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Antibody-Mediated Blockade of Integrin αvβ6 Inhibits Tumor Progression In vivo by a Transforming Growth Factor-β–Regulated Mechanism
Abstract
The αvβ6 integrin is up-regulated on epithelial malignancies and has been implicated in various aspects of cancer progression. Immunohistochemical analysis of αvβ6 expression in 10 human tumor types showed increased expression relative to normal tissues. Squamous carcinomas of the cervix, skin, esophagus, and head and neck exhibited the highest frequency of expression, with positive immunostaining in 92% (n = 46), 84% (n = 49), 68% (n = 56), and 64% (n = 100) of cases, respectively. We studied the role of αvβ6 in Detroit 562 human pharyngeal carcinoma cells in vitro and in vivo. Prominent αvβ6 expression was detected on tumor xenografts at the tumor-stroma interface resembling the expression on human head and neck carcinomas. Nonetheless, coculturing cells in vitro with matrix proteins did not up-regulate αvβ6 expression. Detroit 562 cells showed αvβ6-dependent adhesion and activation of transforming growth factor-β (TGF-β) that was inhibited >90% with an αvβ6 blocking antibody, 6.3G9. Although both recombinant soluble TGF-β receptor type-II (rsTGF-βRII-Fc) and 6.3G9 inhibited TGF-β–mediated Smad2/3 phosphorylation in vitro, there was no effect on proliferation. Conversely, in vivo, 6.3G9 and rsTGF-βRII-Fc inhibited xenograft tumor growth by 50% (n = 10, P < 0.05) and >90% (n = 10, P < 0.001), respectively, suggesting a role for the microenvironment in this response. However, stromal collagen and smooth muscle actin content in xenograft sections were unchanged with treatments. Although further studies are required to consolidate in vitro and in vivo results and define the mechanisms of tumor inhibition by αvβ6 antibodies, our findings support a role for αvβ6 in human cancer and underscore the therapeutic potential of function blocking αvβ6 antibodies. [Cancer Res 2008;68(2):561–70]
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“and small molecules have been developed that prevent integrin β1- and integrin β6-mediated latent TGF-β1 activation316–318.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [317]
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Metadata
- Authors
- Koopman Van Aarsen, L. A., Leone, D. R., Ho, S., Dolinski, B. M., McCoon, P. E., LePage, D. J., Kelly, R., Heaney, G., Rayhorn, P., Reid, C., Simon, K. J., Horan, G. S., Tao, N., Gardner, H. A., Skelly, M. M., Gown, A. M., Thomas, G. J., Weinreb, P. H., Fawell, S. E., & Violette, S. M.
- Affiliations
- 1Departments of Discovery Immunology and Discovery Oncology, Biogen Idec, Cambridge, Massachusetts;
- Biogen (United States) (US)
- 2Phenopath Laboratories, Seattle, Washington; and
- Queen Mary University of London (GB)
- Venue
- Cancer Research
- Published
- 2008-01-15
- Volume
- 68
- Issue
- 2
- Pages
- 561-570
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2106528753
- Cited by
- 146
- References
- 55
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 16 · 2020: 8 · 2019: 7 · 2018: 7 · 2017: 8 · 2016: 9 · 2015: 6 · 2014: 13 · 2013: 9 · 2012: 9
- FWCI
- 6.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- antibody blocking, TGF-beta, Smad2/3 phosphorylation, tumor progression, pharyngeal cancer, xenograft tumor growth, tumor microenvironment, head and neck squamous cell carcinoma, cell adhesion, tumor-stroma interface
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type II, Animals, Antibodies, Monoclonal, Carcinoma, Squamous Cell, Cells, Cultured, Female, Humans, Immunoglobulin Fc Fragments, Mice, Nude, Mink, Pharyngeal Neoplasms, Recombinant Fusion Proteins, Signal Transduction, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Disease Progression, Protein Isoforms, Xenograft Model Antitumor Assays, Integrin alpha5, Cell Proliferation, Mice, Smad Proteins
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