Necroptosis in Cholangiocarcinoma

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.

Keywords: cell death; cholangiocarcinoma; necroptosis; regulated cell death.

Figure 1

A schematic overview of necroptosis in cholangiocarcinoma (CCA). (a) A simplified illustration of the intracellular pathways involved in cell fate in a necroptotic CCA cell. As reported in the text, tumor necrosis factor α (TNFα) activates its receptor, TNFα receptor 1 (TNFR1), which binds a series of proteins to form complex I. The ubiquitylation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) leads to cell survival, through the nuclear factor-kappa B (NF-κB) pathway. When this process is impeded, and caspase-8 is active, complex IIa will assemble, leading to RIPK1-independent apoptosis. The deubiquitylation of RIPK1 in the presence of activated caspase-8 leads to the assembly of complex IIb and, subsequently, to RIPK1-dependent apoptosis. The inhibition of caspase-8 leads to RIPK1/receptor-interacting serine/threonine-protein kinase 3 (RIPK3)/mixed lineage kinase domain-like (MLKL) interaction, forming complex IIc, also named the necrosome. Phosphorylated MLKL and RIPK3 translocate to the plasma membrane, opening membrane pores, and resulting in damage-associated molecular patterns (DAMPs) release. (b) The immunogenic response to DAMPs. Dendritic cells, activated by DAMPs, travel to lymph nodes, mature and expand, and present a tumor antigens to naïve CD8+ T cells, in a process called cross-priming. T cells are then activated and differentiate into cytotoxic T cells primed to specifically attack tumor cells. (c) The morphology of a necroptotic cell. Translucent cytoplasm, the swelling of organelles, patches of condensed chromatin within the nucleus, an increased cell volume, and a disrupted cell membrane can be visualized by electron microscopy. Picture adopted from Vandenabeele et al. [20].