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Cited by 116TGF-β signaling in diseasesCell Adhesion Molecules ResearchCancer Immunotherapy and Biomarkers

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Integrin-Mediated TGFβ Activation Modulates the Tumour Microenvironment

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Brown, Nicholas F., Marshall, John F.·2019·Cancers
DOI 10.3390/cancers11091221PMC PMC6769837
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Abstract

TGFβ (transforming growth factor-beta) is a pleotropic cytokine with contrasting effects in cancer. In normal tissue and early tumours, TGFβ acts as a tumour suppressor, limiting proliferation and inducing apoptosis. However, these effects are eventually abrogated by the loss or inactivation of downstream signalling within the TGFβ pathway, and in established tumours, TGFβ then acts as a tumour promotor through multiple mechanisms including inducing epithelial-to-mesenchymal transition (EMT), promoting formation of cancer-associated fibroblasts (CAFs) and increasing angiogenesis. TGFβ is secrereted as a large latent complex and is embedded in the extracellular matrix or held on the surface of cells and must be activated before mediating its multiple functions. Thus, whilst TGFβ is abundant in the tumour microenvironment (TME), its functionality is regulated by local activation. The αv-integrins are major activators of latent-TGFβ. The potential benefits of manipulating the immune TME have been highlighted by the clinical success of immune-checkpoint inhibitors in a number of solid tumour types. TGFβ is a potent suppressor of T-cell-mediated immune surveillance and a key cause of resistance to checkpoint inhibitors. Therefore, as certain integrins locally activate TGFβ, they are likely to have a role in the immunosuppressive TME, although this remains to be confirmed. In this review, we discussed the role of TGFβ in cancer, the role of integrins in activating TGFβ in the TME, and the potential benefits of targeting integrins to augment immunotherapies.

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Crossref · 10.3390/cancers11091221

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Figures

Figure 1 Integrin αvβ6 conformation states. Integrins comprise an α- and β-subunit associated non-covalently at the head, each connected to a flexible leg that traverses the cell membrane to a short cytoplasmic domain. Ligand affinity is mediated by changes in conformation, with affinity highest in the extended-open state and lowest in the bent-closed state. The black arrows indicate the direction of force that integrins mediate between the extracellular matrix and actin cytoskeleton adapted from [9].
Figure 1 Integrin αvβ6 conformation states. Integrins comprise an α- and β-subunit associated non-covalently at the head, each connected to a flexible leg that traverses the cell membrane to a short cytoplasmic domain. Ligand affinity is mediated by changes in conformation, with affinity highest in the extended-open state and lowest in the bent-closed state. The black arrows indicate the direction of force that integrins mediate between the extracellular matrix and actin cytoskeleton adapted from [9].CC BY · PubMed Central
Figure 2 TGFβ (transforming growth factor-beta) structure and secretion. Dimers of TGFβ and latency-associated peptide (LAP) linked by non-covalent bonds form the small latent complex (SLC). Left: Covalent bonds link the small latent complex to latent TGFβ binding protein (LTBP) which together form the large latent complex (LLC). Once secreted, TGFβ is held in an inactive state, anchored by LTBP to fibronectin and fibrillin in the extracellular matrix. Right: In some cells, notably regulatory T-cells, the SLC binds covalently to glycoprotein-A repititions predominant (GARP), and following secretion is bound to the cell membrane. Adapted from [15,16,29]. SS, disulphide bonds.
Figure 2 TGFβ (transforming growth factor-beta) structure and secretion. Dimers of TGFβ and latency-associated peptide (LAP) linked by non-covalent bonds form the small latent complex (SLC). Left: Covalent bonds link the small latent complex to latent TGFβ binding protein (LTBP) which together form the large latent complex (LLC). Once secreted, TGFβ is held in an inactive state, anchored by LTBP to fibronectin and fibrillin in the extracellular matrix. Right: In some cells, notably regulatory T-cells, the SLC binds covalently to glycoprotein-A repititions predominant (GARP), and following secretion is bound to the cell membrane. Adapted from [15,16,29]. SS, disulphide bonds.CC BY · PubMed Central
Figure 3 Force-mediated liberation of TGFβ by αvβ6. Left: TGFβ is held in a ‘straitjacket’ by LAP with the ‘latency lasso’ preventing covering TGFβ receptor binding sites. αvβ6 activates TGFβ by binding to RGD motifs on the shoulders of LAP and transducing a force (black arrows) from the actin cytoskeleton. A resistant counter-force is generated by LTBPs which are bound to LAP by disulphide bonds (SS). Right: When tensile force is exerted across the structure, the lasso is elongated, the straitjacket unfastens, and active TGFβ is liberated. Adapted from [15].
Figure 3 Force-mediated liberation of TGFβ by αvβ6. Left: TGFβ is held in a ‘straitjacket’ by LAP with the ‘latency lasso’ preventing covering TGFβ receptor binding sites. αvβ6 activates TGFβ by binding to RGD motifs on the shoulders of LAP and transducing a force (black arrows) from the actin cytoskeleton. A resistant counter-force is generated by LTBPs which are bound to LAP by disulphide bonds (SS). Right: When tensile force is exerted across the structure, the lasso is elongated, the straitjacket unfastens, and active TGFβ is liberated. Adapted from [15].CC BY · PubMed Central

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Metadata

Authors
Brown, N. F., & Marshall, J. F.
Affiliations
Queen Mary University of London (GB)
Corresponding author
Marshall, John F.
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2019-08-21
Volume
11
Issue
9
Pages
1221
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers11091221
PMC
PMC6769837
OpenAlex
W2969253527
Cited by
116
References
192
Citations by year
2026: 13 · 2025: 17 · 2024: 18 · 2023: 11 · 2022: 16 · 2021: 23 · 2020: 16 · 2019: 2
FWCI
1.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
Funders
Cancer Research UK (S_3565)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
integrins, ITGAV, tumor microenvironment, TGF-beta signaling, immunosuppression, immune checkpoint inhibitors, cancer-associated fibroblasts, epithelial-mesenchymal transition, angiogenesis

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