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.Cells 2020, 9, 982 2 of 18 (RIPK3) and mixed lineage kinase domain-like (MLKL) [4]. Therefore, necroptosis is an alternative mode of CD when the caspase-8-dependent apoptotic pathway is blocked. It is now 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].A hallmark of cancer is the ability of malignant cells to evade apoptosis. Therefore, the induction of necroptosis could be an alternative strategy for killing cancer cells. Several therapeutics able to affect the necroptotic cascade have recently been developed, and a few of them are already in phase 1 trials for the treatment of inflammatory diseases. Moreover, necroptosis modulation is becoming the target of several new anti-cancer strategies. In fact, 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.Herein, 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. Overview on Types of Cell DeathIn 2005, the Nomenclature Committee on Cell Death (NCCD) defined the first CD classification purely based on morphological criteria. This classification included three major forms of CD: types I, II, and III [7]. Type I CD, termed apoptosis, exhibits cell shrinkage, membrane blebbing, DNA fragmentation, chromatin condensation, and the formation of apoptotic bodies. Apoptosis is a form of RCD and responds to two different death signals: damage from inside the cell, such as DNA damage, which elicits an intrinsic pathway, and extracellular stimuli, such as TNFα and the Fas ligand, ...

Tumor necroptosis is correlated with a favorable immune cell signature and programmed death-ligand 1 expression in cholangiocarcinoma

“…However, none has demonstrated an association between the activation of intratumoral necroptosis and inflammatory/immune cell infiltration in human malignancies. Our study was consistent with a previous study in CCA patients, in which their preliminary data demonstrated a direct association between RIPK3 expression and the intratumoral infiltration of CD8+ T cells (only abstract available 42 , 43 ). In contrast, the analysis of PDA in an experimental mouse model with RIPK3 deletion demonstrated a significantly increased number of CD4+ and CD8+ T cells but decreased number of FOXp3+, TAMs, and myeloid-derived suppressor cells (MDSC), indicating that deletion of RIPK3 was indeed associated with increased T cell infiltration and reduced immunosuppressive myeloid cells 20 .…”

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

“…Mechanistically, FTO-mediated demethylation prevents YTHDF2-dependent decay of Unc-51-like kinase-1 (U51LK1) mRNA by removing methyl groups from the 3′-UTR region, thereby driving autophagy to promote tumorigenesis [ 226 ]. Hence, reduction of adipose accumulation through anti-autophagy pathways activated under conditions of FTO deficiency presents a critical strategy to prevent the harmful effects of increasing obesity [ 227 ]. Other m 6 A methylation regulators are additionally involved in modulation of autophagy.…”

Insights into N6-methyladenosine and programmed cell death in cancer

“…The morphological features are similar to nonregulated necrosis, manifesting as cytoplasmic vacuolization, organelle swelling and membrane rupture, which release DAMPs (damage-associated molecular patterns) to function. Most importantly, necroptosis can establish a cancer immunogenic microenvironment [ 110 ]. Lan et al recently revealed that M2-polarized tumor-associated macrophages (TAMs) and METTL3 in the oxaliplatin-tolerant CRC patient tumor microenvironment (TME) are higher than those in their sensitive counterparts.…”