Unconventional Ways to Live and Die: Cell Death and Survival in Development, Homeostasis, and Disease

Abstract

Balancing cell death and survival is essential for normal development and homeostasis and for preventing diseases, especially cancer. Conventional cell death pathways include apoptosis, a form of programmed cell death controlled by a well-defined biochemical pathway, and necrosis, the lysis of acutely injured cells. New types of regulated cell death include necroptosis, pyroptosis, ferroptosis, phagoptosis, and entosis. Autophagy can promote survival or can cause death. Newly described processes of anastasis and resuscitation show that, remarkably, cells can recover from the brink of apoptosis or necroptosis. Important new work shows that epithelia achieve homeostasis by extruding excess cells, which then die by anoikis due to loss of survival signals. This mechanically regulated process both maintains barrier function as cells die and matches rates of proliferation and death. In this review, we describe these unconventional ways in which cells have evolved to die or survive, as well as the contributions that these processes make to homeostasis and cancer.

Keywords: anastasis; apoptosis; autophagy; cell death; extrusion; necrosis.

Figure 1

Recovery from the brink of death. Eukaryotic cells have been reported to survive the biochemical hallmarks of entosis, apoptosis, and necroptosis. (a) Entosis results when one cell pushes itself into another by Rho- and ROCK-driven myosin contraction. This results in a cell-in-cell structure. The entosed cell, whether a cancer cell or a normal cell, can either be degraded within the host cell or be released and survive. (b) Apoptosis results in cell shrinkage, membrane blebbing, and phosphatidylserine (PS) exposure (purple) due to executioner caspase activation. Cells with activated caspase can break into apoptotic bodies and die or can undergo anastasis and recover. Survival by anastasis can result in an elongated cell morphology and increased motility. (c) Necroptosis is a form of regulated necrosis carried out by the activation of RIPKs (receptor-interacting kinases) and MLKL (mixed lineage kinase–like). Active MLKL damages the plasma membrane of cells, results in PS exposure, and kills the cell by lysis. However, provided that MLKL activity is halted, cells can survive in a process termed resuscitation by ESCRT-mediated membrane repair.

Figure 2

Extrusion removes epithelial cells in response to crowding forces during homeostasis or apoptotic stimuli. (a) During apoptotic apical extrusion, the cell destined to die produces the bioactive lipid sphingosine-1-phosphate (S1P), which binds to the sphingosine-1-phosphate 2 (S1P₂) receptor in the neighboring cells to activate actomyosin contraction and squeeze the extruding cell out. These cells then die by anoikis or death due to loss of matrix-dependent survival signaling. (b) Disruption of apical extrusion signaling in epithelial cells (green; normal cells are shown in gray) can lead to formation of masses at sites where cells should have extruded and died and to basal extrusion, which enables invasion and initiation of metastasis. Oncogenic mutations in K-Ras and APC, and downregulation of S1P₂, disrupt apical extrusion and may account for the chemoresistance and highly invasive nature of pancreatic, lung, and colon tumors driven by these mutations.