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CONCLUDING REMARKS Non‐canonical TRAIL signaling In pursue of novel potent tumor‐selective apoptosis‐inducing strategies the TRAIL receptors provide excellent targets on first sight. Indeed, their favourable property of triggering tumor‐selective apoptosis has been demonstrated in many preclinical studies. However, it is becoming clear that signaling via the TRAIL receptors is much more complex than initially thought and can have different functional outcomes as is illustrated here. TRAIL receptor activation can have antitumor effects by inducing caspase‐dependent apoptosis in TRAIL sensitive cells, whereas in TRAIL resistant tumor cells, the activation can lead to protumorigenic effects such as enhanced proliferation, survival and invasion. Whether TRAIL‐induced necroptosis contributes to anti‐tumor activity remains to be demonstrated. The effects of TRAIL receptor activation in resistant tumor cells resemble that observed in non‐transformed apoptosis resistant (normal) cells. This suggests that the protumorigenic mechanisms elicited by TRAIL in resistant tumor cells are actually part of normal physiological signaling in non‐transformed cells. However, an important difference is that combination therapies that sensitize cancer cells for TRAIL‐induced apoptosis are in most cases not harmful for normal cells, indicating specific changes in tumor cells allowing the activation of caspase‐dependent apoptosis. The precise kinase cascades triggered by TRAIL remain to be further identified, which is complicated due to cross‐activation between kinases, cell type‐dependent variation and the effects of external stimuli produced by the tumor microenvironment. A number of studies have attempted to unravel the molecular mechanisms responsible for the dichotomy in TRAIL signaling but the underlying mechanisms remain poorly understood. Thus far the DISC (FADD, caspase‐8) and the signaling complex (FADD, , caspase‐8, RIP1, TRAF2, NEMO) have been identified [38] as main mediators of apoptosis and non‐ apoptotic signals, respectively. RIP1 dependent signalling can stimulate cell survival and even tumor cell invasion. In addition, TRAIL has been shown to induce RIP1‐dependent necroptosis under specific conditions. The more precise mechanisms by which RIP1 can transmit these signals remain to be determined. Clearly more research is required to unravel the molecular mechanism regulating non‐canonical TRAIL and to identify molecular switches that may be used for setting the system into the ‘apoptosis position’. This will provide new clues for developing better strategies for using TRAIL receptor agonists for the treatment of cancer. Acknowledgements This work was performed within the framework of project T3‐112 of the Dutch Top Institute Pharma and supported by grant RUG2011‐5211 from the Dutch Cancer Society. We thank Esther van Straten for making the figures. ‐ 31 ‐
Chapter 2 Reference List 1. Ashkenazi A. Directing cancer cells to self‐destruct with pro‐apoptotic receptor agonists. Nat Rev Drug Discov. 2008; 7(12):1001‐1012. 2. Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo‐2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem 1996; 271(22):12687‐12690. 3. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995; 3(6):673‐682. 4. Fulda S, Debatin KM. Exploiting death receptor signaling pathways for tumor therapy. Biochim Biophys Acta 2004; 1705(1):27‐41. 5. LeBlanc HN, Ashkenazi A. Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ 2003; 10(1):66‐75. 6. Kim K, Fisher MJ, Xu SQ, El‐Deiry WS. Molecular determinants of response to TRAIL in killing of normal and cancer cells. Clin Cancer Res 2000; 6(2):335‐346. 7. Nimmanapalli R, Perkins CL, Orlando M, O'Bryan E, Nguyen D, Bhalla KN. Pretreatment with paclitaxel enhances apo‐2 ligand/tumor necrosis factor‐related apoptosis‐inducing ligand‐induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels. Cancer Res 2001; 61(2):759‐763. 8. Petak I, Tillman DM, Harwood FG, Mihalik R, Houghton JA. Fas‐dependent and ‐ independent mechanisms of cell death following DNA damage in human colon carcinoma cells. Cancer Res 2000; 60(10):2643‐2650. 9. Reis CR, van der Sloot AM, Szegezdi E, Natoni A, Tur V, Cool RH et al. Enhancement of antitumor properties of rhTRAIL by affinity increase toward its death receptors. Biochemistry 2009; 48(10):2180‐2191. 10. Tur V, van der Sloot AM, Reis CR, Szegezdi E, Cool RH, Samali A et al. DR4‐selective tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) variants obtained by structure‐ based design. J Biol Chem 2008; 283(29):20560‐20568. 11. van der Sloot AM, Tur V, Szegezdi E, Mullally MM, Cool RH, Samali A et al. Designed tumor necrosis factor‐related apoptosis‐inducing ligand variants initiating apoptosis exclusively via the DR5 receptor. Proc Natl Acad Sci U S A 2006; 103(23):8634‐8639. 12. Lemke J, Noack A, Adam D, Tchikov V, Bertsch U, Roder C et al. TRAIL signaling is mediated by DR4 in pancreatic tumor cells despite the expression of functional DR5. J Mol Med (Berl) 2010; 88(7):729‐740. 13. MacFarlane M, Inoue S, Kohlhaas SL, Majid A, Harper N, Kennedy DB et al. Chronic lymphocytic leukemic cells exhibit apoptotic signaling via TRAIL‐R1. Cell Death Differ 2005; 12(7):773‐782. 14. Bellail AC, Tse MC, Song JH, Phuphanich S, Olson JJ, Sun SY et al. DR5‐mediated DISC controls caspase‐8 cleavage and initiation of apoptosis in human glioblastomas. J Cell Mol Med 2010; 14(6A):1303‐1317. 15. Kelley RF, Totpal K, Lindstrom SH, Mathieu M, Billeci K, Deforge L et al. Receptor‐selective mutants of apoptosis‐inducing ligand 2/tumor necrosis factor‐related apoptosis‐inducing ligand reveal a greater contribution of death receptor (DR) 5 than DR4 to apoptosis signaling. J Biol Chem 2005; 280(3):2205‐2212. 16. Pennarun B, Meijer A, de Vries EG, Kleibeuker JH, Kruyt F, de Jong S. Playing the DISC: turning on TRAIL death receptor‐mediated apoptosis in cancer. Biochim Biophys Acta 2010; 1805(2):123‐140. 17. Ozoren N, El‐Deiry WS. Defining characteristics of Types I and II apoptotic cells in response to TRAIL. Neoplasia 2002; 4(6):551‐557. 18. Krammer PH, Arnold R, Lavrik IN. Life and death in peripheral T cells. Nat Rev Immunol 2007; 7(7):532‐542. ‐ 32 ‐
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Page 17 and 18: Chapter 2 ABSTRACT Tumor necrosis f
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Page 67 and 68: Chapter 4 RESULTS TRAIL induces a s
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Page 77 and 78: Chapter 4 DISCUSSION The TRAIL rece
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Chapter 4 ‐ 82 ‐
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Chapter 5 ABSTRACT TRAIL is an inte
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Chapter 5 targets and subsequent pr
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Chapter 5 RESULTS Synergistic activ
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Chapter 5 ng/ml TRAIL (Fig. 3B). Ap
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Chapter 5 by sub‐G1 levels in the
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Chapter 5 DISCUSSION In the present
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Chapter 5 Reference List 1. Jemal A
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Chapter 6 ABSTRACT TRAIL is a tumor
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Chapter 6 various stress stimuli [1
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Chapter 6 Subsequently, the membran
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Chapter 6 B H460 A549 Figure 1. Rep
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Chapter 6 TRAIL‐dependent cell de
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Chapter 6 B H460 A549 C Figure 4 (c
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Chapter 6 Figure 5 (continued). Mec
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Chapter 6 regulation and checkpoint
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Chapter 6 mechanism of immune evasi
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Chapter 7 ABSTRACT Thymidine phosph
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Chapter 7 Figure 1. Schematic overv
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Chapter 7 that was measured before
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Chapter 7 RESULTS TdR conversion to
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Chapter 7 dR is secreted from the c
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Chapter 7 Figure 4. Accumulation of
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Chapter 7 angiogenic properties. Ho
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Chapter 7 activity of enzymes. Natu
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Chapter 8 SUMMARIZING DISCUSSION AN
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Chapter 8 Recently, various differe
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Chapter 8 in phase II clinical tria
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Chapter 8 Reference List 1. Herbst
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Chapter 9 NEDERLANDSE SAMENVATTING
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Chapter 9 waargenomen. Het gebruik
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Chapter 9 CONCLUSIE Het activeren v
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zelfs na werktijden (lees 23:45) ko
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Verder wil ik ook dr. Eric Ronken b
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