Leverkus Martin, Diessenbacher Philip, Geserick Peter
Department of Dermatology and Venerology, Laboratory for Experimental Dermatology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
Exp Dermatol. 2008 Jul;17(7):614-22. doi: 10.1111/j.1600-0625.2008.00728.x.
Keratinocyte skin cancer is a multi-step process, during which a number of obstacles have to be overcome by the tumor cell to allow the development of a manifest tumor. Beside proliferation and immortality, apoptosis resistance is one additional and critical step during skin carcinogenesis. Over the past two decades, much has been learned about the prototypical membrane-bound inducers of apoptosis, namely the death receptors and their ligands, and the apoptosis signalling pathways activated by death receptors have been elucidated in great detail. In contrast, much less is known about the tissue-specific role of the death receptor/ligands systems during the development of skin cancer. Here, we summarize and discuss the role of this intriguing receptor family and the potential mechanistical impact of the intracellular caspase-8 inhibitor cFLIP for keratinocyte skin cancer. Given more recent data about cFLIP and its isoforms, a more complex regulatory role of cFLIP can be suspected. Indeed, cFLIP may not solely interfere with death receptor-mediated apoptosis signalling pathways, but may positively or negatively influence other, potential harmful signalling pathways such as the production of inflammatory cytokines, tumor cell migration or the activation of transcription factors such as NF-kappaB, considered crucial during skin tumorigenesis. In this respect, cFLIP may act to 'FLIP the coin' during the development of keratinocyte skin cancer.
角质形成细胞皮肤癌是一个多步骤过程，在此过程中肿瘤细胞必须克服许多障碍才能形成明显的肿瘤。除了增殖和永生之外，抗凋亡是皮肤癌发生过程中的另一个关键步骤。在过去二十年中，我们对典型的膜结合凋亡诱导剂，即死亡受体及其配体有了很多了解，并且对死亡受体激活的凋亡信号通路也进行了详细阐释。相比之下，我们对死亡受体/配体系统在皮肤癌发生过程中的组织特异性作用了解较少。在此，我们总结并讨论这个有趣的受体家族的作用以及细胞内半胱天冬酶-8抑制剂cFLIP对角质形成细胞皮肤癌的潜在机制影响。鉴于最近有关cFLIP及其异构体的数据，可以推测cFLIP具有更复杂的调节作用。实际上，cFLIP可能不仅会干扰死亡受体介导的凋亡信号通路，还可能对其他潜在的有害信号通路产生正向或负向影响，例如炎性细胞因子的产生、肿瘤细胞迁移或转录因子如核因子κB的激活，这些在皮肤肿瘤发生过程中被认为至关重要。在这方面，cFLIP可能在角质形成细胞皮肤癌的发生过程中起到“翻转硬币”的作用。
