The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

Journal of Molecular Medicine, Journal Year: 2024, Volume and Issue: 102(6), P. 733 - 750

Published: April 11, 2024

Abstract The accumulation of senescent cells within tissues is a hallmark the aging process. Senescent are also commonly present in many age-related diseases and cancer microenvironment. escape abnormal from immune surveillance indicates that there some defect function cytotoxic cells, e.g., CD8 + T natural killer (NK) cells. Recent studies have revealed expression programmed death-ligand 1 (PD-L1) protein abundantly increased An increase amount PD-L1 protects clearance by PD-1 checkpoint receptor In fact, activation suppresses properties NK promoting state immunosenescence. inhibitory PD-1/PD-L1 pathway acts cooperation with immunosuppressive cells; for example, can enhance differentiation regulatory (Treg), myeloid-derived suppressor (MDSC), M2 macrophages, whereas cytokines secreted stimulate protein. Interestingly, signaling pathways known to promote cellular senescence process crucial stimulators protein, epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, AhR signaling. It seems axis has role thus it promotes tissues. Thus, blockade might be potential anti-aging senolytic therapy. Key messages accumulate during diseases. able Expression markedly increases Age-related stimulates Inhibitory

Language: Английский

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Extracellular Vesicle-Associated Proteins in Tissue Repair

Trends in Cell Biology, Journal Year: 2020, Volume and Issue: 30(12), P. 990 - 1013

Published: Oct. 14, 2020

EV-associated proteins modulate different stages of endogenous as well therapeutic tissue repair at multiple cellular levels.Proteins present on EVs activate intracellular pathways in recipient cells involved through direct receptor binding; their delivery into the cytosol, where they exert biological effect; or capture, delivery, conversion bioactive molecules, turn leading to cell activation.Some have specific immune-modulatory, reparative, and remodeling effects individual tissues, while others pleiotropic tissues. The administration (stem) cell-derived extracellular vesicles (EVs) promotes management inflammatory, proliferative processes body. Despite widely observed roles wound healing repair, knowledge how which EV cargo is responsible for subsequent functional limited. Recent studies hint toward an important role cargo. Here, we provide overview promote discuss current challenges evaluating contribution function future directions translating fundamental insights clinically relevant therapies. Apart from conventional secretory (see Glossary), secrete proteins, nucleic acids, lipids that are delivered other generated via endosomal pathway upon budding plasma membrane. Collectively, these called (EVs). initial thoughts about being nothing more than garbage disposal system cells, it now established also play homeostasis short- long-distance intercellular communication. isolated types, body fluids modulation several physiological As a result, bear potential therapeutics regenerative medicine, been demonstrated be component stem progenitor secretome [1.Lener T. et al.Applying based clinical trials – ISEV position paper.J. Extracell. Vesicles. 2015; 4: 30087Crossref PubMed Scopus (526) Google Scholar]. Indeed, found reparative Although many set out identify activation exact mechanisms by remain elusive. In this review, describe why expressed (or in) might contributors function, address Challenges study implication translation will discussed. may classified characteristics including size, density, process release, protein/lipid composition [2.Willms E. al.Cells release subpopulations exosomes with distinct molecular properties.Sci. Rep. 2016; 6: 22519Crossref Scholar,3.Kowal J. al.Proteomic comparison defines novel markers characterize heterogeneous populations vesicle subtypes.Proc. Natl. Acad. Sci. 113: E968-E977Crossref (1053) Three such subgroups exosomes, microvesicles, apoptotic bodies (Box 1). biogenesis, hard capture assign population isolation classes share overlapping physiochemical [4.Jeppesen D.K. al.Reassessment exosome composition.Cell. 2019; 177: 428-445.e18Abstract Full Text PDF (296) To encompass all general term increasingly used, review. enriched acids compared origin, suggests dedicated packaging mechanism associated biogenesis loading. determined donor type physiological, pathological, stress conditions origin [5.Wen S.W. al.Breast cancer-derived reflect cell-of-origin phenotype.Proteomics. 191800180Crossref (12) Scholar].Box 1EV Biogenesis EV-Mediated Activation Intracellular SignalingEVs can subdivided three main categories biogenesis. Exosomes (diameter 30–120 nm) produced multivesicular (MVBs) invagination membrane, thereby capturing cytosolic components. After fusion MVBs released space. Microvesicles, sometimes referred microparticles ectosomes, size 50–1000 encapsulate components cytoplasmic membrane fission. Apoptotic 50–5000 during death. subtypes has reviewed detail elsewhere [104.van Niel G. al.Shedding light biology vesicles.Nat. Rev. Mol. Cell Biol. 2018; 19: 213-228Crossref (1061) Scholar,105.Hessvik N.P. Llorente A. Current release.Cell. Life 75: 193-208Crossref (469) characterized expression trafficking tetraspanins (CD9, CD63, CD81), (syntenin-1, Tsg101, Alix), maturation-related (flotillin annexin), heat-shock (HSPs) [3.Kowal Scholar,106.Théry C. al.Minimal information 2018 (MISEV2018): statement International Society Extracellular Vesicles update MISEV2014 guidelines.J. 7: 1535750Crossref (1129) Also integrins, selectins, CD40 ligand EVs.The interaction suggested mediated protein sugar moieties at, lipid of, both cells. proteoglycans, lectins, ECM components, mediate EV–plasma Scholar,107.Hoshino al.Tumour integrins determine organotropic metastasis.Nature. 527: 329-335Crossref (1679) directly initiate signaling receptor–ligand interactions, but internalized clathrin-dependent clathrin-independent macropinocytosis, phagocytosis, caveolae- raft-mediated endocytosis, processing canonical [6.Mathieu M. al.Specificities secretion uptake cell-to-cell communication.Nat. 21: 9-17Crossref (408) Scholar,104.van endosomes lysosomes degradation leads recycling contents within cell. Alternatively, event luminal cargoes cytoplasm lead exchange transmembrane EV-mediated occur molecules prevents binding receptors Also, (proteolytic) enzymes convert EVs. activating However, remains unresolved if targeting stochastic. Some types reported preferentially taken up Scholar,7.Horibe S. al.Mechanism cell-dependent differences uptake.BMC Cancer. 18: 47Crossref (41) Upon activation, plethora cascades modulating responses homeostasis. display depend cargos capacity transfer groups confirmed presence miRNAs ability induce target [8.Valadi H. al.Exosome-mediated mRNAs microRNAs genetic between cells.Nat. 2007; 9: 654-659Crossref (6468) Scholar], its low abundance makes less likely account majority [9.Reshke R. al.Reduction dose silencing RNA pre-microRNA backbone.Nat. Biomed. Eng. 2020; 52-68Crossref (3) Scholar, 10.Stevanato L. al.Investigation content, stoichiometry miRNA human neural line derived exosomes.PLoS One. 11e0146353Crossref (53) 11.Toh W.S. al.MSC works protein-based action.Biochem. Soc. Trans. 46: 843-853Crossref (46) 12.Chevillet J.R. al.Quantitative stoichiometric analysis microRNA content exosomes.Proc. U. 2014; 111: 14888-14893Crossref (456) importance surface observation proteinase K trypsin digestion loss downstream [13.Crain S.K. al.Extracellular Wharton's Jelly mesenchymal suppress CD4 expressing T transforming growth factor beta adenosine canine model.Stem Cells Dev. 28: 212-226Crossref (10) removal hampers uptake, often minutes exposure hints interactions instead includes [14.Zheng al.Exosomes dendritic attenuate liver injury balance Treg Th17 after ischemia reperfusion.Cell. Physiol. Biochem. 740-756Crossref (11) Scholar,15.Zhang B. al.Mesenchymal immunologically active exosomes.Stem 23: 1233-1244Crossref (288) This further underpinned activated even when only limited numbers up, postulating affect contact soluble [16.Vicencio J.M. al.Plasma protect myocardium ischemia-reperfusion injury.J. Am. Coll. Cardiol. 65: 1525-1536Crossref (217) Scholar,17.Li F. al.Mast Th2 differentiation OX40L-OX40 ligation.J Immunol Res. 2016: 1-10Google following sections, highlight evidence might, great extent, regulated mechanism. Tissue result various stimuli, infections, autoimmune reactions, toxins, radiation, trauma. Multiple essential damaged tissues: (1) apoptosis inhibition promotion survival prevent extensive loss, (2) immune response uncontrolled inflammation, angiogenesis endothelial migrate proliferate new blood vessels, (4) proliferation repopulate lost replace injured and/or fibrosis matrix (ECM) synthesis scar formation. These modulatory differentiated, mostly stromal, body, stimulated (Figure Investigation led discovery EV-enriched EV-induced (Table Examples cancer models included could protein-mediated activation. discussed sections.Table 1EV-Associated Proteins Promoting Repair ProcessesProteinDonor cellModelTarget cell(s)EV methodMethod manipulationReparative effectInvolved mechanismRefsPrevention deathMIFhB-MSCIn vitro; MI rat modelCMRIBO Exosome Isolation ReagentOverexpressionInhibition apoptosis; reduction mitochondrial fission fragmentation; infarct improvement cardiac functionDecreased ROS production; enhanced AMPK phosphorylation[18.Liu X. overexpressing MIF enhance myocardial repair.J. Cell. 235: 8010-8022Crossref (9) Scholar]MIFaProteins discovered tumor (immune-)biology.m-pancreatic ductal adenocarcinomaIn vitroHepatic stellate cell; Kupffer macrophagedUCshRNAActivation fibrotic microenvironment; premetastatic niche formation promoting metastasisIncrease α-SMA, TGFβ, FN expression[97.Costa-Silva al.Pancreatic pre-metastatic liver.Nat. 17: 816-826Crossref (1010) Scholar]GJA-20k / Connexin 43r-astrocytesIn traumatic brain modelNeurondUCshRNAInhibition recovery function; improved recoveryReduction Bcl-2, Bax, cytochrome C, caspase-3; downregulation Cx43 phosphorylation[19.Chen W. al.Astrocytes-derived neuronal delivering gap junction alpha 1-20 k.J. Regen. Med. 14: 412-423Crossref Scholar]PAPPAhCPCIn modelCMdUCsiRNAInhibition size; functionCleavage IGFBP4/IGF complexes; stimulation Akt, ERK1/2, IGFR phosphorylation; caspase-7 activation[20.Barile al.Cardioprotection cell-secreted exosomes: pregnancy-associated protein-A.Cardiovasc. 114: 992-1005Crossref (58) Scholar]SDF1/CXCL12huc-MSCIn mouse modelPrimary celldUCOverexpressionStimulation angiogenesis; decreasing inflammationUpregulated MMP-2, MMP-9, VEGF; increase PI3K, mTOR Bcl-2 expression, decrease Beclin-1 Bax expression[21.Gong SDF1-overexpressing inhibit ischemic microvascular regeneration mice infarction.J. 234: 13878-13893Crossref Scholar]MnSOD (SOD2)huc-MSCIn hepatic I/R modelHepatocytedUCsiRNAReduction respiratory burst neutrophils prevention oxidative stress-induced death; infiltrating alleviating stressDecrease proinflammatory cytokines (IL-1β, IL-6, TNF-α); levels; caspase-3[22.Yao umbilical cord alleviate suppressing neutrophil inflammatory response.FASEB 33: 1695-1710Crossref (23) Scholar]HSP20m-primary CMIn STZ-induced diabetic modelEC; CMdUCOverexpressionStimulation functionIncrease phosphorylated survivin, SOD1 (chaperone function); cell[24.Wang al.Hsp20-mediated cardiomyocytes improves mice.Diabetes. 3111-3128Crossref (72) Scholar]HSP70Human plasmaIn Langendorff modelCMdUCAbReduction sizeActivation TLR4 p38MAPK; ERK1/2 HSP27 phosphorylation[16.Vicencio Scholar]HSP70Plasma Goto Kakizaki rats II diabetes; hyperglycemic HUVECIn vitroCMdUC/No protective effects[25.Davidson S.M. impaired setting diabetes rescued use non-diabetic vitro.J. 22: 141-151Crossref (7) Scholar]HSP70, HSP90aProteins (immune-)biology.m-lung carcinoma cellIn vitroMyotubesExoQuick (System Biosciences)Ab; siRNAStimulation catabolic muscle wastingActivation TLR4; p38 elevation cytokines[26.Zhang al.Tumor induces wasting releasing Hsp70 Hsp90.Nat. Commun. 2017; 8: 589Crossref (61) Scholar]VEGFhuc-MSCIn newborn Sprague-Dawley exposed hyperoxiaRat lung epithelial challenged H2O2dUCsiRNAAttenuation attenuation hyperoxic injury; alveolarization, angiogenesis, macrophage activationActivation cytokine response[28.Ahn S.Y. al.Vascular mediates efficacy against neonatal injury.Exp. 50: 26Crossref (30) Scholar]VEGFR1h-amniotic fluid SCIn glomeruli Alport syndromeGlomerular EC VEGF overexposuredUCshRNAPrevention damage; amelioration proteinuria levelsTrapping VEGFR2 VEGFR1 expression[27.Sedrakyan al.Amniotic VEGF-induced damage.Sci. 16875Crossref Scholar]SP1h-iPSC-MSCIn renal modelRenal tubular cellExoQuick Biosciences)CRISPR/Cas9Inhibition necroptosis; protection injuryTranscriptional SK1; S1P[111.Yuan human-induced pluripotent stromal (hiPSC-MSCs) ischemia/reperfusion specificity (SP1) transcriptional sphingosine kinase.Cell Death Dis. 3200Crossref (29) Scholar]Immune modulationPD-L1TGF-β-stimulated h-lung FBIn vitroFB; celldUCAb (Avelumab); FB migration; T-cell proliferation[33.Kang al.Transforming fibroblasts express immunomodulatory PD-L1 vesicles.FASEB 34: 2213-2226Crossref Scholar]EDA-FN1h-embryonic MSCIn allogeneic skin graft modelMonocyte; CD4+ cellTFF, SECAnti-EDA AbInduction M2 polarization, mediating enhancing skinTLR4 activation; MyD88-dependent alkaline phosphatase expression; NF-κB translocation[15.Zhang Scholar]CCR2mBM-MSCI/R modelMacrophagedUCsiRNASuppression M1 damage injuryCCL2 p65 phosphorylation[34.Shen al.CCR2 positive suppresses functions alleviates ischemia/reperfusion-induced injury.Stem Int. 1-9Crossref (57) Scholar]pSTAT3m-adipose-derived diet-induced obesity modelMacrophageExoQuick Biosciences)Inhibitor (cryptotanshinone)Induction polarizationIncrease STAT3 phosphorylation Arg-1 expression[112.Zhao adipose-derived adipose inflammation polarizing macrophages beiging white tissue.Diabetes. 67: 235-247Crossref (119) Scholar]TSG-6Dog dextran sulfate sodium-induced colitis miceT macrophagedUCsiRNAAlleviation colon; induction polarization differentiationDecrease TNF-α, IL-1β, IFN-γ, iNOS IL-10 expression[35.An J.-H. al.TSG-6 stem/stromal major relieving DSS-induced colitis.PLoS 15e0220756Crossref Scholar]TSG-6huc-MSCNeonatal hyperoxia-induced BPD modelLung, braindUCsiRNA; AbReduction release; alveolar-capillary leakage disrupted barrierReduced IL-1β expression[113.Chaubey al.Early gestational attenuates experimental bronchopulmonary dysplasia part exosome-associated TSG-6.Stem Res Ther. 173Crossref (31) Scholar]HSP70mBM-DC supernatant I/R-treated primary hepatocytesIn modelNaïve celldUCAbInduction differentiation; injuryInduction PI3K Akt phosphorylation[14.Zheng

Language: Английский

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Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases

Cancers, Journal Year: 2021, Volume and Issue: 13(12), P. 3034 - 3034

Published: June 17, 2021

Upon T-cell receptor stimulation, the Programmed cell Death-1 (PD-1) expressed on T-cells can interact with its ligand PD-L1 at surface of cancer cells or antigen-presenting cells. Monoclonal antibodies targeting PD-1 are routinely used for treatment cancers, but their clinical efficacy varies largely across variety tumor types. A part variability is linked to existence several forms PD-L1, either plasma membrane (mPD-L1), secreted cellular exosomes (exoPD-L1), in nuclei (nPD-L1), as a circulating, soluble protein (sPD-L1). Here, we have reviewed different origins and roles sPD-L1 humans highlight biochemical functional heterogeneity protein. isoforms be generated essentially by two non-exclusive processes: (i) proteolysis m/exoPD-L1 metalloproteases, such metalloproteinases (MMP) disintegrin metalloproteases (ADAM), which capable shedding release an active form, (ii) alternative splicing pre-mRNA, leading some cases lacking transmembrane domain. The expression secretion been observed large pathologies, well beyond cancer, notably pulmonary diseases, chronic inflammatory autoimmune disorders, viral diseases. role during pregnancy also evoked. structural proteins, associated functional/cellular plurality, should kept mind when considering biomarker drug target. membrane, exosomal all integral parts highly dynamic PD-1/PD-L1 signaling pathway, essential immune-tolerance immune-escape.

Language: Английский

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The Evolving Landscape of PD-1/PD-L1 Pathway in Head and Neck Cancer

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Sept. 18, 2020

Over the past ten years, cancer immunotherapy has made significant progress in multiple types and gradually been applied to clinical care, which programmed cell death protein-1 (PD-1)/programmed ligand 1 (PD-L1) pathway is one of most attractive targets. Compared with traditional therapies, emerging PD-1/PD-L1 blockade exhibited more satisfactory curative effects lower toxicity for patients advanced head neck squamous carcinoma (HNSCC). This review analyzes expression characteristics significance HNSCC, immunosuppressive roles tumor stromal expressing this disease, present development landscape inhibitors, may provide new alternatives recurrent or metastatic HNSCC.

Language: Английский

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Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Lung Diseases: Current Status and Perspectives

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Feb. 15, 2021

Extracellular vesicles (EVs) have emerged as a potential therapy for several diseases. These plasma membrane-derived fragments are released constitutively by virtually all cell types—including mesenchymal stromal cells (MSCs)—under stimulation or following cell-to-cell interaction, which leads to activation inhibition of distinct signaling pathways. Based on their size, intracellular origin, and secretion pathway, EVs been grouped into three main populations: exosomes, microvesicles (or microparticles), apoptotic bodies. Several molecules can be found inside MSC-derived EVs, including proteins, lipids, mRNA, microRNAs, DNAs, well organelles that transferred damaged recipient cells, thus contributing the reparative process promoting relevant anti-inflammatory/resolutive actions. Indeed, paracrine/endocrine actions induced demonstrated therapeutic mitigate even reverse tissue damage, raising interest in regenerative medicine field, particularly lung In this review, we summarize features current understanding mechanisms action diseases, such chronic obstructive pulmonary disease (COPD), infections [including coronavirus 2019 (COVID-19)], asthma, acute respiratory distress syndrome (ARDS), idiopathic fibrosis (IPF), cystic (CF), among others. Finally, list number limitations associated with strategy must overcome order translate effective EV-based therapies clinical practice.

Language: Английский

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Immunomodulatory Factor TIM3 of Cytolytic Active Genes Affected the Survival and Prognosis of Lung Adenocarcinoma Patients by Multi-Omics Analysis

Biomedicines, Journal Year: 2022, Volume and Issue: 10(9), P. 2248 - 2248

Published: Sept. 10, 2022

[Objective] Using multi-omics research methods to explore cytolytic activity-related genes through the immunoregulatory factors HAVCR2 (TIM3) affecting survival and prognosis of lung adenocarcinoma. [Methods] We combined Cox single factor regression lasso feature selection algorithm screen out key activity in adenocarcinoma, applied clinical predictive value model, including onset risk, independent prognosis, relevance, signal transduction pathways, drug sensitivity, correlation immune regulatory factors, etc. TCGA data are used as experimental group, GEO is external control group verify stability model. The curve was generated by Kaplan-Meier method compared log-rank, proportional hazard model for multivariate analysis. In this study, 10 fresh tissue samples adenocarcinoma were collected cellular immunohistochemical experiments analyze expression cancer tissues, verified screened out. [Results] A total 450 related differentially expressed, which 273 up-regulated 177 down-regulated. 91 regression. ROC results showed that AUC values 1, 3, 5 years training set test all greater than 0.7, indicating has a valid verification. level risk score significantly sensitivity patients AKT inhibitor VIII, Lenalidomide, Tipifarnib. addition, our study also found receptor MHC immunomodulatory, chemokines, HAVCR2, more highly expressed low-risk group. [Conclusions] affect cells, some extent indirectly with

Language: Английский

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PD-L1 mediates lung fibroblast to myofibroblast transition through Smad3 and β-catenin signaling pathways

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: Feb. 23, 2022

Abstract Programmed death ligand-1 (PD-L1) is an immune checkpoint protein that has been linked with idiopathic pulmonary fibrosis (IPF) and fibroblast to myofibroblast transition (FMT). However, it remains largely unclear how PD-L1 mediates this process. We found significantly increased in the lungs of patients mice induced by bleomycin TGF-β. In primary human lung fibroblasts (HLFs), TGF-β expression dependent on both Smad3 p38 pathways. knockdown using siRNA attenuated TGF-β-induced markers α-SMA, collagen-1, fibronectin normal IPF HLFs. Further, we interacts Smad3, induces their interaction. Interestingly, reduced α-SMA reporter activity HLFs, suggesting might act as a co-factor promote target gene expression. treatment also phosphorylates GSK3β upregulates β-catenin levels. Inhibiting signaling pharmaceutical inhibitor ICG001 FMT. phosphorylation/inhibition upregulation, implicating GSK3β/β-catenin PD-L1-mediated Collectively, our findings demonstrate may through represent novel interventional for IPF.

Language: Английский

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Extracellular Vesicles and Transforming Growth Factor β Signaling in Cancer

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: April 13, 2022

Complexity in mechanisms that drive cancer development and progression is exemplified by the transforming growth factor β (TGF-β) signaling pathway, which suppresses early-stage hyperplasia, yet assists aggressive tumors to achieve metastasis. Of note, several molecules, including mRNAs, non-coding RNAs, proteins known be associated with TGF-β pathway have been reported as constituents cargo of extracellular vesicles (EVs). EVs are secreted delimited a lipid bilayer play critical functions intercellular communication, regulation tumor microenvironment development. Thus, this review aims at summarizing impact on focusing EV can influence tumorigenesis, metastatic spread, immune evasion response anti-cancer treatment. Moreover, we emphasize potential TGF-β-related molecules present circulating useful biomarkers prognosis, diagnosis, prediction treatment patients.

Language: Английский

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The therapeutic potential of PD-1/PD-L1 pathway on immune-related diseases: Based on the innate and adaptive immune components

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 167, P. 115569 - 115569

Published: Sept. 26, 2023

Currently, immunotherapy targeting programmed cell death 1 (PD-1) or ligand (PD-L1) has revolutionized the treatment strategy of human cancer patients. Meanwhile, PD-1/PD-L1 pathway also been implicated in pathogenesis many immune-related diseases, such as autoimmune chronic infection diseases and adverse pregnancy outcomes, by regulating components innate adaptive immune systems. Given power new therapy, a better understanding regulatory effects on responses will facilitate discovery novel biomarkers therapeutic drug targets. Targeting this may successfully halt potentially even reverse these pathological processes. In review, we discuss recent major advances axis diseases. We reveal that impact system is complex manifold multi-strategies targeted are taken Consequently, pathway, alone combination with other treatments, represent for future intervention

Language: Английский

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Crosstalk between CAFs and tumour cells in head and neck cancer

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: June 26, 2024

Abstract Head and neck squamous cell carcinomas (HNSCCs) are amongst the most aggressive, complex, heterogeneous malignancies. The standard of care treatments for HNC patients include surgery, radiotherapy, chemotherapy, or their combination. However, around 50% do not benefit while suffering severe toxic side effects, costing individuals society. Decades have been spent to improve HNSCC treatment outcomes with only limited success. Much research in has focused on understanding genetics malignant cells, but it become clear that tumour microenvironment (TME) plays an important role progression as well response HNSCC. Understanding crosstalk between cancer cells TME is crucial inhibiting resistance. Cancer-associated fibroblasts (CAFs), predominant component stroma HNSCC, serve primary source extra-cellular matrix (ECM) various pro-tumoral composites TME. activation CAFs primarily driven by cell-secreted molecules, which turn induce phenotypic changes, elevated secretive status, altered ECM production profile. Concurrently, play a pivotal modulating cycle, stemness, epithelial-mesenchymal transition (EMT), resistance targeted chemoradiotherapy cells. This modulation occurs through interactions secreted molecules direct contact CAF. Co-culture 3D models other types allows mimic milieu enable hypoxia reprograming stem (CSC). review aims provide update development comprising obtain better interaction providing preclinical testing platforms current combination emerging therapeutics.

Language: Английский

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