scholarly journals Carcinogenesis-relevant biological events in the pathophysiology of the efferocytosis phenomenon

2017 ◽  
Author(s):  
Gargi Sachin Sarode ◽  
Sachin C. Sarode ◽  
Nikunj Maniyar ◽  
Nilesh Kumar Sharma ◽  
Shankargouda Patil
Keyword(s):  
Wound Healing ◽  
Cell Death ◽  
Tumor Microenvironment ◽  
Programmed Cell Death ◽  
Tissue Repair ◽  
Antitumor Immunity ◽  
Surrounding Tissue ◽  
Effective Removal ◽  
Immunosuppressive Action ◽  
Dying Cells

The effective removal of cells undergoing programmed cell death, which is referred to as efferocytosis, prevents the leakage of intracellular contents into the surrounding tissue, which could lead to tissue damage and inflammation. Efferocytosis involves a coordinated orchestration of multiple steps that lead to a swift, coherent and immunologically silent removal of dying cells. The release of wound healing cytokines, which resolve inflammation and enhance tissue repair, is an important feature of efferocytosis. However, in addition to the healing cytokines released during efferocytosis, the immunosuppressive action of cytokines promotes the tumor microenvironment, enhances the motility of cancer cells and promotes the evasion of antitumor immunity. The aim of the present review was to comprehensively discuss the efferocytosis phenomenon, the important players associated with this process and their role in cancer-related biological events.

Decoding Cell Death: From a Veritable Library of Babel to Vade Mecum?

2021 ◽  
Vol 39 (1) ◽  
pp. 791-817
Author(s):  
Lindsey D. Hughes ◽  
Yaqiu Wang ◽  
Alexandre P. Meli ◽  
Carla V. Rothlin ◽  
Sourav Ghosh
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Host Defense ◽  
Tissue Repair ◽  
Fundamental Question ◽  
Tissue Morphogenesis ◽  
Dying Cells ◽  
Effector Response

Programmed cell death (PCD) is a requisite feature of development and homeostasis but can also be indicative of infections, injuries, and pathologies. In concordance with these heterogeneous contexts, an array of disparate effector responses occur downstream of cell death and its clearance—spanning tissue morphogenesis, homeostatic turnover, host defense, active dampening of inflammation, and tissue repair. This raises a fundamental question of how a single contextually appropriate response ensues after an event of PCD. To explore how complex inputs may together tailor the specificity of the resulting effector response, here we consider ( a) the varying contexts during which different cell death modalities are observed, ( b) the nature of the information that can be passed on by cell corpses, and ( c) the ways by which efferocyte populations synthesize signals from dying cells with those from the surrounding microenvironment.

scholarly journals Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates antitumor immunity

2019 ◽  
Vol 4 (36) ◽  
pp. eaaw2004 ◽  
Author(s):  
Annelise G. Snyder ◽  
Nicholas W. Hubbard ◽  
Michelle N. Messmer ◽  
Sigal B. Kofman ◽  
Cassidy E. Hagan ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Microenvironment ◽  
Antitumor Immunity ◽  
De Novo ◽  
Immune Checkpoint Blockade ◽  
Treatment Modalities ◽  
Interacting Protein ◽  
Multiple Treatment ◽  
Proinflammatory Mediators ◽  
Dying Cells

Although the signaling events that induce different forms of programmed cell death are well defined, the subsequent immune responses to dying cells in the context of cancer remain relatively unexplored. Necroptosis occurs downstream of the receptor-interacting protein kinases RIPK1 and RIPK3, whose activation leads to lytic cell death accompanied by de novo production of proinflammatory mediators. Here, we show that ectopic introduction of necroptotic cells to the tumor microenvironment promotes BATF3+ cDC1− and CD8+ leukocyte–dependent antitumor immunity accompanied by increased tumor antigen loading by tumor-associated antigen-presenting cells. Furthermore, we report the development of constitutively active forms of the necroptosis-inducing enzyme RIPK3 and show that delivery of a gene encoding this enzyme to tumor cells using adeno-associated viruses induces tumor cell necroptosis, which synergizes with immune checkpoint blockade to promote durable tumor clearance. These findings support a role for RIPK1/RIPK3 activation as a beneficial proximal target in the initiation of tumor immunity. Considering that successful tumor immunotherapy regimens will require the rational application of multiple treatment modalities, we propose that maximizing the immunogenicity of dying cells within the tumor microenvironment through specific activation of the necroptotic pathway represents a beneficial treatment approach that may warrant further clinical development.

Programmed cell death during Drosophila embryogenesis

Development ◽  
1993 ◽  
Vol 117 (1) ◽  
pp. 29-43 ◽  
Author(s):  
J.M. Abrams ◽  
K. White ◽  
L.I. Fessler ◽  
H. Steller
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Acridine Orange ◽  
Nile Blue ◽  
Molecular Genetic ◽  
Blue Staining ◽  
Nuclear Condensation ◽  
The Central Nervous System ◽  
Ultrastructural Appearance ◽  
Dying Cells

The deliberate and orderly removal of cells by programmed cell death is a common phenomenon during the development of metazoan animals. We have examined the distribution and ultrastructural appearance of cell deaths that occur during embryogenesis in Drosophila melanogaster. A large number of cells die during embryonic development in Drosophila. These cells display ultrastructural features that resemble apoptosis observed in vertebrate systems, including nuclear condensation, fragmentation and engulfment by macrophages. Programmed cell deaths can be rapidly and reliably visualized in living wild-type and mutant Drosophila embryos using the vital dyes acridine orange or nile blue. Acridine orange appears to selectively stain apoptotic forms of death in these preparations, since cells undergoing necrotic deaths were not significantly labelled. Likewise, toluidine blue staining of fixed tissues resulted in highly specific labelling of apoptotic cells, indicating that apoptosis leads to specific biochemical changes responsible for the selective affinity to these dyes. Cell death begins at stage 11 (approximately 7 hours) of embryogenesis and thereafter becomes widespread, affecting many different tissues and regions of the embryo. Although the distribution of dying cells changes drastically over time, the overall pattern of cell death is highly reproducible for any given developmental stage. Detailed analysis of cell death in the central nervous system of stage 16 embryos (13-16 hours) revealed asymmetries in the exact number and position of dying cells on either side of the midline, suggesting that the decision to die may not be strictly predetermined at this stage. This work provides the basis for further molecular genetic studies on the control and execution of programmed cell death in Drosophila.

Internucleosomal DNA fragmentation and programmed cell death (apoptosis) in the interdigital tissue of the embryonic chick leg bud

1993 ◽  
Vol 106 (1) ◽  
pp. 201-208 ◽  
Author(s):  
V. Garcia-Martinez ◽  
D. Macias ◽  
Y. Ganan ◽  
J.M. Garcia-Lobo ◽  
M.V. Francia ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Dna Fragmentation ◽  
Limb Development ◽  
Light Transmission ◽  
Morphological Changes ◽  
Death Process ◽  
Chondrogenic Potential ◽  
Cell Death Process ◽  
Dying Cells

In this work we have attempted to characterize the programmed cell death process in the chick embryonic interdigital tissue. Interdigital cell death is a prominent phenomenon during limb development and has the role of sculpturing the digits. Morphological changes in the regressing interdigital tissue studied by light, transmission and scanning electron microscopy were correlated with the occurrence of internucleosomal DNA fragmentation, evaluated using agarose gels. Programming of the cell death process was also analyzed by testing the chondrogenic potential of the interdigital mesenchyme, in high density cultures. Our results reveal a progressive loss of the chondrogenic potential of the interdigital mesenchyme, detectable 36 hours before the onset of the degenerative process. Internucleosomal DNA fragmentation was only detected concomitant with the appearance of cells dying with the morphology of apoptosis, but unspecific DNA fragmentation was also present at the same time. This unspecific DNA fragmentation was explained by a precocious activation of the phagocytic removal of the dying cells, confirmed in the tissue sections. From our observations it is suggested that programming of cell death involves changes before endonuclease activation. Further, cell surface changes involved in the phagocytic uptake of the dying cells appear to be as precocious as endonuclease activation.

Widespread programmed cell death in proliferative and postmitotic regions of the fetal cerebral cortex

Development ◽  
1996 ◽  
Vol 122 (4) ◽  
pp. 1165-1174 ◽  
Author(s):  
A.J. Blaschke ◽  
K. Staley ◽  
J. Chun
Keyword(s):  
Cell Death ◽  
Cerebral Cortex ◽  
Programmed Cell Death ◽  
Nuclear Dna ◽  
Temporal Distribution ◽  
Embryonic Cell ◽  
Postnatal Life ◽  
Neuron Development ◽  
Cortical Cells ◽  
Dying Cells

A key event in the development of the mammalian cerebral cortex is the generation of neuronal populations during embryonic life. Previous studies have revealed many details of cortical neuron development including cell birthdates, migration patterns and lineage relationships. Programmed cell death is a potentially important mechanism that could alter the numbers and types of developing cortical cells during these early embryonic phases. While programmed cell death has been documented in other parts of the embryonic central nervous system, its operation has not been previously reported in the embryonic cortex because of the lack of cell death markers and the difficulty in following the entire population of cortical cells. Here, we have investigated the spatial and temporal distribution of dying cells in the embryonic cortex using an in situ endlabelling technique called ‘ISEL+’ that identifies fragmented nuclear DNA in dying cells with increased sensitivity. The period encompassing murine cerebral cortical neurogenesis was examined, from embryonic days 10 through 18. Dying cells were rare at embryonic day 10, but by embryonic day 14, 70% of cortical cells were found to be dying. This number declined to 50% by embryonic day 18, and few dying cells were observed in the adult cerebral cortex. Surprisingly, while dying cells were observed throughout the cerebral cortical wall, the majority were found within zones of cell proliferation rather than in regions of postmitotic neurons. These observations suggest that multiple mechanisms may regulate programmed cell death in the developing cortex. Moreover, embryonic cell death could be an important factor enabling the selection of appropriate cortical cells before they complete their differentiation in postnatal life.

Metabolic events during programmed cell death in insect labial glands

1994 ◽  
Vol 72 (11-12) ◽  
pp. 597-601 ◽  
Author(s):  
Reginald Halaby ◽  
Zahra Zakeri ◽  
Richard A. Lockshin
Keyword(s):  
Cell Death ◽  
Protein Synthesis ◽  
Acid Phosphatase ◽  
Programmed Cell Death ◽  
Manduca Sexta ◽  
Adenosine Triphosphate ◽  
Mitochondrial Respiration ◽  
Second Messengers ◽  
Labial Gland ◽  
Dying Cells

The labial gland of Manduca sexta is a valuable system to study the mechanisms of programmed cell death since the death of the gland is nearly synchronous and, except for the anterior duct, involves all of the tissue. The gland degenerates in 5 days during pupation. Our previous work documents a drop in total protein synthesis as the gland degenerates. To evaluate potential causes of this altered protein synthesis, we monitored several parameters of metabolism in dying cells: levels of adenosine triphosphate to estimate the energy resources of the gland; reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to assess mitochondrial respiration; levels of acid phosphatase to assay lysosomal enzyme activity; and concentrations of cyclic nucleotides and inositol triphosphate to monitor signaling. While protein synthesis fell precipitously on day 0, total adenosine triphosphate and mitochondrial respiration were unchanged until the cells underwent massive collapse on day 3. Lysosomal acid phosphatase increased during early metamorphosis, and ultimately the bulk of the cytoplasm was destroyed in autophagic vacuoles. Changes in the concentrations of second messengers were modest and late. The relationships between the metabolism and the collapse of the labial gland are under investigation.Key words: programmed cell death, Manduca sexta, energetics, lysosomes, second messengers, protein synthesis.

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.

scholarly journals The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

2021 ◽  
Vol 9 ◽  
Author(s):  
Nádia Ghinelli Amôr ◽  
Paulo Sérgio da Silva Santos ◽  
Ana Paula Campanelli
Keyword(s):  
Cell Death ◽  
Monoclonal Antibodies ◽  
Tumor Microenvironment ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Molecules

Squamous cell carcinoma (SCC) is the second most common skin cancer worldwide and, despite the relatively easy visualization of the tumor in the clinic, a sizeable number of SCC patients are diagnosed at advanced stages with local invasion and distant metastatic lesions. In the last decade, immunotherapy has emerged as the fourth pillar in cancer therapy via the targeting of immune checkpoint molecules such as programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). FDA-approved monoclonal antibodies directed against these immune targets have provide survival benefit in a growing list of cancer types. Currently, there are two immunotherapy drugs available for cutaneous SCC: cemiplimab and pembrolizumab; both monoclonal antibodies (mAb) that block PD-1 thereby promoting T-cell activation and/or function. However, the success rate of these checkpoint inhibitors currently remains around 50%, which means that half of the patients with advanced SCC experience no benefit from this treatment. This review will highlight the mechanisms by which the immune checkpoint molecules regulate the tumor microenvironment (TME), as well as the ongoing clinical trials that are employing single or combinatory therapeutic approaches for SCC immunotherapy. We also discuss the regulation of additional pathways that might promote superior therapeutic efficacy, and consequently provide increased survival for those patients that do not benefit from the current checkpoint inhibitor therapies.

scholarly journals Necrosis-induced apoptosis promotes regeneration in Drosophila wing imaginal discs

Genetics ◽  
2021 ◽  
Author(s):  
Jacob Klemm ◽  
Michael J Stinchfield ◽  
Robin E Harris
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Tissue Loss ◽  
Similar Response ◽  
Wound Edge ◽  
Jnk Signaling ◽  
Drosophila Wing ◽  
Complex Process ◽  
Induced Apoptosis ◽  
Dying Cells

Abstract Regeneration is a complex process that requires a coordinated genetic response to tissue loss. Signals from dying cells are crucial to this process and are best understood in the context of regeneration following programmed cell death, like apoptosis. Conversely, regeneration following unregulated forms of death such as necrosis have yet to be fully explored. Here we have developed a method to investigate regeneration following necrosis using the Drosophila wing imaginal disc. We show that necrosis stimulates regeneration at an equivalent level to that of apoptosis-mediated cell death and activates a similar response at the wound edge involving localized JNK signaling. Unexpectedly however, necrosis also results in significant apoptosis far from the site of ablation, which we have termed necrosis-induced apoptosis (NiA). This apoptosis occurs independent of changes at the wound edge and importantly does not rely on JNK signaling. Furthermore, we find that blocking NiA limits proliferation and subsequently inhibits regeneration, suggesting that tissues damaged by necrosis can activate programmed cell death at a distance from the injury to promote regeneration.

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