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Integrin-Mediated TGFβ Activation Modulates the Tumour Microenvironment
Open accessAbstract
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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![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].](/paper-figures/7bdbf31386bd43749adb6df23f78c331/integrin-mediated-tgf-activation-modulates-the-tumour-microenvironment-figure-1.jpg)
![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.](/paper-figures/2c4f342c20df4570b2963ffcb6db1765/integrin-mediated-tgf-activation-modulates-the-tumour-microenvironment-figure-2.jpg)
![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].](/paper-figures/3f0b730b4df04a68b8c99c6c1e93e3c2/integrin-mediated-tgf-activation-modulates-the-tumour-microenvironment-figure-3.jpg)
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“A recent report further demonstrated that Atf4 expression is enriched in hepatic Tregs from Western diet-induced obese mice, where it contributes to liver fibrosis by promoting TGF-β activation through integrin αvβ8.”
From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Brown and Marshall 2019
Experimental — accuracy not yet measuredIn the citing paper
“Since αvβ1, αvβ6 and αvβ8 mediate TGF-β1 activation81”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [81]
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Cites
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989
Epithelial-Mesenchymal Transitions in Development and Disease
Thiery, J. P., Acloque, H., Huang, R. Y. J., & Nieto, M. A. (2009) · Cell · doi:10.1016/j.cell.2009.11.007 · Cited by 9,931
Hynes (2002) · doi:10.1016/s0092-8674(02)00971-6 · Cited by 8,606
Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus
Shi, Y., & Massagué, J. (2003) · Cell · doi:10.1016/s0092-8674(03)00432-x · Cited by 5,860
Smad-dependent and Smad-independent pathways in TGF-β family signalling
Derynck, R., & Zhang, Y. E. (2003) · Nature · doi:10.1038/nature02006 · Cited by 5,498
TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells
Mariathasan, S., Turley, S. J., Nickles, D., Castiglioni, A., Yuen, K., Wang, Y., Kadel III, E. E., Koeppen, H., Astarita, J. L., Cubas, R., et al. (2018) · Nature · doi:10.1038/nature25501 · Cited by 5,400
Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients
Herbst, R. S., Soria, J.-C., Kowanetz, M., Fine, G. D., Hamid, O., Gordon, M. S., Sosman, J. A., McDermott, D. F., Powderly, J. D., Gettinger, S. N., et al. (2014) · Nature · doi:10.1038/nature14011 · Cited by 5,231
Massagué, J. (2008) · Cell · doi:10.1016/j.cell.2008.07.001 · Cited by 3,907
Rosenberg, J. E., Hoffman-Censits, J., Powles, T., van der Heijden, M. S., Balar, A. V., Necchi, A., Dawson, N., O'Donnell, P. H., Balmanoukian, A., Loriot, Y., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)00561-4 · Cited by 3,669
Polarization of Tumor-Associated Neutrophil Phenotype by TGF-β: “N1” versus “N2” TAN
Fridlender, Z. G., Sun, J., Kim, S., Kapoor, V., Cheng, G., Ling, L. E., Worthen, G. S., & Albelda, S. Μ. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.06.017 · Cited by 3,470
Cited by
Sorted by citations
TGFβ biology in cancer progression and immunotherapy
Derynck, R., Turley, S. J., & Akhurst, R. J. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-020-0403-1 · Cited by 944
Emerging therapeutic opportunities for integrin inhibitors
Slack, R. J., Macdonald, S. J. F., Roper, J. A., Jenkins, G. R., & Hatley, R. J. D. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00284-4 · Cited by 558
TGF-β1 – A truly transforming growth factor in fibrosis and immunity
Lodyga, M., & Hinz, B. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.12.010 · Cited by 467
Targeting TGFβ signal transduction for cancer therapy
Liu, S., Ren, J., & ten Dijke, P. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00436-9 · Cited by 413
“Previous studies showed that genetically and pharmacologically inhibition of αvβ integrin can inhibit TGFβ signaling and suppress metastasis.(201,203) For example, the cyclic RGD pentapeptide cilengitide (EMD121974) is a potent and selective inhibitor of integrin αvβ3/5 that showed a reduction of TGFβ1 and TGFβ2 messe…”
BackgroundOvercoming TGFβ-mediated immune evasion in cancer
Tauriello, D. V. F., Sancho, E., & Batlle, E. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-021-00413-6 · Cited by 377
Metadata
- Authors
- Brown, N. F., & Marshall, J. F.
- Affiliations
- Queen Mary University of London (GB)
- Corresponding author
- Marshall, John F.
- Venue
- Cancers
- Publisher
- MDPI AG
- Published
- 2019-08-21
- Volume
- 11
- Issue
- 9
- Pages
- 1221
- ISSN
- 2072-6694 (ISSN-L)
- 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
- gold
- dx.doi.org
- 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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