The Apoptosis Paradox in Cancer Morana, Ornella; Wood, Will; Gregory, Christopher D
International journal of molecular sciences,
01/2022, Letnik:
23, Številka:
3
Journal Article
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Cancer growth represents a dysregulated imbalance between cell gain and cell loss, where the rate of proliferating mutant tumour cells exceeds the rate of those that die. Apoptosis, the most renowned ...form of programmed cell death, operates as a key physiological mechanism that limits cell population expansion, either to maintain tissue homeostasis or to remove potentially harmful cells, such as those that have sustained DNA damage. Paradoxically, high-grade cancers are generally associated with high constitutive levels of apoptosis. In cancer, cell-autonomous apoptosis constitutes a common tumour suppressor mechanism, a property which is exploited in cancer therapy. By contrast, limited apoptosis in the tumour-cell population also has the potential to promote cell survival and resistance to therapy by conditioning the tumour microenvironment (TME)-including phagocytes and viable tumour cells-and engendering pro-oncogenic effects. Notably, the constitutive apoptosis-mediated activation of cells of the innate immune system can help orchestrate a pro-oncogenic TME and may also effect evasion of cancer treatment. Here, we present an overview of the implications of cell death programmes in tumour biology, with particular focus on apoptosis as a process with "double-edged" consequences: on the one hand, being tumour suppressive through deletion of malignant or pre-malignant cells, while, on the other, being tumour progressive through stimulation of reparatory and regenerative responses in the TME.
Macrophages are multifunctional innate immune cells that seed all tissues within the body and play disparate roles throughout development and in adult tissues, both in health and disease. Their ...complex developmental origins and many of their functions are being deciphered in mammalian tissues, but opportunities for live imaging and the genetic tractability of Drosophila are offering complementary insights into how these fascinating cells integrate a multitude of guidance cues to fulfill their many tasks and migrate to distant sites to either direct developmental patterning or raise an inflammatory response.
Wood and Martin discuss the similarities between mouse and Drosophila macrophages in the contexts of development, phagocytosis, patterning and immune response, and disease states. They discuss the advances allowed by live imaging and fly genetics, and how insights from both insect and mammalian systems can be combined.
What are the earliest signals produced at a wound edge that mobilise epithelial cells to heal the wound? Live analysis of wound healing in the worm Caenorhabditis elegans shows that calcium may be ...the key early trigger.
Adipocytes have many functions in various tissues beyond energy storage, including regulating metabolism, growth, and immunity. However, little is known about their role in wound healing. Here we use ...live imaging of fat body cells, the equivalent of vertebrate adipocytes in Drosophila, to investigate their potential behaviors and functions following skin wounding. We find that pupal fat body cells are not immotile, as previously presumed, but actively migrate to wounds using an unusual adhesion-independent, actomyosin-driven, peristaltic mode of motility. Once at the wound, fat body cells collaborate with hemocytes, Drosophila macrophages, to clear the wound of cell debris; they also tightly seal the epithelial wound gap and locally release antimicrobial peptides to fight wound infection. Thus, fat body cells are motile cells, enabling them to migrate to wounds to undertake several local functions needed to drive wound repair and prevent infections.
•Fat body cells actively migrate to wounds using a peristaltic mode of motility•Fat body cells tightly seal the gap by forming lamellipodia around the wound margin•Fat body cells collaborate with macrophages to clear wound debris•Fat body cells locally release antimicrobial peptides at infected wounds
Adipocytes and their fly equivalent, fat body cells, have been considered immotile, but Franz et al. now show the latter can actively migrate to wounds using a peristaltic-like “swimming” motility. Once there, they multitask to clear wound cell debris, plug the epithelial gap, and upregulate AMPs to prevent infection.
A crucial early wound response is the recruitment of inflammatory cells drawn by danger cues released by the damaged tissue. Hydrogen peroxide (H2O2) has recently been identified as the earliest ...wound attractant in Drosophila embryos and zebrafish larvae 1, 2. The H2O2 signal is generated by activation of an NADPH oxidase, DUOX, and as a consequence, the first inflammatory cells are recruited to the wound within minutes. To date, nothing is known about how wounding activates DUOX. Here, we show that laser wounding of the Drosophila embryo epidermis triggers an instantaneous calcium flash, which travels as a wave via gap junctions several cell rows back from the wound edge. Blocking this calcium flash inhibits H2O2 release at the wound site and leads to a reduction in the number of immune cells migrating to the wound. We suggest that the wound-induced calcium flash activates DUOX via an EF hand calcium-binding motif and thus triggers the production of the attractant damage cue H2O2. Therefore, calcium represents the earliest signal in the wound inflammatory response.
► Wounding the Drosophila embryo epidermis leads to a rapid intracellular Ca2+ wave ► Blocking the Ca2+ response leads to reduced H2O2 and hemocytes at wounds ► DUOX’s EF hand domain is indispensible to interpret wound-induced Ca2+ flashes
In healthy individuals, injured tissues rapidly repair themselves following damage. Within a healing skin wound, recruited inflammatory cells release a multitude of bacteriocidal factors, including ...reactive oxygen species (ROS), to eliminate invading pathogens. Paradoxically, while these highly reactive ROS confer resistance to infection, they are also toxic to host tissues and may ultimately delay repair. Repairing tissues have therefore evolved powerful cytoprotective “resilience” machinery to protect against and tolerate this collateral damage. Here, we use in vivo time-lapse imaging and genetic manipulation in Drosophila to dissect the molecular and cellular mechanisms that drive tissue resilience to wound-induced stress. We identify a dynamic, cross-regulatory network of stress-activated cytoprotective pathways, linking calcium, JNK, Nrf2, and Gadd45, that act to both “shield” tissues from oxidative damage and promote efficient damage repair. Ectopic activation of these pathways confers stress protection to naive tissue, while their inhibition leads to marked delays in wound closure. Strikingly, the induction of cytoprotection is tightly linked to the pathways that initiate the inflammatory response, suggesting evolution of a fail-safe mechanism for tissue protection each time inflammation is triggered. A better understanding of these resilience mechanisms—their identities and precise spatiotemporal regulation—is of major clinical importance for development of therapeutic interventions for all pathologies linked to oxidative stress, including debilitating chronic non-healing wounds.
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•Tissue damage and inflammation activate cytoprotective genes to confer resilience•Nrf2 and Gadd45 resilience factors are required for effective wound repair in vivo•Nrf2 and Gaddd45 limit inflammatory ROS damage and promote DNA damage repair•Ectopic resilience gene induction can protect naive unwounded tissue from damage
Weavers et al. use live-imaging and genetic approaches in Drosophila to identify how tissue damage activates a dynamic cytoprotective network (involving JNK, Nrf2, and Gadd45) within the repairing epithelium, which confers stress “resilience” by protecting against inflammatory ROS damage, and is essential for driving efficient wound repair.
Macrophages must not only be responsive to an array of different stimuli, such as infection and cellular damage, but also perform phagocytosis within the diverse and complex tissue environments found ...in vivo. This requires a high degree of morphological and therefore cytoskeletal plasticity. Here, we use the exceptional genetics and in vivo imaging of Drosophila embryos to study macrophage phagocytic versatility during apoptotic corpse clearance. We find that macrophage phagocytosis is highly robust, arising from their possession of two distinct modes of engulfment that utilize exclusive suites of actin-regulatory proteins. “Lamellipodial phagocytosis” is Arp2/3-complex-dependent and allows cells to migrate toward and envelop apoptotic corpses. Alternatively, Diaphanous and Ena drive filopodial phagocytosis to reach out and draw in debris. Macrophages switch to “filopodial phagocytosis” to overcome spatial constraint, providing the robust plasticity necessary to ensure that whatever obstacle they encounter in vivo, they fulfil their critical clearance function.
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•Macrophages use two distinct modes of engulfment: lamellipodial and filopodial phagocytosis•Arp2/3-complex-dependent lamellipodial phagocytosis involves envelopment via a lamellipod•Filopodial phagocytosis involves phagocytic filopods extended by Dia and/or Ena•Macrophages switch to filopodial phagocytosis to overcome spatial constraint in vivo
Through the use of Drosophila genetics and the excellent in vivo imaging possible in the fly embryo, Davidson and Wood demonstrate that macrophages switch from engulfing debris via sheet-like lamellipods (lamellipodial phagocytosis) to extending phagocytic filopods (filopodial phagocytosis) when spatially confined, thus maintaining their critical clearance function in vivo.
Wound repair is a fundamental, conserved mechanism for maintaining tissue homeostasis and shares many parallels with embryonic morphogenesis. Small wounds in simple epithelia rapidly assemble a ...contractile actomyosin cable at their leading edge, as well as dynamic filopodia that finally knit the wound edges together. Most studies of wound re-epithelialisation have focused on the actin machineries that assemble in the leading edge of front row cells and that resemble the contractile mechanisms that drive morphogenetic episodes, including Drosophila dorsal closure, but, clearly, multiple cell rows back must also contribute for efficient repair of the wound. Here, we examine the role of cells back from the wound edge and show that they also stretch towards the wound and cells anterior-posterior to the wound edge rearrange their junctions with neighbours to drive cell intercalation events. This process in anterior-posterior cells is active and dependent on pulses of actomyosin that lead to ratcheted shrinkage of junctions; the actomyosin pulses are targeted to breaks in the cell polarity protein Par3 at cell vertices. Inhibiting actomyosin dynamics back from the leading edge prevents junction shrinkage and inhibits the wound edge from advancing. These events recapitulate cell rearrangements that occur during germband extension, in which intercalation events drive the elongation of tissues.
The function of immune cells is critically dependent on their capacity to respond to a complex series of navigational cues that enable them to home to various organ sites in the body or to respond to ...inflammatory cues such as those released at sites of tissue damage. From early embryonic stages, immune cells are faced with a barrage of signals that will not all be directing the cell to do the same thing. Here we use the
Drosophila embryo to investigate how hemocytes (
Drosophila macrophages), are able to prioritize key guidance signals and ignore others so that they are not pulled every which way. We identify the immediate wound attractant signal as H
2O
2 and investigate how
Drosophila macrophages respond to competing guidance cues—those emanating from a wound—versus standard developmental guidance cues, as well as those signals drawing cells toward neighboring dying cells. We reveal a hierarchy of responsiveness to attractant cues that varies over time and we identify why there is a wound refractile period early in embryonic development when macrophages cannot be distracted from their developmental migratory pathway to a site of tissue damage.
► The immediate damage signal that attracts hemocytes to wounds is H
2O
2 ► In the early embryo, hemocytes are refractile to wounds and prioritize guidance cues ► Apoptotic signals override developmental cues even during the wound refractile period.
Drosophila melanogaster hemocytes are highly motile macrophage-like cells that undergo a stereotypic pattern of migration to populate the whole embryo by late embryogenesis. We demonstrate that the ...migratory patterns of hemocytes at the embryonic ventral midline are orchestrated by chemotactic signals from the PDGF/VEGF ligands Pvf2 and -3 and that these directed migrations occur independently of phosphoinositide 3-kinase (PI3K) signaling. In contrast, using both laser ablation and a novel wounding assay that allows localized treatment with inhibitory drugs, we show that PI3K is essential for hemocyte chemotaxis toward wounds and that Pvf signals and PDGF/VEGF receptor expression are not required for this rapid chemotactic response. Our results demonstrate that at least two separate mechanisms operate in D. melanogaster embryos to direct hemocyte migration and show that although PI3K is crucial for hemocytes to sense a chemotactic gradient from a wound, it is not required to sense the growth factor signals that coordinate their developmental migrations along the ventral midline during embryogenesis.
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