8/15/2023 0 Comments Dead cells routes 1.2![]() In cancers where vascularization is often poor and nutrients can be scarce, the scavenging of extracellular protein through macropinocytosis is known to supply amino acids in support of cancer growth. Similarly, pancreatic cancer cells have been shown to utilize amino acids from macropinocytosed necrotic cell debris to fuel the accumulation of biomass in support of proliferation. The metabolic load from apoptotic cell digestion may be significant in some contexts, as individual macrophages can contain up to 10 to 20 phagocytosed corpses. The phagocytic clearance of apoptotic cells, for example, has been shown to lead to macrophage utilization of amino acids derived from ingested corpses, demonstrating that nutrients recovered from engulfed cells can be used to support metabolism. One after-death function of cell death that may be shared among different mechanisms is the transfer of nutrients from dead cells to the engulfing cells that ingest them ( Figure 1). ![]() Nutrient Transfer From Cell Corpses Through Engulfment We discuss how these may be shared or distinct between different mechanisms, and how after-death functions may contribute to the many different roles of cell death in physiology. Here we consider one particular feature, that the remnants that are left behind by death may have specific “after-death” functions. ![]() That numerous mechanisms have emerged to eliminate cells suggests the presence of additional distinguishing features that may underlie the utilization of particular forms of cell death in different contexts. While differences in the crosstalk between apoptosis and necrosis and the immune system may underlie, at least in part, the different physiologic functions of these mechanisms, there are now numerous additional forms of cell death, up to at least 12 in total, that have been discovered. Whereas apoptosis removes cells during development and under normal physiologic conditions, necrotic mechanisms are not utilized in normal tissues, likely due to their potent pro-inflammatory activity. Numerous regulated mechanisms of necrosis, including necroptosis, pyroptosis, and ferroptosis, have been discovered that eliminate damaged or infected cells. By releasing pro-inflammatory cytokines and intracellular damage-associated molecular pattern molecules (DAMPs) that signal to activate immune cells, necrotic deaths promote immune responses that protect the organism from infection. Notably, several forms of necrosis can be induced by cell damage or infection that differ from apoptosis because they involve rapid rupture of the plasma membrane. Research over the last two decades has revealed numerous additional regulated mechanisms of cell death. Because apoptotic bodies typically remain intact and do not release intracellular contents that can be pro-inflammatory, apoptotic death generally occurs in an immunologically silent manner, a feature that avoids potentially harmful immune responses when cells undergo death as part of normal physiology. ![]() Cells undergoing apoptosis shrink and fragment into pieces, called apoptotic bodies, that are cleared by neighboring cells or immune cells through phagocytosis. Tissue regression occurs as a result of the programmed death of individual cells, typically through a mechanism called apoptosis that is executed by the activation of caspase proteases. The idea that death is a regulated cell fate originated from observations of insect metamorphosis, where developmental tissue structures undergo hormone-induced regression. Some cells also die as part of a normal cycle of rapid cell turnover that supports the function of specific tissues, or are removed to eliminate specialized structures during development. Individual cells undergo death and are removed from tissues when they are damaged, aged, or infected, and their dysfunction presents a threat to the organism. To choose to die instead of live is one of numerous cell fate decisions that individual cells make, along with entering quiescence or senescence, or undergoing differentiation, that contributes to maintaining proper tissue function.
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