Abstract
Necroptosis is a type of regulated cell death that is increasingly being recognized as a relevant pathway in different pathological conditions. Necroptosis can occur in response to multiple stimuli, is triggered by the activation of death receptors, and is regulated by receptor-interacting protein kinases 1 and 3 and mixed-lineage kinase domain-like, which form a regulatory complex called the necrosome. Accumulating evidence suggests that necroptosis plays a complex role in cancer, which is likely context-dependent and can vary among different types of neoplasms. Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis and, as a pro-inflammatory death type, it may inhibit tumor progression by releasing damage-associated molecular patterns to elicit robust cross-priming of anti-tumor CD8+ T cells. The development of therapeutic strategies triggering necroptosis shows great potential for anti-cancer therapy. In this review, we summarize the current knowledge on necroptosis and its role in liver biliary neoplasms, underlying the potential of targeting necroptosis components for cancer treatment.
Highlights
A continuous process of cell death (CD) and renewal takes place on a daily basis in all mammal organ systems
Necroptosis is a type of tightly regulated cell death (RCD) mimicking the morphological features of necrosis [2]
Type I CD was definitively split into two different processes, termed intrinsic and extrinsic apoptosis, while type III CD was renamed mitochondrial permeability transition-driven necrosis, pointing out the importance acquired by the molecular aspects in defining CD modalities [9]
Summary
A continuous process of cell death (CD) and renewal takes place on a daily basis in all mammal organ systems Disturbances in these processes interrupt the normal regulation of development and tissue homeostasis with the potential to induce pathological conditions, including cancer [1]. Necroptosis is an alternative mode of CD when the caspase-8-dependent apoptotic pathway is blocked It is well-established that various stimuli can initiate necroptosis, including intra- and extracellular factors, such as tumor necrosis factor α (TNFα) and reactive oxygen species (ROS) [5]. It has been demonstrated that apoptosis-resistant tumors respond to necroptosis, and that necroptosis can create an immunogenic microenvironment that enhances tumor clearance [6] These aspects will be further discussed in the following chapters. We will discuss the general aspects of necroptosis and what is currently known on its involvement in cholangiocarcinoma (CCA), in order to provide perspectives for future studies in this relatively new field
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