Apoptose-Mechanismen in der Onkogenese von Hauttumoren[*]

Zusammenfassung

Tumorerkrankungen der Haut werden zentral durch die Fähigkeit der Tumorzellen, im Rahmen von Tumorinitiation und -progression Apoptoseresistenz zu erlangen, befördert. So trägt die Apoptoseresistenz entscheidend dazu bei, dass Hauttumorerkrankungen wie das maligne Melanom und das Plattenepithelkarzinom im metastasierten Zustand therapeutisch nur schwer beeinflussbar sind und eine kurative Behandlung dieser Tumorstadien erschwert ist. Ebenso bedingt das multilokuläre Auftreten von Basalzellkarzinomen eine nicht unerhebliche Komorbidität, sodass auch diese Entität neuer Therapieformen bedarf. In den letzten Jahren mehrt sich die Evidenz, dass durch gezielte Beeinflussung zentraler Schaltstellen der apoptotischen Signaltransduktionskaskade eine bessere Behandlung dermatoonkologischer Patienten ermöglicht werden könnte. Dazu gehören p53-Reaktivatoren, Sonic-Hedgehog-Antagonisten, aber auch Bcl-2-Antagonisten, IAP-Antagonisten oder Todesrezeptor-Agonisten, die sich gegenwärtig in der präklinischen oder frühen klinischen Erprobung befinden. Der Artikel fasst den gegenwärtigen Stand zusammen und gibt einen Ausblick auf potenzielle mechanismusbasierte Therapieoptionen zur Durchbrechung der Apoptoseresistenz bei dermatoonkologischen Erkrankungen.

Abstract

The prognosis of cutaneous neoplasia such as squamous cell carcinoma (SCC), basal cell carcinoma (BCC), or malignant melanoma (MM) are severely influenced by the ability of tumor cells to develop or maintain apoptosis resistance throughout tumor progression and metastasis. Furthermore, the ability to overcome apoptosis resistance is a critical factor that determines therapeutic failure or success in metastatic SCC or MM. Moreover apoptosis resistence is a major obstacle to curative efforts in these dermatooncologic diseases. In BCC, the multitude of tumors results in a substantial comorbidity that require innovative treatment options. Over the past years, there is increasing evidence that targeted therapy aiming at the apoptotic signalling cascade in a tumor type-specific manner may result in a better success of oncological treatment. In this context, reactivators of p53, antagonists of sonic hedgehog, but also Bcl-2- or IAP antagonists as well as death receptor agonists that are currently in preclinical or early clinical development may prove to be useful in dermatooncology. The article explains the current knowledge in this rapidly moving field and summarizes potential mechanism-based therapeutic options to overcome apoptosis resistance in the different forms of skin cancer.

1 Vortrag anlässlich des Jahressymposiums der Berliner Stiftung für Dermatologie am 31. 5. 2008.

Literatur

• 1 Aszterbaum M, Epstein J, Oro A. et al . Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice.  Nat Med. 1999;  5 1285-1291
• 2 Athar M, Tang X, Lee J L. et al . Hedgehog signalling in skin development and cancer.  Exp Dermatol. 2006;  15 667-677
• 3 Bigelow R L, Jen E Y, Delehedde M. et al . Sonic hedgehog induces epidermal growth factor dependent matrix infiltration in HaCaT keratinocytes.  J Invest Dermatol. 2005;  124 457-465
• 4 Boukamp P. UV-induced skin cancer: similarities – variations.  J Dtsch Dermatol Ges. 2005;  3 493-503
• 5 Braakhuis B J, Leemans C R, Brakenhoff R H. Expanding fields of genetically altered cells in head and neck squamous carcinogenesis.  Semin Cancer Biol. 2005;  15 113-120
• 6 Brantsch K D, Meisner C, Schonfisch B. et al . Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study.  Lancet Oncol. 2008;  9 713-720
• 7 Bykov V J, Issaeva N, Shilov A. et al . Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound.  Nat Med. 2002;  8 282-288
• 8 Chalah A, Khosravi-Far R. The mitochondrial death pathway.  Adv Exp Med Biol. 2008;  615 25-45
• 9 Daniel P T, Schulze-Osthoff K, Belka C, Guner D. Guardians of cell death: the Bcl-2 family proteins.  Essays Biochem. 2003;  39 73-88
• 10 Degterev A, Yuan J. Expansion and evolution of cell death programmes.  Nat Rev Mol Cell Biol. 2008;  9 378-390
• 11 Fecker L F, Geilen C C, Tchernev G. et al . Loss of proapoptotic Bcl-2-related multidomain proteins in primary melanomas is associated with poor prognosis.  J Invest Dermatol. 2006;  126 1366-1371
• 12 Geserick P, Drewniok C, Hupe M. et al . Suppression of cFLIP is sufficient to sensitize human melanoma cells to TRAIL- and CD95L-mediated apoptosis.  Oncogene. 2008;  27 3211-3220
• 13 Green C L, Khavari P A. Targets for molecular therapy of skin cancer.  Semin Cancer Biol. 2004;  14 63-69
• 14 Hanahan D, Weinberg R A. The hallmarks of cancer.  Cell. 2000;  100 57-70
• 15 Huntzicker E G, Estay I S, Zhen H. et al . Dual degradation signals control Gli protein stability and tumor formation.  Genes Dev. 2006;  20 276-281
• 16 Ikram M S, Neill G W, Regl G. et al . GLI2 is expressed in normal human epidermis and BCC and induces GLI1 expression by binding to its promoter.  J Invest Dermatol. 2004;  122 1503-1509
• 17 Irmler M, Thome M, Hahne M. et al . Inhibition of death receptor signals by cellular FLIP.  Nature. 1997;  388 190-195
• 18 Johnson R L, Rothman A L, Xie J. et al . Human homolog of patched, a candidate gene for the basal cell nevus syndrome.  Science. 1996;  272 1668-1671
• 19 Kump E, Ji J, Wernli M, Hausermann P, Erb P. Gli2 upregulates cFlip and renders basal cell carcinoma cells resistant to death ligand-mediated apoptosis.  Oncogene. 2008;  27 3856-3864
• 20 Lavrik I N, Golks A, Krammer P H. Caspases: pharmacological manipulation of cell death.  J Clin Invest. 2005;  115 2665-2672
• 21 Leiter U, Garbe C. Epidemiology of melanoma and nonmelanoma skin cancer – the role of sunlight.  Adv Exp Med Biol. 2008;  624 89-103
• 22 Leverkus M, Diessenbacher P, Geserick P. FLIPing the coin? Death receptor-mediated signals during skin tumorigenesis.  Exp Dermatol. 2008;  17 614-622
• 23 Leverkus M, Neumann M, Mengling T. et al . Regulation of tumor necrosis factor-related apoptosis-inducing ligand sensitivity in primary and transformed human keratinocytes.  Cancer Res. 2000;  60 553-559
• 24 Meier F, Busch S, Lasithiotakis K. et al . Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment.  Br J Dermatol. 2007;  156 1204-1213
• 25 Oltersdorf T, Elmore S W, Shoemaker A R. et al . An inhibitor of Bcl-2 family proteins induces regression of solid tumours.  Nature. 2005;  435 677-681
• 26 Regl G, Kasper M, Schnidar H. et al . Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2.  Cancer Res. 2004;  64 7724-7731
• 27 Regl G, Neill G W, Eichberger T. et al . Human GLI2 and GLI1 are part of a positive feedback mechanism in basal cell carcinoma.  Oncogene. 2002;  21 5529-5539
• 28 Selivanova G, Wiman K G. Reactivation of mutant p53: molecular mechanisms and therapeutic potential.  Oncogene. 2007;  26 2243-2254
• 29 Sinha S, Chen J K. Purmorphamine activates the Hedgehog pathway by targeting smoothened.  Nat Chem Biol. 2006;  2 29-30
• 30 Soengas M S, Lowe S W. Apoptosis and melanoma chemoresistance.  Oncogene. 2003;  22 138-3151
• 31 Taipale J, Chen J K, Cooper M K. et al . Effects of oncogenic mutations in smoothened and patched can be reversed by cyclopamine.  Nature. 2000;  406 1005-1009
• 32 Tang X, Zhu Y, Han L. et al . CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice.  J Clin Invest. 2007;  117 3753-3764
• 33 Tse C, Shoemaker A R, Adickes J. et al . ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor.  Cancer Res. 2008;  68 3421-3428
• 34 van Loo G, Saelens X, van Gurp M. et al . The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet.  Cell Death Differ. 2002;  9 1031-1042
• 35 Vaux D L, Silke J. IAPs, RINGs and ubiquitylation.  Nat Rev Mol Cell Biol. 2005;  6 287-297
• 36 Ventura A, Kirsch D G, McLaughlin M E. et al . Restoration of p53 function leads to tumour regression in vivo.  Nature. 2007;  445 661-665
• 37 von Hoff D D, Rudin C M, LoRusso P M. et al . Efficacy data of GDC-0449, a systemic Hedgehog pathway antagonist, in a first-in-human, first-in-class Phase I study with locally advanced, multifocal or metastatic basal cell carcinoma patients.  AACR. 2008;  Abstract LBG-138
• 38 Weisz L, Damalas A, Liontos M. et al . Mutant p53 enhances nuclear factor kappaB activation by tumor necrosis factor alpha in cancer cells.  Cancer Res. 2007;  67 2396-2401
• 39 Wiman K G. Restoration of wild-type p53 function in human tumors: strategies for efficient cancer therapy.  Adv Cancer Res. 2007;  97 321-338
• 40 Wolfrum C, Shi S, Jayaprakash K N. et al . Mechanisms and optimization of in vivo delivery of lipophilic siRNAs.  Nat Biotechnol. 2007;  25 1149-1157
• 41 Xue W, Zender L, Miething C. et al . Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.  Nature. 2007;  445 656-660

1 Vortrag anlässlich des Jahressymposiums der Berliner Stiftung für Dermatologie am 31. 5. 2008.