scholarly journals Apoptosis-induced FGF signalling promotes non-cell autonomous resistance to cell death

2020 ◽  
Author(s):  
Florian J. Bock ◽  
Catherine Cloix ◽  
Desiree Zerbst ◽  
Stephen W.G. Tait
Keyword(s):  
Cell Death ◽  
Apoptotic Cells ◽  
Potential Danger ◽  
Fgf Receptor ◽  
A Cell ◽  
Response To Stress ◽  
Cancer Types ◽  
Fgf Signalling ◽  
Dying Cells ◽  
Worse Prognosis

AbstractDamaged or superfluous cells are often eliminated by apoptosis. Although a cell-autonomous process, apoptotic cells communicate with their environment in different ways. However, the extent to which apoptotic cells alerting their neighbours to potential danger is unclear. Addressing this question, here we describe a mechanism whereby dying cells can promote survival of neighbouring cells. We find that during apoptosis, cells release the growth factor FGF2, leading to MEK/ERK-dependent transcriptional upregulation of pro-survival BCL-2 proteins in a non-cell autonomous manner. This transient upregulation of prosurvival BCL-2 proteins in turn can protect neighbouring cells from apoptosis. Accordingly, we find in certain cancer types a correlation between FGF-signalling, BCL-2 expression and worse prognosis. Importantly, either co-treatment with FGF-receptor inhibitors or removal of apoptotic stress restores apoptotic sensitivity. These data reveal a pathway by which dying cells can increase resistance to cell death in surrounding cells. Beyond mediating cytotoxic drug resistance, this process may serve additional roles, for instance limiting tissue damage in response to stress.

scholarly journals Apoptotic stress-induced FGF signalling promotes non-cell autonomous resistance to cell death

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Florian J. Bock ◽  
Egor Sedov ◽  
Elle Koren ◽  
Anna L. Koessinger ◽  
Catherine Cloix ◽  
...  
Keyword(s):  
Cell Death ◽  
Dependent Manner ◽  
Fgf Receptor ◽  
Skin Repair ◽  
Potential Link ◽  
A Cell ◽  
Cancer Types ◽  
Fgf Signalling ◽  
Worse Prognosis

AbstractDamaged or superfluous cells are typically eliminated by apoptosis. Although apoptosis is a cell-autonomous process, apoptotic cells communicate with their environment in different ways. Here we describe a mechanism whereby cells under apoptotic stress can promote survival of neighbouring cells. We find that upon apoptotic stress, cells release the growth factor FGF2, leading to MEK-ERK-dependent transcriptional upregulation of pro-survival BCL-2 proteins in a non-cell autonomous manner. This transient upregulation of pro-survival BCL-2 proteins protects neighbouring cells from apoptosis. Accordingly, we find in certain cancer types a correlation between FGF-signalling, BCL-2 expression and worse prognosis. In vivo, upregulation of MCL-1 occurs in an FGF-dependent manner during skin repair, which regulates healing dynamics. Importantly, either co-treatment with FGF-receptor inhibitors or removal of apoptotic stress restores apoptotic sensitivity to cytotoxic therapy and delays wound healing. These data reveal a pathway by which cells under apoptotic stress can increase resistance to cell death in surrounding cells. Beyond mediating cytotoxic drug resistance, this process also provides a potential link between tissue damage and repair.

scholarly journals “Dead Cells Talking”: The Silent Form of Cell Death Is Not so Quiet

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Richard Jäger ◽  
Howard O. Fearnhead
Keyword(s):  
Cell Death ◽  
Cancer Therapy ◽  
Apoptotic Cell ◽  
Surrounding Tissue ◽  
Apoptotic Cells ◽  
Cancer Cell Proliferation ◽  
Loss Of Function ◽  
Molecular Events ◽  
Dying Cells

After more than twenty years of research, the molecular events of apoptotic cell death can be succinctly stated; different pathways, activated by diverse signals, increase the activity of proteases called caspases that rapidly and irreversibly dismantle condemned cell by cleaving specific substrates. In this time the ideas that apoptosis protects us from tumourigenesis and that cancer chemotherapy works by inducing apoptosis also emerged. Currently, apoptosis research is shifting away from the intracellular events within the dying cell to focus on the effect of apoptotic cells on surrounding tissues. This is producing counterintuitive data showing that our understanding of the role of apoptosis in tumourigenesis and cancer therapy is too simple, with some interesting and provocative implications. Here, we will consider evidence supporting the idea that dying cells signal their presence to the surrounding tissue and, in doing so, elicit repair and regeneration that compensates for any loss of function caused by cell death. We will discuss evidence suggesting that cancer cell proliferation may be driven by inappropriate or corrupted tissue-repair programmes that are initiated by signals from apoptotic cells and show how this may dramatically modify how we view the role of apoptosis in both tumourigenesis and cancer therapy.

Cell death in normal and rough eye mutants of Drosophila

Development ◽  
1991 ◽  
Vol 113 (3) ◽  
pp. 825-839 ◽  
Author(s):  
T. Wolff ◽  
D.F. Ready
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Compound Eye ◽  
Cell Lineage ◽  
Cell Fates ◽  
Cone Cells ◽  
A Cell ◽  
Retinal Epithelium ◽  
Fly Eye ◽  
Dying Cells

The regular, reiterated cellular pattern of the Drosophila compound eye makes it a sensitive amplifier of defects in cell death. Quantitative and histological methods reveal a phase of cell death between 35 and 50 h of development which removes between 2 and 3 surplus cells per ommatidium. The timing of this epoch is consistent with cell death as the last fate to be specified in the progressive sequence of cell fates that build the ommatidium. An ultrastructural survey of cell death suggests dying cells in the fly eye have similarities as well as differences with standard descriptions of programmed cell death. A failure of cell death to remove surplus cells disorganizes the retinal lattice. A screen of rough eye mutants identifies two genes, roughest and echinus, required for the normal elimination of cells from the retinal epithelium. The use of an enhancer trap as a cell lineage marker shows that the cone cells, like other retinal cells, are not clonally related to each other or to their neighbors.

scholarly journals Distinct Modes of Macrophage Recognition for Apoptotic and Necrotic Cells Are Not Specified Exclusively by Phosphatidylserine Exposure

2001 ◽  
Vol 12 (4) ◽  
pp. 919-930 ◽  
Author(s):  
Regina E. Cocco ◽  
David S. Ucker
Keyword(s):  
Macrophage Activation ◽  
Apoptotic Cells ◽  
Activated Macrophages ◽  
Necrotic Cell ◽  
Phagocytic Cells ◽  
Marked Contrast ◽  
Proinflammatory Responses ◽  
A Cell ◽  
Dying Cells ◽  
Specific Ligand

The distinction between physiological (apoptotic) and pathological (necrotic) cell deaths reflects mechanistic differences in cellular disintegration and is of functional significance with respect to the outcomes that are triggered by the cell corpses. Mechanistically, apoptotic cells die via an active and ordered pathway; necrotic deaths, conversely, are chaotic and passive. Macrophages and other phagocytic cells recognize and engulf these dead cells. This clearance is believed to reveal an innate immunity, associated with inflammation in cases of pathological but not physiological cell deaths. Using objective and quantitative measures to assess these processes, we find that macrophages bind and engulf native apoptotic and necrotic cells to similar extents and with similar kinetics. However, recognition of these two classes of dying cells occurs via distinct and noncompeting mechanisms. Phosphatidylserine, which is externalized on both apoptotic and necrotic cells, is not a specific ligand for the recognition of either one. The distinct modes of recognition for these different corpses are linked to opposing responses from engulfing macrophages. Necrotic cells, when recognized, enhance proinflammatory responses of activated macrophages, although they are not sufficient to trigger macrophage activation. In marked contrast, apoptotic cells profoundly inhibit phlogistic macrophage responses; this represents a cell-associated, dominant-acting anti-inflammatory signaling activity acquired posttranslationally during the process of physiological cell death.

The final step in programmed cell death: phagocytes carry apoptotic cells to the grave

2003 ◽  
Vol 39 ◽  
pp. 105-117 ◽  
Author(s):  
Aimee M deCathelineau ◽  
Peter M Henson
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
The Body ◽  
Apoptotic Cells ◽  
Cytokines And Chemokines ◽  
Cell Clearance ◽  
And Function ◽  
Multicellular Organisms ◽  
Dying Cells ◽  
High Degree

As cells undergo apoptosis, they are recognized and removed from the body by phagocytes. This oft-overlooked yet critical final step in the cell-death programme protects tissues from exposure to the toxic contents of dying cells and also serves to prevent further tissue damage by stimulating production of anti-inflammatory cytokines and chemokines. The clearance of apoptotic-cell corpses occurs throughout the lifespan of multicellular organisms and is important for normal development during embryogenesis, the maintenance of normal tissue integrity and function, and the resolution of inflammation. Many of the signal-transduction molecules implicated in the phagocytosis of apoptotic cells appear to have a high degree of evolutionary conservation, and therefore the engulfment of apoptotic cells is likely to represent one of the most primitive forms of phagocytosis. With the realization that the signals that govern apoptotic-cell removal also serve to attenuate inflammation and the immune response, as well as initiate signals for tissue repair and remodelling in response to cell death, the study of apoptotic cell clearance is a field experiencing a dynamic increase in interest and momentum.

Apoptosis in the lung: induction, clearance and detection

2008 ◽  
Vol 294 (4) ◽  
pp. L601-L611 ◽  
Author(s):  
P. M. Henson ◽  
R. M. Tuder
Keyword(s):  
Cell Death ◽  
Tissue Repair ◽  
Alternative Explanation ◽  
Apoptotic Cell ◽  
Lung Cells ◽  
Apoptotic Cells ◽  
Local Responses ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Dying Cells

Apoptosis and other forms of programmed cell death are important contributors to lung pathophysiology. In this brief review, we discuss some of the implications of finding apoptotic cells in the lung and methods for their detection. The balance between induction of apoptosis and the normally highly efficient clearance of such cells shows that these are highly dynamic processes and suggests that abnormalities of apoptotic cell clearance may be an alternative explanation for their detection. Because recognition of apoptotic cells by other lung cells has additional effects on inflammation, immunity, and tissue repair, local responses to the dying cells may also have important consequences in addition to the cell death itself.

scholarly journals Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabditis elegans.

Genetics ◽  
1991 ◽  
Vol 129 (1) ◽  
pp. 79-94 ◽  
Author(s):  
R E Ellis ◽  
D M Jacobson ◽  
H R Horvitz
Keyword(s):  
Cell Death ◽  
Caenorhabditis Elegans ◽  
Programmed Cell Death ◽  
Nematode Caenorhabditis Elegans ◽  
Electron Microscopic ◽  
New Genes ◽  
Microscopic Studies ◽  
A Cell ◽  
Cell Corpse ◽  
Dying Cells

Abstract After programmed cell death, a cell corpse is engulfed and quickly degraded by a neighboring cell. For degradation to occur, engulfing cells must recognize, phagocytose and digest the corpses of dying cells. Previously, three genes were known to be involved in eliminating cell corpses in the nematode Caenorhabditis elegans: ced-1, ced-2 and nuc-1. We have identified five new genes that play a role in this process: ced-5, ced-6, ced-7, ced-8 and ced-10. Electron microscopic studies reveal that mutations in each of these genes prevent engulfment, indicating that these genes are needed either for the recognition of corpses by other cells or for the initiation of phagocytosis. Based upon our study of double mutants, these genes can be divided into two sets. Animals with mutations in only one of these sets of genes have relatively few unengulfed cell corpses. By contrast, animals with mutations in both sets of genes have many unengulfed corpses. These observations suggest that these two sets of genes are involved in distinct and partially redundant processes that act in the engulfment of cell corpses.

scholarly journals Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Ainhoa Pérez-Garijo ◽  
Yaron Fuchs ◽  
Hermann Steller
Keyword(s):  
Cell Death ◽  
Local Environment ◽  
Wing Disc ◽  
Follicle Cells ◽  
Apoptotic Cells ◽  
Jnk Pathway ◽  
Tnf Α ◽  
Induced Apoptosis ◽  
Dying Cells ◽  
Necrosis Factor

Apoptotic cells can produce signals to instruct cells in their local environment, including ones that stimulate engulfment and proliferation. We identified a novel mode of communication by which apoptotic cells induce additional apoptosis in the same tissue. Strong induction of apoptosis in one compartment of the Drosophila wing disc causes apoptosis of cells in the other compartment, indicating that dying cells can release long-range death factors. We identified Eiger, the Drosophila tumor necrosis factor (TNF) homolog, as the signal responsible for apoptosis-induced apoptosis (AiA). Eiger is produced in apoptotic cells and, through activation of the c-Jun N-terminal kinase (JNK) pathway, is able to propagate the initial apoptotic stimulus. We also show that during coordinated cell death of hair follicle cells in mice, TNF-α is expressed in apoptotic cells and is required for normal cell death. AiA provides a mechanism to explain cohort behavior of dying cells that is seen both in normal development and under pathological conditions.

scholarly journals Anti-apogens and anti-engulfens: monoclonal antibodies reveal specific antigens on apoptotic and engulfment cells during chicken embryonic development

Development ◽  
1994 ◽  
Vol 120 (6) ◽  
pp. 1421-1431 ◽  
Author(s):  
R.J. Rotello ◽  
P.A. Fernandez ◽  
J. Yuan
Keyword(s):  
Cell Death ◽  
Monoclonal Antibodies ◽  
Programmed Cell Death ◽  
Apoptotic Cell ◽  
Cell Types ◽  
Apoptotic Cells ◽  
Specific Antigens ◽  
Common Leukocyte Antigen ◽  
Cell Death Mechanisms ◽  
Dying Cells

We have isolated a group of monoclonal antibodies that specifically recognize either apoptotic or engulfment cells in the interdigit areas of chicken hind limb foot plates, and throughout the embryo. Ten of these antibodies (anti-apogens) detect epitopes on dying cells that colocalize to areas of programmed cell death, characterized by the presence of apoptotic cells and bodies with typical cellular and nuclear morphology. Our results indicate that cells destined to die, or that are in the process of dying, express specific antigens that are not detectable in or on the surface of living cells. The detection of these apoptotic cell antigens in other areas of programmed cell death throughout the chick embryo indicates that different cell types, which form specific tissues and organs, may utilize similar cell death mechanisms. Six of the monoclonal antibodies (antiengulfens) define a class of engulfment cells which contain various numbers of apoptotic cells and/or apoptotic bodies in areas of programmed cell death. The immunostaining pattern of the anti-engulfen R15F is similar to that of an antibody against a common leukocyte antigen, suggesting the participation of cells from the immune system in the removal of apoptotic cell debris. These novel monoclonal antibody markers for apoptotic and engulfment cells will provide new tools to assist the further understanding of developmental programmed cell death in vertebrates.

scholarly journals Current Understanding of the Mechanisms for Clearance of Apoptotic Cells—A Fine Balance

2013 ◽  
Vol 6 ◽  
pp. JCD.S11037 ◽  
Author(s):  
Lois A. Hawkins ◽  
Andrew Devitt
Keyword(s):  
Cell Death ◽  
Innate Immune System ◽  
Inflammatory Process ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Apoptotic Cells ◽  
Viable Cells ◽  
Effective Removal ◽  
Multicellular Organisms ◽  
Dying Cells

Apoptosis is an important cell death mechanism by which multicellular organisms remove unwanted cells. It culminates in a rapid, controlled removal of cell corpses by neighboring or recruited viable cells. Whilst many of the molecular mechanisms that mediate corpse clearance are components of the innate immune system, clearance of apoptotic cells is an anti-inflammatory process. Control of cell death is dependent on competing pro-apoptotic and anti-apoptotic signals. Evidence now suggests a similar balance of competing signals is central to the effective removal of cells, through so called ‘eat me’ and ‘don't eat me’ signals. Competing signals are also important for the controlled recruitment of phagocytes to sites of cell death. Consequently recruitment of phagocytes to and from sites of cell death can underlie the resolution or inappropriate propagation of cell death and inflammation. This article highlights our understanding of mechanisms mediating clearance of dying cells and discusses those mechanisms controlling phagocyte migration and how inappropriate control may promote important pathologies.

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