDCD1 PROTEIN, HUMAN; PROGRAMMED DEATH 1 RECEPTOR;

ARTICLE; CANCER CELL; CANCER IMMUNOTHERAPY; CELL DEATH; CELL KILLING; CELL SURVIVAL; CROSS PRESENTATION; CYTOTOXIC T LYMPHOCYTE; ENZYME ACTIVITY; EXOCYTOSIS; GENE DELETION; HUMAN; IMMUNE RESPONSE; IMMUNE SYSTEM; IMMUNOMODULATION; IMMUNOSURVEILLANCE; LYMPHOCYTE FUNCTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; ANTAGONISTS AND INHIBITORS; APOPTOSIS; CYTOTOXICITY; DRUG EFFECTS; IMMUNOLOGY; IMMUNOTHERAPY; NATURAL KILLER CELL; NEOPLASMS;

APOPTOSIS; CTLA-4 ANTIGEN; CYTOTOXICITY, IMMUNOLOGIC; HUMANS; IMMUNOTHERAPY; KILLER CELLS, NATURAL; NEOPLASMS; PROGRAMMED CELL DEATH 1 RECEPTOR; T-LYMPHOCYTES, CYTOTOXIC;

EID: 84954103951     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-15-0685     Document Type: Article

References (107)

1. Russell JH, Ley TJ. Lymphocyte-mediated cytotoxicity. Annu Rev Immunol 2002;20:323-70.
2. Bolitho P, Voskoboinik I, Trapani JA, Smyth MJ. Apoptosis induced by the lymphocyte effector molecule perforin. Curr Opin Immunol 2007;19: 339-47.
3. Fulda S. Promises and challenges of Smac mimetics as cancer therapeutics. Clin Cancer Res 2015;21:5030-6.
4. Gibson CJ, Davids MS. BCL-2 antagonism to target the intrinsic mitochondrial pathway of apoptosis. Clin Cancer Res 2015;21:5021-9.
5. Voskoboinik I, Whisstock JC, Trapani JA. Perforin and granzymes: Function, dysfunction and human pathology. Nat Rev Immunol 2015;15: 388-400.
6. Ewen CL, Kane KP, Bleackley RC. A quarter century of granzymes. Cell Death Differ 2011;19:28-35.
7. Pardo J, Aguilo JI, Anel A, Martin P, Joeckel L, Borner C, et al. The biology of cytotoxic cell granule exocytosis pathway: Granzymes have evolved to induce cell death and inflammation. Microbes Infect 2009;11:452-9.
8. Chowdhury D, Lieberman J. Death by a thousand cuts: Granzyme pathways of programmed cell death. Annu Rev Immunol 2008;26:389-420.
9. Zitvogel L, Kepp O, Senovilla L, Menger L, Chaput N, Kroemer G. Immunogenic tumor cell death for optimal anticancer therapy: The calreticulin exposure pathway. Clin Cancer Res 2010;16:3100-4.
10. Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med 2005;202:1691-701.
11. Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 2001;7:94-100.
12. Screpanti V, Wallin RP, Grandien A, Ljunggren HG. Impact of FASLinduced apoptosis in the elimination of tumor cells by NK cells. Mol Immunol 2005;42:495-9.
13. Anel A, Buferne M, Boyer C, Schmitt-Verhulst AM, Golstein P. T cell receptor-induced Fas ligand expression in cytotoxic T lymphocyte clones is blocked by protein tyrosine kinase inhibitors and cyclosporin A. Eur J Immunol 1994;24:2469-76.
14. Bossi G, Griffiths GM. CTL secretory lysosomes: Biogenesis and secretion of a harmful organelle. Semin Immunol 2005;17:87-94.
15. de Saint Basile G, Menasche G, Fischer A. Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat Rev Immunol 2010;10:568-79.
16. Voskoboinik I, Smyth MJ, Trapani JA. Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol 2006;6:940-52.
17. Krensky AM, Clayberger C. Biology and clinical relevance of granulysin. Tissue Antigens 2009;73:193-8.
18. Bovenschen N, Kummer JA. Orphan granzymes find a home. Immunol Rev 2010;235:117-27.
19. Lopez JA, Susanto O, Jenkins MR, Lukoyanova N, Sutton VR, Law RH, et al. Perforin forms transient pores on the target cell plasma membrane to facilitate rapid access of granzymes during killer cell attack. Blood 2013;121:2659-68.
20. Metkar SS, Wang B, Catalan E, Anderluh G, Gilbert RJ, Pardo J, et al. Perforin rapidly induces plasmamembrane phospholipid flip-flop. PLoS ONE 2011;6:e24286.
21. Pipkin ME, Lieberman J. Delivering the kiss of death: Progress on understanding how perforin works. Curr Opin Immunol 2007;19:301-8.
22. Voskoboinik I, Thia MC, De Bono A, Browne K, Cretney E, Jackson JT, et al. The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene. J Exp Med 2004;200:811-6.
23. Lehmann C, Zeis M, Schmitz N, Uharek L. Impaired binding of perforin on the surface of tumor cells is a cause of target cell resistance against cytotoxic effector cells. Blood 2000;96:594-600.
24. Antia R, Schlegel RA, Williamson P. Binding of perforin to membranes is sensitive to lipid spacing and not headgroup. Immunol Lett 1992;32: 153-7.
25. Andrade F. Non-cytotoxic antiviral activities of granzymes in the context of the immune antiviral state. Immunol Rev 2010;235:128-46.
26. Parkinson LG, Toro A, Zhao H, Brown K, Tebbutt SJ, Granville DJ. Granzyme B mediates both direct and indirect cleavage of extracellular matrix in skin after chronic low-dose ultraviolet light irradiation. Aging Cell 2014;14:67-77.
27. Hiebert PR, Granville DJ.Granzyme B in injury, inflammation, and repair. Trends Mol Med 2012;18:732-41.
28. Hendel A, Hiebert PR, Boivin WA, Williams SJ, Granville DJ. Granzymes in age-related cardiovascular and pulmonary diseases. Cell Death Differ 2010;17:596-606.
29. van den Broek ME, Kagi D, Ossendorp F, Toes R, Vamvakas S, Lutz WK, et al. Decreased tumor surveillance in perforin-deficient mice. J Exp Med 1996;184:1781-90.
30. Pardo J, BalkowS, Anel A, SimonMM.Granzymes are essential for natural killer cell-mediated and perf-facilitated tumor control. Eur J Immunol 2002;32:2881-7.
31. Davis JE, Smyth MJ, Trapani JA. Granzyme A and B-deficient killer lymphocytes are defective in eliciting DNA fragmentation but retain potent in vivo anti-tumor capacity. Eur J Immunol 2001;31:39-47.
32. Smyth MJ, Thia KY, Cretney E, Kelly JM, Snook MB, Forbes CA, et al. Perforin is a major contributor to NK cell control of tumor metastasis. J Immunol 1999;162:6658-62.
33. Kagi D, Ledermann B, Burki K, Seiler P, Odermatt B, Olsen KJ, et al. Cytotoxicitymediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 1994;369:31-7.
34. Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med 2000;192:755-60.
35. Bolitho P, Street SE, Westwood JA, Edelmann W, Macgregor D, Waring P, et al. Perforin-mediated suppression of B-cell lymphoma. Proc Natl Acad Sci U S A 2009;106:2723-8.
36. Trapani JA, Thia KY, Andrews M, Davis ID, Gedye C, Parente P, et al. Human perforin mutations and susceptibility to multiple primary cancers. Oncoimmunology 2013;2:e24185.
37. Street SE, Zerafa N, Iezzi M, Westwood JA, Stagg J, Musiani P, et al. Host perforin reduces tumor number but does not increase survival in oncogene-driven mammary adenocarcinoma. Cancer Res 2007;67: 5454-60.
38. Macagno M, Bandini S, Stramucci L, Quaglino E, Conti L, Balmas E, et al. Multiple roles of perforin in hampering ERBB-2 (Her-2/neu) carcinogenesis in transgenic male mice. J Immunol 2014;192:5434-41.
39. Revell PA, Grossman WJ, Thomas DA, Cao X, Behl R, Ratner JA, et al. Granzyme B and the downstream granzymes C and/or F are important for cytotoxic lymphocyte functions. J Immunol 2005;174:2124-31.
40. Fehniger TA, Cai SF, Cao X, Bredemeyer AJ, Presti RM, French AR, et al. Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity 2007;26:798-811.
41. Smyth MJ, Street SE, Trapani JA. Cutting edge: Granzymes A and B are not essential for perforin-mediated tumor rejection. J Immunol 2003;171: 515-8.
42. Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, et al. Granzyme B and perforin are important for regulatory T Cell-mediated suppression of tumor clearance. Immunity 2007;27:635-46.
43. Pao LI, Sumaria N, Kelly JM, van Dommelen S, Cretney E, Wallace ME, et al. Functional analysis of granzyme M and its role in immunity to infection. J Immunol 2005;175:3235-43.
44. Joeckel LT, Wallich R, Martin P, Sanchez-Martinez D, Weber FC, Martin SF, et al. Mouse granzyme K has pro-inflammatory potential. Cell Death Differ 2011;18:1112-9.
45. Kagi D, Vignaux F, Ledermann B, Burki K, Depraetere V, Nagata S, et al. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 1994;265:528-30.
46. Lowin B, Hahne M, Mattmann C, Tschopp J. Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 1994;370:650-2.
47. Afshar-Sterle S, Zotos D, Bernard NJ, Scherger AK, Rodling L, Alsop AE, et al. Fas ligand-mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas. Nat Med 2015;20:283-90.
48. Peng SL, Robert ME, Hayday AC, Craft J. A tumor-suppressor function for Fas (CD95) revealed in T cell-deficient mice. J Exp Med 1996;184: 1149-54.
49. Davidson WF, Giese T, Fredrickson TN. Spontaneous development of plasmacytoid tumors in mice with defective Fas-Fas ligand interactions. J Exp Med 1998;187:1825-38.
50. Price S, Shaw PA, Seitz A, JoshiG, Davis J, Niemela JE, et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood 2014;123:1989-99.
51. Straus SE, Jaffe ES, Puck JM, Dale JK, Elkon KB, Rosen-Wolff A, et al. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood 2001;98:194-200.
52. Martinez-Lostao L, Marzo I, Anel A, Naval J. Targeting the Apo2L/TRAIL system for the therapy of autoimmune diseases and cancer. Biochem Pharmacol 2013;83:1475-83.
53. Falschlehner C, Emmerich CH, Gerlach B, Walczak H. TRAIL signalling: Decisions between life and death. Int J Biochem Cell Biol 2007;39:1462-75.
54. Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ, Smyth MJ. Increased susceptibility to tumor initiation and metastasis in TNFrelated apoptosis-inducing ligand-deficient mice. J Immunol 2002; 168:1356-61.
55. Sedger LM, Glaccum MB, Schuh JC, Kanaly ST, Williamson E, Kayagaki N, et al. Characterization of the in vivo function of TNF-alpha-related apoptosis-inducing ligand, TRAIL/Apo2L, using TRAIL/Apo2L gene-deficient mice. Eur J Immunol 2002;32: 2246-54.
56. Finnberg N, Klein-Szanto AJ, El-Deiry WS. TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis. J Clin Invest 2008;118:111-23.
57. Diehl GE, Yue HH,Hsieh K, Kuang AA,HoM, Morici LA, et al. TRAIL-R as a negative regulator of innate immune cell responses. Immunity 2004; 21:877-89.
58. Zerafa N, Westwood JA, Cretney E, Mitchell S, Waring P, Iezzi M, et al. Cutting edge: TRAIL deficiency accelerates hematological malignancies. J Immunol 2005;175:5586-90.
59. Yue HH, Diehl GE, Winoto A. Loss of TRAIL-R does not affect thymic or intestinal tumor development in p53 and adenomatous polyposis coli mutant mice. Cell Death Differ 2005;12:94-7.
60. Smyth MJ, Cretney E, Takeda K,Wiltrout RH, Sedger LM, KayagakiN, et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. J Exp Med 2001;193:661-70.
61. Takeda K, Smyth MJ, Cretney E, Hayakawa Y, Kayagaki N, Yagita H, et al. Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med 2002; 195:161-9.
62. Grosse-Wilde A, Voloshanenko O, Bailey SL, Longton GM, Schaefer U, Csernok AI, et al. TRAIL-R deficiency in mice enhances lymph node metastasis without affecting primary tumor development. J Clin Invest 2008;118:100-10.
63. Allard B, Pommey S, Smyth MJ, Stagg J. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res 2013;19:5626-35.
64. Knight DA, Ngiow SF, Li M, Parmenter T, Mok S, Cass A, et al. Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. J Clin Invest 2013;123:1371-81.
65. Morales-Kastresana A, Catalan E, Hervas-Stubbs S, Palazon A, Azpilikueta A, Bolanos E, et al. Essential complicity of perforin-granzyme and FAS-L mechanisms to achieve tumor rejection following treatment with anti-CD137 mAb. J Immunother Cancer 2013;1:3.
66. Song K, Chang Y, Prud'homme GJ. IL-12 plasmid-enhanced DNA vaccination against carcinoembryonic antigen (CEA) studied in immune-gene knockout mice. Gene Ther 2000;7:1527-35.
67. Sin JI, Park JB, Lee IH, Park D, Choi YS, Choe J, et al. Intratumoral electroporation of IL-12 cDNA eradicates established melanomas by Trp2(180-188)-specific CD8 CTLs in a perforin/granzymemediated and IFN-gamma-dependent manner: Application of Trp2(180-188) peptides. Cancer Immunol Immunother 2012;61: 1671-82.
68. Liu RB, Engels B, Arina A, Schreiber K, Hyjek E, Schietinger A, et al. Densely granulated murine NK cells eradicate large solid tumors. Cancer Res 2012;72:1964-74.
69. Schultz J, Pavlovic J, Strack B, Nawrath M, Moelling K. Long-lasting antimetastatic efficiency of interleukin 12-encoding plasmid DNA. Hum Gene Ther 1999;10:407-17.
70. Kodama T, Takeda K, Shimozato O, Hayakawa Y, Atsuta M, Kobayashi K, et al. Perforin-dependent NK cell cytotoxicity is sufficient for anti-metastatic effect of IL-12. Eur J Immunol 1999;29:1390-6.
71. Hayakawa Y, Takeda K, Yagita H, Kakuta S, Iwakura Y, Van Kaer L, et al. Critical contribution of IFN-gamma and NK cells, but not perforinmediated cytotoxicity, to anti-metastatic effect of alpha-galactosylceramide. Eur J Immunol 2001;31:1720-7.
72. Hashimoto W, Osaki T,Okamura H, Robbins PD, KurimotoM, Nagata S, et al. Differential antitumor effects of administration of recombinant IL-18 or recombinant IL-12 are mediated primarily by Fas-Fas ligand-and perforin-induced tumor apoptosis, respectively. J Immunol 1999;163: 583-9.
73. Smyth MJ, Taniguchi M, Street SE. The anti-tumor activity of IL-12: Mechanisms of innate immunity that are model and dose dependent. J Immunol 2000;165:2665-70.
74. Takeda K, NakayamaM, SakakiM,Hayakawa Y, ImawariM,Ogasawara K, et al. IFN-g production by lung NK cells is critical for the natural resistance to pulmonary metastasis of B16 melanoma in mice. J Leukoc Biol 2011;90:777-85.
75. Dobrzanski MJ, Reome JB, Dutton RW. Role of effector cell-derived IL-4, IL-5, and perforin in early and late stages of type 2 CD8 effector cellmediated tumor rejection. J Immunol 2001;167:424-34.
76. Pegram HJ, Haynes NM, Smyth MJ, Kershaw MH, Darcy PK. Characterizing the anti-tumor function of adoptively transferred NK cells in vivo. Cancer Immunol Immunother 2010;59:1235-46.
77. Metkar SS, Menaa C, Pardo J, Wang B, Wallich R, Freudenberg M, et al. Human and mouse granzyme A induce a proinflammatory cytokine response. Immunity 2008;29:720-33.
78. Kaiserman D, Bird CH, Sun J, Matthews A, Ung K, Whisstock JC, et al. The major human and mouse granzymes are structurally and functionally divergent. J Cell Biol 2006;175:619-30.
79. Joeckel LT, Bird PI. Are all granzymes cytotoxic in vivo? Biol Chem 2014;395:181-202.
80. Abdool K, Cretney E, Brooks AD, Kelly JM, Swann J, Shanker A, et al. NK cells use NKG2D to recognize a mouse renal cancer (Renca), yet require intercellular adhesion molecule-1 expression on the tumor cells for optimal perforin-dependent effector function. J Immunol 2006;177: 2575-83.
81. Seki N, Brooks AD, Carter CR, Back TC, Parsoneault EM, Smyth MJ, et al. Tumor-specific CTL kill murine renal cancer cells using both perforin and Fas ligand-mediated lysis in vitro, but cause tumor regression in vivo in the absence of perforin. J Immunol 2002;168: 3484-92.
82. Shanker A, Brooks AD, Jacobsen KM, Wine JW, Wiltrout RH, Yagita H, et al. Antigen presented by tumors in vivo determines the nature of CD8 T-cell cytotoxicity. Cancer Res 2009;69:6615-23.
83. Simon MM, Hausmann M, Tran T, Ebnet K, Tschopp J, ThaHla R, et al. In vitro-and ex vivo-derived cytolytic leukocytes from granzyme A x B double knockout mice are defective in granule-mediated apoptosis but not lysis of target cells. J Exp Med 1997;186: 1781-6.
84. Pardo J, Bosque A, Brehm R, Wallich R, Naval J, Mullbacher A, et al. Apoptotic pathways are selectively activated by granzyme A and/or granzyme B in CTL-mediated target cell lysis. J Cell Biol 2004;167: 457-68.
85. Hoves S, Sutton VR, Haynes NM, Hawkins ED, Fernandez Ruiz D, Baschuk N, et al. A critical role for granzymes in antigen crosspresentation through regulating phagocytosis of killed tumor cells. J Immunol 2011;187:1166-75.
86. Waterhouse NJ, Sutton VR, Sedelies KA, Ciccone A, Jenkins M, Turner SJ, et al. Cytotoxic T lymphocyte-induced killing in the absence of granzymes A and B is unique and distinct from both apoptosis and perforindependent lysis. J Cell Biol 2006;173:133-44.
87. Pardo J, Galvez EM, Koskinen A, Simon MM, Lobigs M, Regner M, et al. Caspase-dependent inhibition of mousepox replication by gzmB. PLoS ONE 2009;4:e7512.
88. Hoves S, Trapani JA, Voskoboinik I. The battlefield of perforin/granzyme cell death pathways. J Leukoc Biol 2010;87:237-43.
89. Wensink AC, Hack CE, Bovenschen N. Granzymes regulate proinflammatory cytokine responses. J Immunol 2015;194:491-7.
90. Pardo J, Balkow S, Anel A, Simon MM. The differential contribution of granzyme A and granzyme B in cytotoxic T lymphocyte-mediated apoptosis is determined by the quality of target cells. Eur J Immunol 2002; 32:1980-5.
91. Susanto O, Stewart SE, Voskoboinik I, Brasacchio D, HagnM, Ellis S, et al. Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis. Cell Death Differ 2013;20:1183-93.
92. Heusel JW, Wesselschmidt RL, Shresta S, Russell JH, Ley TJ. Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells. Cell 1994;76:977-87.
93. Pardo J, Wallich R, Martin P, Urban C, Rongvaux A, Flavell RA, et al. Granzyme B-induced cell death exerted by ex vivo CTL: Discriminating requirements for cell death and some of its signs. Cell Death Differ 2008;15:567-79.
94. Adrain C, Duriez PJ, Brumatti G, Delivani P, Martin SJ. The cytotoxic lymphocyte protease, granzyme B, targets the cytoskeleton and perturbs microtubule polymerization dynamics. J Biol Chem 2006;281:8118-25.
95. Goping IS, Sawchuk T, Underhill DA, Bleackley RC. Identification of {alpha}-tubulin as a granzyme B substrate during CTL-mediated apoptosis. J Cell Sci 2006;119:858-65.
96. Catalan E, Jaime-Sanchez P, Aguilo N, Simon MM, Froelich CJ, Pardo J. Mouse cytotoxic T cell-derived granzyme B activates the mitochondrial cell death pathway in a Bim-dependent fashion. J Biol Chem 2015; 290:6868-77.
97. Sedelies KA, Ciccone A, Clarke CJ, Oliaro J, Sutton VR, Scott FL, et al. Blocking granule-mediated death by primary human NK cells requires both protection of mitochondria and inhibition of caspase activity. Cell Death Differ 2008;15:708-17.
98. Mahrus S, Craik CS. Selective chemical functional probes of granzymes A and B reveal granzyme B is amajor effector of natural killer cell-mediated lysis of target cells. Chem Biol 2005;12:567-77.
99. Sanchez-Martinez D, Azaceta G, Muntasell A, Aguilo N, Nunez D, Galvez EM, et al. Human NK cells activated by EBV lymphoblastoid cells overcome anti-apoptotic mechanisms of drug resistance in haematological cancer cells. Oncoimmunology 2015;4:e991613.
100. White E, Mehnert JM, Chan CS. Autophagy, metabolism, and cancer. Clin Cancer Res 2015;21:5037-46.
101. Anthony DA, Andrews DM, Chow M, Watt SV, House C, Akira S, et al. A role for granzyme M in TLR4-driven inflammation and endotoxicosis. J Immunol 2010;185:1794-803.
102. Arias MA, Jimenezde Bagues MP, Aguilo N, Menao S, Hervas-Stubbs S, de Martino A, et al. Elucidating sources and roles of granzymes A and B during bacterial infection and sepsis. Cell Rep 2014;8:420-9.
103. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: An ordered cellular explosion. Nat Rev Mol Cell Biol 2010;11:700-14.
104. Azijli K, Weyhenmeyer B, Peters GJ, de Jong S, Kruyt FA. Non-canonical kinase signaling by the death ligand TRAIL in cancer cells: Discord in the death receptor family. Cell Death Differ 2013;20:858-68.
105. Trauzold A, Siegmund D, Schniewind B, Sipos B, Egberts J, Zorenkov D, et al. TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma. Oncogene 2006;25:7434-9.
106. Barnhart BC, Legembre P, Pietras E, Bubici C, Franzoso G, Peter ME. CD95 ligand induces motility and invasiveness of apoptosis-resistant tumor cells. EMBO J 2004;23:3175-85.
107. von Karstedt S, Conti A, Nobis M, Montinaro A, Hartwig T, Lemke J, et al. Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis. Cancer Cell 2015;27:561-73.