FLIP ing the coin? Death receptor-mediated signals during skin tumorigenesis.

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.