Antibody-Mediated Blockade of Integrin αvβ6 Inhibits Tumor Progression In vivo by a Transforming Growth Factor-β–Regulated Mechanism

Koopman Van Aarsen, Louise A.; Leone, Diane R.; Ho, Steffan; Dolinski, Brian M.; McCoon, Patricia E.; LePage, Doreen J.; Kelly, Rebecca; Heaney, Glenna; Rayhorn, Paul; Reid, Carl; Simon, Kenneth J.; Horan, Gerald S.; Tao, Nianjun; Gardner, Humphrey A.; Skelly, Marilyn M.; Gown, Allen M.; Thomas, Gareth J.; Weinreb, Paul H.; Fawell, Stephen E.; Violette, Shelia M.

doi:10.1158/0008-5472.can-07-2307

Cited by 146Cell Adhesion Molecules ResearchTGF-β signaling in diseasesProtease and Inhibitor Mechanisms

Antibody-Mediated Blockade of Integrin αvβ6 Inhibits Tumor Progression In vivo by a Transforming Growth Factor-β–Regulated Mechanism

Koopman Van Aarsen, Louise A., Leone, Diane R., Ho, Steffan, Dolinski, Brian M., McCoon, Patricia E., LePage, Doreen J., Kelly, Rebecca, Heaney, Glenna +12 more·2008·Cancer Research

DOI 10.1158/0008-5472.can-07-2307

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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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Small molecules have been developed that prevent integrin β1- and integrin β6-mediated latent TGF-β1 activation.
“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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Targeting of αv-Integrins in Stem/Progenitor Cells and Supportive Microenvironment Impairs Bone Metastasis in Human Prostate Cancer
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αvβ6 Integrin Promotes the Invasion of Morphoeic Basal Cell Carcinoma through Stromal Modulation
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Connective tissue growth factor and integrin αvβ6: A new pair of regulators critical for ductular reaction and biliary fibrosis in mice
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The Coagulation System Contributes to αVβ6 Integrin Expression and Liver Fibrosis Induced by Cholestasis
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Targeting of Aberrant αvβ6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells
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TGFβ signaling networks in ovarian cancer progression and plasticity
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Targeting of Aberrant αvβ6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells
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Integrin modulators: a patent review
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Markers of Cancer Cell Invasion: Are They Good Enough?
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In Vivo Retargeting of Adenovirus Type 5 to αvβ6 Integrin Results in Reduced Hepatotoxicity and Improved Tumor Uptake following Systemic Delivery
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Selecting Tumor-Specific Molecular Targets in Pancreatic Adenocarcinoma: Paving the Way for Image-Guided Pancreatic Surgery
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Cutting Edge: Epigenetic Regulation of Foxp3 Defines a Stable Population of CD4+ Regulatory T Cells in Tumors from Mice and Humans
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A novel serum carbohydrate marker on mucin 5AC
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Integrin α v β 6 –Targeted SPECT Imaging for Pancreatic Cancer Detection
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Integrin Alpha v Beta 6 (αvβ6) and Its Implications in Cancer Treatment
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Colocalized targeting of TGF-β and PD-L1 by bintrafusp alfa elicits distinct antitumor responses
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Ad5NULL-A20: A Tropism-Modified, αvβ6 Integrin-Selective Oncolytic Adenovirus for Epithelial Ovarian Cancer Therapies
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Integrin Inhibitors in Prostate Cancer
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Chimeric Antigen Receptor T Cells Targeting Integrin αvβ6 Expressed on Cholangiocarcinoma Cells
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Synthesis and characterization of a high-affinity αvβ6-specific ligand for in vitro and in vivo applications
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There is a world beyond αvβ3-integrin: Multimeric ligands for imaging of the integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1 by positron emission tomography
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Development and characterization of human monoclonal antibodies that neutralize multiple TGFβ isoforms
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“xenografts by rTGFbrII-HuFc (a putative pan inhibitor of TGFb function) has previously been reported in the literature.(39) In the current study, we used the Detroit 562 xenograft model to determine the effects of TGFb neutralizing antibody XPA.”
Method
A Skin-depth Analysis of Integrins: Role of the Integrin Network in Health and Disease
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TGF-β Signaling in Progression of Oral Cancer
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Pseudotyped αvβ6 integrin-targeted adenovirus vectors for ovarian cancer therapies
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Metalloproteinases ADAM10 and ADAM17 Mediate Migration and Differentiation in Glioblastoma Sphere-Forming Cells
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EGFR and αvβ6 as Promising Targets for Molecular Imaging of Cutaneous and Mucosal Squamous Cell Carcinoma of the Head and Neck Region
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SGN-B6A: A New Vedotin Antibody–Drug Conjugate Directed to Integrin Beta-6 for Multiple Carcinoma Indications
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Down-regulation of αv integrin by retroviral delivery of small interfering RNA reduces multicellular resistance of HT29
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Integrin αvβ6 and Mediators of Extracellular Matrix Deposition Are Up-Regulated in Experimental Biliary Atresia
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NIR Imaging of the Integrin-Rich Head and Neck Squamous Cell Carcinoma Using Ternary Copper Indium Selenide/Zinc Sulfide-Based Quantum Dots
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αvβ6 integrin is required for TGFβ1-mediated matrix metalloproteinase2 expression
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Recent developments in peptide-based SPECT radiopharmaceuticals for breast tumor targeting
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TGFβ upregulates PAR-1 expression and signalling responses in A549 lung adenocarcinoma cells
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It’s Time to Shift the Paradigm: Translation and Clinical Application of Non-αvβ3 Integrin Targeting Radiopharmaceuticals
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Recent advances in therapeutic use of transforming growth factor-beta inhibitors in cancer and fibrosis
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The integrin αvβ6: a novel target for CAR T-cell immunotherapy?
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Targeting cancer metastasis with antibody therapeutics
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NDRG2 correlated with favorable recurrence-free survival inhibits metastasis of mouse breast cancer cells via attenuation of active TGF-β production
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Inhibition of αvβ6 Promotes Acute Renal Allograft Rejection in Nonhuman Primates
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Stromal issues in cervical cancer: a review of the role and function of basement membrane, stroma, immune response and angiogenesis in cervical cancer development
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Identification of folate receptor α (FRα) binding oligopeptides and their evaluation for targeted virotherapy applications
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α(V)β(6) integrin expression is induced in the POET and Pten(pc-/-) mouse models of prostatic inflammation and prostatic adenocarcinoma.
Garlick, D. S., Li, J., Sansoucy, B. G., Wang, T., Griffith, L., FitzGerald, T. J., Butterfield, J. E., Charbonneau, B., Violette, S. M., Weinreb, P. H., et al. (2012) · Europe PMC (PubMed Central) · Cited by 15 · see citing works
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Targeting Transforming Growth Factor-β (TGF-β) in Cancer and Non-Neoplastic Diseases
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Selective inhibition of integrin αvβ6 leads to rapid induction of urinary bladder tumors in cynomolgus macaques
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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)
ORCID: McCoon, Patricia E.
Gown, Allen M.
Thomas, Gareth J.
Weinreb, Paul H.
Fawell, Stephen E.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2008-01-15
Volume: 68
Issue: 2
Pages: 561-570
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-07-2307
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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Antibody-Mediated Blockade of Integrin αvβ6 Inhibits Tumor Progression In vivo by a Transforming Growth Factor-β–Regulated Mechanism

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