Inflammatory signaling in genomically instable cancers

Talens, Francien; Vugt, Marcel A.T.M. van

doi:10.1080/15384101.2019.1638192

Cited by 26 publications

(21 citation statements)

References 188 publications

(237 reference statements)

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“…This indicates a possible altered response to cytosolic dsDNA in the tumor cells, as DNA can already be present in their cytosol. The presence of DNA in the cytosol of tumor cells was also demonstrated in previous studies primarily due to genomic instability [ 30 , 31 ]. This could explain the more potent response in RAW 264.7 macrophages, since these cells are the first line of defense against microorganisms and do not have a high baseline level of DNA in their cytosol, although they were derived from a tumor.…”

Section: Discussionmentioning

confidence: 99%

Radiation Induced Upregulation of DNA Sensing Pathways is Cell-Type Dependent and Can Mediate the Off-Target Effects

Jesenko

Bošnjak

Markelc

et al. 2020

Cancers

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Irradiation of tumors generates danger signals and inflammatory cytokines that promote the off-target bystander and abscopal effects, evident especially when radiotherapy is administered in combination with the immune checkpoint inhibitors (ICI). The underlying mechanisms are not fully understood; however, cGAS-STING pathway was recognized as the main mediator. In our study, we demonstrate by immunofluorescent staining that tumor cells as well as macrophages, cell types abundant in the tumor microenvironmeent (TME) accumulate DNA in their cytosol soon after irradiation. This accumulation activated several distinct DNA sensing pathways, most prominently activated DNA sensors being DDX60, DAI, and p204 in tumor cells and DDX60, DAI, p204, and RIG-I in macrophages as determined by PCR and immunofluorescence imaging studies. This was accompanied by increased expression of cytokines evaluated by flow cytometry, TNFα, and IFNβ in tumor cells and IL1β and IFNβ in macrophages, which can alter the TME and mediate off-target effects (bystander or abscopal effects). These results give insight into the mechanisms involved in the stimulation of antitumor immunity by radiation.

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Section: Discussionmentioning

confidence: 99%

Radiation Induced Upregulation of DNA Sensing Pathways is Cell-Type Dependent and Can Mediate the Off-Target Effects

Jesenko

Bošnjak

Markelc

et al. 2020

Cancers

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“…Mild DNA damage normally induces cell cycle arrest, while severe injury can activate the senescence program or the death programs; the latter includes apoptosis, mitotic catastrophe, autophagy, and necrosis [21].p53 plays a pivotal role in determining the fate of the cells, and, in the context of senescence, its activation can take place in a DDR-dependent or DDR-independent way [22,23]. In the first case, telomere erosion, DNA damage, as well as hyperactivation of oncogenes and inactivation of onco-suppressors (oncogene induced senescence, OIS) resulting from replicative stress activate the DNA damage repair cascade [24]. DDR activates the stress sensors' telangiectasia-muted (ATM) or ataxia telangiectasia and Rad3-related (ATR) kinases.…”

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confidence: 99%

Role of p53 in the Regulation of Cellular Senescence

et al. 2020

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The p53 transcription factor plays a critical role in cellular responses to stress. Its activation in response to DNA damage leads to cell growth arrest, allowing for DNA repair, or directs cellular senescence or apoptosis, thereby maintaining genome integrity. Senescence is a permanent cell-cycle arrest that has a crucial role in aging, and it also represents a robust physiological antitumor response, which counteracts oncogenic insults. In addition, senescent cells can also negatively impact the surrounding tissue microenvironment and the neighboring cells by secreting pro-inflammatory cytokines, ultimately triggering tissue dysfunction and/or unfavorable outcomes. This review focuses on the characteristics of senescence and on the recent advances in the contribution of p53 to cellular senescence. Moreover, we also discuss the p53-mediated regulation of several pathophysiological microenvironments that could be associated with senescence and its development.Biomolecules 2020, 10, 420 2 of 16 focus on the p53-dependent senescence signaling pathways involved with different stages of senescence and with a consideration for the associated key biomarkers. We also provide an overview on the regulation of p53-mediated cellular senescence in the context of different pathophysiological conditions. Senescence as Cellular Response to StressCellular senescence is defined as a cell state characterized by prolonged and generally irreversible cell-cycle arrest [14] and the acquisition of different phenotypic alterations, including morphological changes, chromatin remodeling, metabolic reprogramming, and secretion of pro-inflammatory factors or SASP (senescence associated secretory phenotypes). These latter count cytokines, growth factors, proteases, and non-soluble extracellular matrix proteins [15]. All these features ultimately limit the replication of both old and damaged cells. Upon physiological conditions, proliferating cells commit to a regular cell cycle [15,16]. On the other hand, both physiological aging, characterized by telomere shortening, and long-term chronic stress, which impairs genomic integrity and stability, could lead to the activation of the senescence pathway [17]. In this sense, the senescence can be viewed as an adaptative response of cells and organisms when exposed to certain unfavorable environmental conditions.Stressors include both intrinsic factors, such as oxidative damage, telomere attrition, hyperproliferation, oncogene activation, and environmental sources, including UV-light, γ-irradiation, and chemotherapeutic drugs [18,19]. Regardless of their origin, the stress factors trigger DNA damage responses (DDR) in the affected cells, which can result in different outcomes, depending on the cell type and the extent of the damage [20]. Mild DNA damage normally induces cell cycle arrest, while severe injury can activate the senescence program or the death programs; the latter includes apoptosis, mitotic catastrophe, autophagy, and necrosis [21].p53 plays a pivotal role in determining the fate of th...

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“…Previous reports have shown that the innate immune STING-TBK1-IRF3 pathway plays an important role in anti-cancer immunity in vivo via activation of the type I interferon (IFN) response. ( 20, 30, 32 ) Functionally, cancer cell production of type I IFN enhances recruitment of natural killer (NK) cells, T lymphocytes, and macrophages. ( 20, 30, 32 ) Cytotoxic T lymphocytes, NK cells and macrophages play major roles in controlling tumor growth and thus we decided to assess if mtp53 modulated the immune infiltration within the tumor microenvironment.…”

Section: Resultsmentioning

confidence: 99%

“…( 20, 30, 32 ) Functionally, cancer cell production of type I IFN enhances recruitment of natural killer (NK) cells, T lymphocytes, and macrophages. ( 20, 30, 32 ) Cytotoxic T lymphocytes, NK cells and macrophages play major roles in controlling tumor growth and thus we decided to assess if mtp53 modulated the immune infiltration within the tumor microenvironment. Whereas PLVX tumors had an abundance of both CD4+ and CD8+ T-lymphocytes, the p53R249S tumors showed relatively less infiltration by these cells.…”

Section: Resultsmentioning

confidence: 99%

Mutant p53 suppresses innate immune signaling to promote tumorigenesis

Ghosh

Saha

Bettke

et al. 2020

Preprint

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29Mutations in the p53 tumor suppressor occur very frequently in human cancer. 30Often, such mutations lead to the constitutive overproduction of mutant p53 31 (mtp53) proteins, which can exert a cancer-promoting gain-of-function (GOF). We 32 have identified a novel mechanism by which mtp53 controls both cell-autonomous 33 and non-cell autonomous signaling to promote cancer cell survival and suppress 34 tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic 35 DNA sensing machinery, cGAS-STING-TBK1-IRF3, that controls the activation of 36 the innate immune response. We find that mtp53, but not wildtype p53, binds to 37 TANK binding protein kinase (TBK1) and inhibits both its basal and agonist-38 induced activity. The association of mtp53 with TBK1 prevents the formation of a 39 trimeric complex between TBK1-STING-IRF3, which is required for activation, 40 nuclear translocation and transcriptional activity of IRF3. Mtp53 knockdown 41 restores TBK1 activity, resulting in the transcriptional induction of IRF3 target 42 genes and IRF3-dependent apoptosis. Furthermore, inactivation of innate immune 43 signaling by mtp53 alters cytokine production resulting in immune evasion. 44 Restored TBK1 signaling was sufficient to bypass mtp53 and reactivate cell-45 autonomous and non-cell autonomous tumor control. Thus, overriding mtp53's 46 inhibition of this cytosolic DNA sensing pathway may ultimately lead to restored 47 an oncogenic mtp53 protein that exhibits gain-of function activities.(5) Recently, it has been 62 reported that 91% of cancers that have a mtp53 allele have lost their second allele through 63 mutation or chromosomal loss.(6) Furthermore, the presence of mtp53 correlates with increased 64 chromosomal instability leading to loss of tumor suppressor genes and amplification of 65 oncogenes.(6, 7) 66 Aneuploidy is considered one of the hallmarks of cancer and is thought to play an 67 important role in driving tumor cell evolution.(8) Aneuploidy has been shown to provoke cell 68 cycle arrest, senescence, increased pro-inflammatory cytokine production and upregulation of 69 Natural Killer (NK) cell ligands in tumor cells, resulting in their subsequent killing by NK 70 cells.(9) In an in vivo setting, the increased production of pro-inflammatory cytokines coupled 71 with increased NK cell ligand expression permits the recruitment of immune cells and clearance 72 of abnormal cells.(10) Thus, in addition to the cell-autonomous mechanisms that suppress 73 genetic instability, cells also utilize non-cell autonomous mechanisms to signal their own 74 destruction.(9) However, chromosomal instability can give rise to micronuclei, which are prone 75 to rupturing and releasing the DNA into the cytoplasm.(11) DNA leaked into the cytoplasm is 76 recognized by the DNA binding protein, cyclic GMP-AMP synthase (cGAS), which in turn triggers 77 innate immune signaling that results in the production of type I interferons.(12) Mechanistically, 78 DNA promotes cGAS homodimerization and production of the secon...

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Inflammatory signaling in genomically instable cancers

Cited by 26 publications

References 188 publications

Radiation Induced Upregulation of DNA Sensing Pathways is Cell-Type Dependent and Can Mediate the Off-Target Effects

Radiation Induced Upregulation of DNA Sensing Pathways is Cell-Type Dependent and Can Mediate the Off-Target Effects

Role of p53 in the Regulation of Cellular Senescence

Mutant p53 suppresses innate immune signaling to promote tumorigenesis

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