Neue Erkenntnisse über die Zelltodregulation: Bedeutung für die Tumorpathologie

Zusammenfassung

Krebszellen haben bestimmte Eigenschaften entwickelt, die ihnen gegenüber normalen Zellen einen Selektionsvorteil sichern. Über Jahrzehnte befasste sich die Krebsforschung mit den molekularen Mechanismen der Apoptose, insbesondere mit Mechanismen zur Überwindung der Apoptoseresistenz von Tumorzellen. Inzwischen sind neue Formen des programmierten Zelltodes für sowohl physiologische als auch pathologische Prozesse bedeutsam. Neueste Forschungsergebnisse lassen erwarten, dass die Auslösung alternativer Zelltodformen wie der Nekroptose eine wichtige Strategie sein könnte, um Apoptose-resistente Tumorzellen wieder für die konventionelle Chemo- und Radiotherapie zu sensibilisieren.

Abstract

During tumorigenesis cancer cells acquire certain features allowing for sustained growth and circumvention of programmed cell death. For decades cancer research has been focused on the molecular mechanisms of apoptosis and how to overcome apoptosis resistance in tumor cells. Meanwhile, novel types of programmed cell death turned out to be important for both physiologic and pathologic processes. Recent findings imply that induction of alternative forms of programmed cell death, such as necroptosis, might be used as a therapeutic approach to overcome therapy resistance in cancer.

Schlüsselwörter

Apoptose - Nekrose - Zelltod - Tumorpathologie

Keywords

apoptosis - necrosis - cell death - tumor pathology

• Literatur

• 1 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-674
• 2 Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239-257
• 3 Kroemer G, Galluzzi L, Vandenabeele P et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 2009; 16: 3-11
• 4 Festjens N, Vanden Berghe T, Vandenabeele P. Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta 2006; 1757: 1371-1387
• 5 Kreuzaler P, Watson CJ. Killing a cancer: what are the alternatives?. Nat Rev Cancer 2012; doi: [Epub ahead of print]
• 6 Long JS, Ryan KM. New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy. Oncogene 2012;
• 7 Laster SM, Wood JG, Gooding LR. Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis. J Immunol 1988; 141: 2629-2634
• 8 Vandenabeele P, Galluzzi L, Vanden Berghe T et al. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 2010; 11: 700-714
• 9 Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 2003; 114: 181-190
• 10 Hsu H, Huang J, Shu HB et al. TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 1996; 4: 387-396
• 11 Holler N, Zaru R, Micheau O et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 2000; 1: 489-495
• 12 Brummelkamp TR, Nijman SM, Dirac AM et al. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 2003; 424: 797-801
• 13 Feoktistova M, Geserick P, Kellert B et al. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol Cell 43: 449-463
• 14 He S, Wang L, Miao L et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 2009; 137: 1100-1111
• 15 Degterev A, Hitomi J, Germscheid M et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 2008; 4: 313-321
• 16 Kaiser WJ, Upton JW, Long AB et al. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 2011; 471: 368-372
• 17 Gunther C, Martini E, Wittkopf N et al. Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis. Nature 2011; 477: 335-339
• 18 Welz PS, Wullaert A, Vlantis K et al. FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 2011; 477: 330-334
• 19 Liedtke C, Bangen JM, Freimuth J et al. Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury. Gastroenterology 2011; 141: 2176-2187
• 20 Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer 2009; 9: 361-371
• 21 Tenev T, Bianchi K, Darding M et al. The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol Cell 2011; 43: 432-448
• 22 Coupienne I, Fettweis G, Piette J. RIP3 expression induces a death profile change in U2OS osteosarcoma cells after 5-ALA-PDT. Lasers Surg Med 2012; 43: 557-564
• 23 Mantel F, Frey B, Haslinger S et al. Combination of ionising irradiation and hyperthermia activates programmed apoptotic and necrotic cell death pathways in human colorectal carcinoma cells. Strahlenther Onkol 2012; 186: 587-599
• 24 Nehs MA, Lin CI, Kozono DE et al. Necroptosis is a novel mechanism of radiation-induced cell death in anaplastic thyroid and adrenocortical cancers. Surgery 2012; 150: 1032-1039
• 25 Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 2005; 5: 331-342
• 26 Gdynia G, Keith M, Kopitz J et al. Danger signaling protein HMGB1 induces a distinct form of cell death accompanied by formation of giant mitochondria. Cancer Res 2010; 70: 8558-8568