Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression

International Journal of Molecular Sciences, Год журнала: 2021, Номер 23(1), С. 146 - 146

Опубликована: Дек. 23, 2021

Cancer progression with uncontrolled tumor growth, local invasion, and metastasis depends largely on the proteolytic activity of numerous matrix metalloproteinases (MMPs), which affect tissue integrity, immune cell recruitment, turnover by degrading extracellular (ECM) components releasing matrikines, surface-bound cytokines, growth factors, or their receptors. Among MMPs, MMP-14 is driving force behind destruction during cancer invasion metastasis. also influences both intercellular as well cell-matrix communication regulating many plasma membrane-anchored proteins. cells other stroma, embedded in a common matrix, interact means various adhesive structures, particularly invadopodia are capable to remodel through spatially temporally finely tuned proteolysis. As deeper understanding underlying functional mechanisms beneficial for development new prognostic predictive markers targeted therapies, this review examined current knowledge interplay MMPs context protein, subcellular, cellular level focus MMP14.

Язык: Английский

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The extracellular matrix and the immune system: A mutually dependent relationship

Science, Год журнала: 2023, Номер 379(6633)

Опубликована: Фев. 16, 2023

For decades, immunologists have studied the role of circulating immune cells in host protection, with a more recent appreciation resident within tissue microenvironment and intercommunication between nonhematopoietic cells. However, extracellular matrix (ECM), which comprises at least third structures, remains relatively underexplored immunology. Similarly, biologists often overlook regulation complex structural matrices by system. We are only beginning to understand scale ECM structures determine cell localization function. Additionally, we need better how dictate complexity. This review aims highlight potential for biological discovery interface immunology biology.

Язык: Английский

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The Functional Role of Extracellular Matrix Proteins in Cancer

Cancers, Год журнала: 2022, Номер 14(1), С. 238 - 238

Опубликована: Янв. 4, 2022

The extracellular matrix (ECM) is highly dynamic as it constantly deposited, remodeled and degraded to maintain tissue homeostasis. ECM a major structural component of the tumor microenvironment, cancer development progression require its extensive reorganization. Cancerized biochemically different in composition stiffer compared normal ECM. abnormal affects by directly promoting cell proliferation, survival, migration differentiation. restructured degradation fragments (matrikines) also modulate signaling cascades mediated interaction with cell-surface receptors, deregulate stromal behavior lead emergence an oncogenic microenvironment. Here, we summarize current state understanding how structure changes during progression. We describe functional role key proteins, especially tenascin C fibronectin, molecules involved formation well pathways that they activate cells.

Язык: Английский

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Targeting the tumor stroma for cancer therapy

Molecular Cancer, Год журнала: 2022, Номер 21(1)

Опубликована: Ноя. 2, 2022

Tumors are comprised of both cancer cells and surrounding stromal components. As an essential part the tumor microenvironment, stroma is highly dynamic, heterogeneous commonly tumor-type specific, it mainly includes noncellular compositions such as extracellular matrix unique cancer-associated vascular system well a wide variety cellular components including activated fibroblasts, mesenchymal cells, pericytes. All these elements operate with each other in coordinated fashion collectively promote initiation, progression, metastasis therapeutic resistance. Over past few decades, numerous studies have been conducted to study interaction crosstalk between neoplastic cells. Meanwhile, we also witnessed exponential increase investigation recognition critical roles solid tumors. A series clinical trials targeting launched continually. In this review, introduce discuss current advances understanding various their cancers. We elaborate on potential novel approaches for tumor-stroma-based targeting, aim leap from bench bedside.

Язык: Английский

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Cell–3D matrix interactions: recent advances and opportunities

Trends in Cell Biology, Год журнала: 2022, Номер 32(10), С. 883 - 895

Опубликована: Апрель 8, 2022

The diversity of hundreds extracellular matrix (ECM) molecules in different tissues and their interactions are now being documented 'matrisome' databases.Physical properties the 3D ECM, including viscoelasticity microarchitecture, can govern cell adhesion, mechanotransduction, multiple modes migration.New advances ECM biology identifying mechanisms cancer progression fibrosis, as well potential therapeutic targets.Characterizations cell–ECM feedback loops computational modeling providing new insights opportunities for intervention diseases disorders. Tissues consist cells surrounding (ECM). Cell–ECM play crucial roles embryonic development, differentiation, tissue remodeling, fibrosis cancer. Recent research characterizing cell–matrix include detailed descriptions associated molecules, complex intermolecular development disease, identification distinctive migration ECMs, into organ formation. Exploring physical features microenvironments bidirectional regulation signaling organization emphasize dynamic nature these interactions, which that exacerbate disease. Understanding potentially lead to targeted interventions. New on interactionsThe with (see Glossary) during formation adult homeostasis, pathogenesis such This field has expanded explosively after discovery many surface receptors. Our goal this brief review is highlight recent conceptual experimental should provide exciting future cell–3D interactions.Diversity interactionsA starting ~2019 been widespread adoption term – is, comprising it changes disease pathogenesis. holistic concept matrisomes moves beyond classical studies focusing a single protein or family not only structural proteins, collagens, elastin, proteoglycans, fibronectin, but also matrix-associated enzymes inhibitors, matrix-bound growth factors, some cases receptors [1.Karamanos N.K. et al.A guide composition functions matrix.FEBS J. 2021; 288: 6850-6912Crossref PubMed Scopus (65) Google Scholar,2.Izzi V. al.Pan-cancer analysis genomic alterations mutations matrisome.Cancers (Basel). 2020; 12: 2046Crossref (27) Scholar]. Among examples, have used matrisome analyses characterize basement membranes (https://bmbase.manchester.ac.uk/), discover ECM-associated genes more than other [2.Izzi Scholar], identify thrombospondin tenascin links collagen alignment breast [3.Tomko L.A. al.Targeted identifies thrombospondin-2 tenascin-C aligned stroma from invasive carcinoma.Sci. Rep. 2018; 8: 12941Crossref (37) bioengineered models human pancreatic [4.Osuna de la Pena D. al.Bioengineered recapitulate vivo tumour biology.Nat. Commun. 5623Crossref (11) Scholar].Many publications still at descriptive level. There considerable overlaps between components 'adhesome,' comprises adhesions, especially focal adhesions (e.g., see www.adhesome.org). Both 'omics' approaches major applying increasingly sophisticated methods understand involving networks rather just few selected proteins past. Unexpected findings may arise terms groups regulating components. Exemplifying crosstalk, planar membrane two its biochemically unrelated constituents, laminin IV, strongly regulate assembly fibrillar component, variety types [5.Lu al.Basement regulates fibronectin using sliding driven by contractile winch.Dev. Cell. 52: 631-646 e634Abstract Full Text PDF (24) Scholar].We know vary widely depending type biochemical mechanical (Figure 1). Multiple characterized recently range lamellipodial characteristic mesenchymal fibroblast-like rounded amoeboid immune certain [6.Bodor D.L. al.Of shapes motion: basis animal migration.Dev. 550-562Abstract (45) Scholar,7.Yamada K.M. Sixt M. Mechanisms migration.Nat. Rev. Mol. Cell Biol. 2019; 20: 738-752Crossref (262) lobopodial cross-linked linearly elastic spatially confined intracellular pressure, cortical actin flow, ion fluxes, [8.Zhao R. al.Cell sensing decision-making confinement: role TRPM7 tug war hydraulic pressure cross-sectional area.Sci. Adv. 5eaaw7243Crossref (35) Scholar, 9.Patel S. al.Myosin II Arp2/3 cross-talk governs lamellipodia formation.Mol. 32: 579-589Crossref 10.Ullo M.F. Logue J.S. ADF cofilin-1 collaborate promote flow leader bleb-based cells.eLife. 10e67856Crossref (6) 11.Reversat A. al.Cellular locomotion environmental topography.Nature. 582: 582-585Crossref (69) 12.Yolland L. al.Persistent polarized global essential directionality 21: 1370-1381Crossref (22) Scholar].The microarchitecture affect differentiation [13.Doyle A.D. al.Local microenvironment through spatiotemporal dynamics contractility-dependent adhesions.Nat. 2015; 6: 8720Crossref (268) Scholar,14.Seo B.R. al.Collagen mechanically controls myofibroblast differentiation.Proc. Natl. Acad. Sci. U. 117: 11387-11398Crossref (58) For example, networks, fiber thickness pore size, adipose stromal toward process independent overall stiffness previously known stem [14.Seo Scholar,15.Chaudhuri O. al.Effects cellular behaviour.Nature. 584: 535-546Crossref (427) Scholar].Matrix propertiesThe local migratory speed show differences molecular elasticity [15.Chaudhuri Examining whether an soft stiff numerous previous [16.Hayward M.K. al.Tissue mechanics fate, cancer.Dev. 56: 1833-1847Abstract (20) Scholar,17.Xue B. al.Engineering hydrogels homogeneous controlling lineage specification.Proc. 118e2110961118Crossref (13) Scholar] ideally be complemented behavior environments differing viscoelasticity. reason biological matrices often viscoelastic, they display combination viscosity thick fluid attempts return material original form deforming force released. results plastic deformation slipping, creep 'stress relaxation' response deformed, without returning form. Viscoelasticity modulated extent crosslinking property effects behavior, although underlying yet clear. altered rheology filopodial versus protrusions leading edge cell, rates spreading migration, processes morphogenesis, epithelial-mesenchymal transition, invasion, [18.Adebowale K. al.Enhanced substrate stress relaxation promotes filopodia-mediated Mater. 1290-1299Crossref (36) 19.Gong Z. al.Matching timescales maximizes viscoelastic substrates.Proc. 115: E2686-E2695Crossref (129) 20.Wisdom al.Matrix plasticity confining microenvironments.Nat. 9: 4144Crossref (162) 21.Yang mechanosensing synthetic controlled biophysical dynamics.Nat. 3514Crossref 22.Indana al.Viscoelasticity adhesion biomaterials control pluripotent morphogenesis culture.Adv. 33e2101966Crossref (17) 23.Chang A.C. al.Precise tuning characterization interfaces study early transition behaviors.Langmuir. 2022; (Published online February 10, 2022)https://doi.org/10.1021/acs.langmuir.1c03048Crossref (3) 24.Hui E. al.The combined influence adhesive cues fibroblast organization.Cell. Bioeng. 14: 427-440Crossref (9) fact chemical substantially alter mode, speed, means one cannot simply 'work 3D' due factors An ongoing challenge will generate accurately mimic specific use ex tissues. Development physiological simple gels current valuable accurate platforms testing translational approaches.MechanotransductionDifferent elicit distinct responses cells. 2D revealed test repetitively probing [25.Plotnikov S.V. al.Force fluctuations within mediate ECM-rigidity directed migration.Cell. 2012; 151: 1513-1527Abstract (559) analogous hikers footing when crossing unstable terrain. Cells sense respond ECM-transmitted forces tension involves integrin-based where actomyosin-mediated transmitted substrata [26.Zuidema al.Crosstalk complexes mechanotransduction.Bioessays. 42e2000119Crossref (31) Scholar,27.Doyle al.Cell-extracellular dynamics.Phys. 19https://doi.org/10.1088/1478-3975/ac4390Crossref (8) In environments, mechanotransduction level resembles under conditions stiffer substrates stabilize while softer, flexible shorter lifetimes faster Scholar].Mechanotransduction becomes particularly concerning cycle. evidence fibroblasts migrating reveals prior translocation, initially deform (prestrain) fibrils, increasing self-generated contracting transmitting essentially first 'pulling up slack rope' (i.e., fibrils [28.Doyle al.3D anterior contraction generates prestrain.Dev. 826-841.e4Abstract Scholar]). Interestingly, epithelial relatively equal-and-opposite strain transmission posterior directions 2A ) [29.Hall M.S. al.Fibrous nonlinear enables positive ECMs.Proc. 2016; 113: 14043-14048Crossref (174) (nonepithelial) cancers constant prestrains twofold greater front rear suggesting disconnect propagation 2A) prestrain likely genetically primed contractility-centric mode higher expression myosin II) enhanced microenvironment. sequence events distinctive, actomyosin contractions preceding leading-edge protrusive activity, helps establish unique cycle 2B–C) Discrepancies cycles importance conditions.Figure 2Mechanotransduction migration.Show full caption(A) Schematic showing directionally gels. Mesenchymal (left) high extensive integrin ligation large strains larger rear. Similar attributes seen fibrosarcoma cells, majority (right) smaller, transient rear, lower graph summarizing latter concept, requires further testing). (B C) schematic shows matrix. Yellow arrows depict directional applied matrix, magenta indicate relative summed given region. During cycle, (C) retrograde pull stabilizes (gray ovals) edge. A contralateral anterograde (increased direction migration) leads pinching followed increase protrusion (broken white line). Abbreviation: matrix.View Large Image Figure ViewerDownload Hi-res image Download (PPT)In addition, (elastic etc.) alters mechanotransduction. suggest ECMs Viscoelastic effective eliciting compared Future evaluate interacting properties, vitro microenvironments.The nucleus migrationSome 'nuclear piston' pulled anteriorly contractility pressurize drive 'lobopodial' forward [30.Petrie R.J. al.Activating nuclear piston mechanism tumor cells.J. 2017; 216: 93-100Crossref (63) (plastic), mechanosensitive channels generated elevated hydrostatic triggering channel activation; resulting influx sodium calcium ions enhances osmotic provides additional extending promoting efficient [31.Lee H.P. activates paths microenvironments.Sci. 7eabd4058Google Scholar].Another intriguing finding stiff, bulky ruler help choice wider, readily traversed passageway [32.Renkawitz al.Nuclear positioning facilitates along path least resistance.Nature. 568: 546-550Crossref (125) Scholar,33.Lomakin A.J. acts tailoring spatial constraints.Science. 370eaba2894Crossref (110) Besides serving ruler, conjunction cytoskeleton function, gauge activate epigenetic pathways 3) Scholar,34.Venturini measures shape proprioception behavior.Science. 370eaba2644Crossref (102) 35.Maurer Lammerding driving force: disease.Annu. Biomed. Eng. 443-468Crossref (80) 36.Alisafaei F. al.Regulation architecture, mechanics, nucleocytoplasmic shuttling geometric constraints.Proc. 116: 13200-13209Crossref (82) Scholar].Figure 3Multiple mechanosensing, mechanotransduction.Show captionThe nucleus, largest organelle, function entry narrow spaces channels. contraction, thereby termed lobopodia. serve sensor responding confinement. Finally, signal transducer initiating gene expression.View (PPT)Cancer dynamicsCancer invasion continues another very active investigation various ECM. Before malignant invade interstitial tissues, must usually breach barrier surrounds 4). Although proteases degrade protease-independent breaching occur. Physical extension penetrate expand holes ATP production Caenorhabditis elegans [37.Kelley L.C. al.Adaptive F-actin polymerization localized absence MMPs.Dev. 48: 313-328.e8Abstract Human nonproteolytic repetitive microspikes widen filopodia enlarging perforations; protruding subsequently probe [38.Chang Chaudhuri Beyond proteases: invasion.J. 218: 2456-2469Crossref 39.Eschenbruch al.From fibers: remodeling acini drives II-mediated invasion.Cells. 10: 1979Crossref 40.Gong al.Recursive dissipation chemo-mechanical oscillatory invadopodia.Cell 35109047Abstract Cellular metabolic activation important successful crosstalk Scholar,41.Zanotelli M.R. al.Mechanoresponsive metabolism metastasis.Cell Metab. 33: 1307-1321Abstract 42.Romani P. metabolism.Nat. 22: 22-38Crossref (94) 43.Torrino al.Mechano-induced microtubule glutamylation 1342-1357.e10Abstract (18) 4Different membrane.Show captionCancer transiently barriers mechanisms. proteases, metalloproteinases (MMPs), locally, MMPs tips invadopodia. Even if inhibited, tiny perforations requiring energy (orange shading) (yellow arrows) push laterally ridge around expanding hole (red mounds). both processes, proteolysis perforations.View (PPT)Although generation thought involve contractility, relationship levels nonmuscle invasiveness complex. Some isoforms actomyosin-associated predicted facilitate others decreased consistent suppressor Scholar,44.Parajon mechanobiome: goldmine therapeutics.Am. Physiol. 320: C306-C323Crossref Scholar,45.Picariello H.S. IIA suppresses glioblastoma sensitive manner.Proc. 15550-15559Crossref (25) bifunctional complexity myosin-X enhancing suppressing modulating [46.Peuhu al.Myosin-X-dependent limits invasion.bioRxiv. October 22, 2021)https://doi.org/10.1101/2021.10.22.464987Google Scholar].Although obvious source disrupting structure breaching, contributor lateral branches density [47.Papalazarou Maches

Язык: Английский

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MatrisomeDB 2.0: 2023 updates to the ECM-protein knowledge database

Nucleic Acids Research, Год журнала: 2022, Номер 51(D1), С. D1519 - D1530

Опубликована: Ноя. 18, 2022

Abstract The extracellular matrix (ECM) is a complex assembly of proteins that constitutes the scaffold organizing cells, tissues, and organs. Over past decade, mass-spectrometry-based proteomics has become method choice to profile composition ECM, or matrisome, tissues. To assist non-specialists with reuse ECM proteomic datasets, we released MatrisomeDB (https://matrisomedb.org) in 2020. Here, report expansion database include 25 new curated studies on 24 tissues addition datasets previously included, more than doubling size original achieving near-complete coverage in-silico predicted matrisome. We further enhanced data visualization by maps peptides post-translational-modifications detected onto domain-based representations 3D structures proteins. also referenced external resources facilitate design targeted mass spectrometry assays. Last, implemented an abstract-mining tool generates enrichment word cloud from abstracts which queried protein found higher confidence abundance relative other MatrisomeDB.

Язык: Английский

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Adipose‐Derived Mesenchymal Stem Cell‐Derived Exosomes Biopotentiated Extracellular Matrix Hydrogels Accelerate Diabetic Wound Healing and Skin Regeneration

Advanced Science, Год журнала: 2023, Номер 10(30)

Опубликована: Сен. 15, 2023

Wound healing is an urgent clinical challenge, particularly in the case of chronic wounds. Traditional approaches to wound have limited therapeutic efficacy due lengthy times, risk immune rejection, and susceptibility infection. Recently, adipose-derived mesenchymal stem cell-derived exosomes (ADSC-exos) emerged as a promising modality for tissue regeneration repair. In this study, development novel extracellular matrix hydrogel@exosomes (ECM@exo) reported, which entails incorporation ADSC-exos into hydrogel (ECM hydrogel). This solution forms at physiological temperature (≈37 °C) upon local injection site. ECM@exo enables sustained release from ECM hydrogel, maintains high concentrations The displays good biocompatibility biodegradability. vivo vitro results demonstrate that treatment effectively reduces inflammation promotes angiogenesis, collagen deposition, cell proliferation, migration, thereby accelerating process. Overall, innovative approach offers new avenue via biological with controlled exosome release.

Язык: Английский

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Synthetic extracellular matrices with function-encoding peptides

Nature Reviews Bioengineering, Год журнала: 2023, Номер 1(7), С. 518 - 536

Опубликована: Апрель 25, 2023

Язык: Английский

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Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Март 14, 2023

Abstract The ageing process is a systemic decline from cellular dysfunction to organ degeneration, with more predisposition deteriorated disorders. Rejuvenation refers giving aged cells or organisms youthful characteristics through various techniques, such as reprogramming and epigenetic regulation. great leaps in rejuvenation prove that not one-way street, many rejuvenative interventions have emerged delay even reverse the process. Defining mechanism by which roadblocks signaling inputs influence complex programs essential for understanding developing strategies. Here, we discuss intrinsic extrinsic factors counteract cell rejuvenation, targeted core mechanisms involved this Then, critically summarize latest advances state-of-art strategies of rejuvenation. Various methods also provide insights treating specific ageing-related diseases, including reprogramming, removal senescence (SCs) suppression senescence-associated secretory phenotype (SASP), metabolic manipulation, stem cells-associated therapy, dietary restriction, immune heterochronic transplantation, etc. potential applications therapy extend cancer treatment. Finally, analyze detail therapeutic opportunities challenges technology. Deciphering will further into anti-ageing disease treatment clinical settings.

Язык: Английский

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Angiogenesis in adipose tissue and obesity

Angiogenesis, Год журнала: 2022, Номер 25(4), С. 439 - 453

Опубликована: Июль 20, 2022

Abstract While most tissues exhibit their greatest growth during development, adipose tissue is capable of additional massive expansion in adults. Adipose expandability advantageous when temporarily storing fuel for use fasting, but becomes pathological upon continuous food intake, leading to obesity and its many comorbidities. The dense vasculature provides necessary oxygen nutrients, supports delivery from adipocytes under fed or fasting conditions. Moreover, the comprises a major niche multipotent progenitor cells, which give rise new are repair. Given multiple, pivotal roles vasculature, impairments angiogenic capacity may underlie obesity-associated diseases such as diabetes cardiometabolic disease. Exciting studies on single-cell single-nuclei composition mouse humans providing insights into mechanisms angiogenesis. modes intercellular communication involving micro vesicle exosome transfer proteins, nucleic acids organelles also being recognized play key roles. This review focuses cellular signaling underlying angiogenesis, impact pathophysiological consequences.

Язык: Английский

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