Antibody-Mediated Blockade of Integrin v 6 Inhibits Tumor Progression In vivo by a Transforming Growth Factor- Regulated Mechanism

Department of Discovery Immunology, Biogen Idec, Cambridge, Massachusetts 02142, USA.
Cancer Research (Impact Factor: 9.33). 01/2008; 68(2):561-70. DOI: 10.1158/0008-5472.CAN-07-2307
Source: PubMed


The alpha(v)beta(6) integrin is up-regulated on epithelial malignancies and has been implicated in various aspects of cancer progression. Immunohistochemical analysis of alpha(v)beta(6) 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 alpha(v)beta(6) in Detroit 562 human pharyngeal carcinoma cells in vitro and in vivo. Prominent alpha(v)beta(6) 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 alpha(v)beta(6) expression. Detroit 562 cells showed alpha(v)beta(6)-dependent adhesion and activation of transforming growth factor-beta (TGF-beta) that was inhibited >90% with an alpha(v)beta(6) blocking antibody, 6.3G9. Although both recombinant soluble TGF-beta receptor type-II (rsTGF-beta RII-Fc) and 6.3G9 inhibited TGF-beta-mediated Smad2/3 phosphorylation in vitro, there was no effect on proliferation. Conversely, in vivo, 6.3G9 and rsTGF-beta RII-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 alpha(v)beta(6) antibodies, our findings support a role for alpha(v)beta(6) in human cancer and underscore the therapeutic potential of function blocking alpha(v)beta(6) antibodies.

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Available from: Gareth J Thomas, Oct 09, 2014
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    • "In addition, a promising approach which has demonstrated efficacy as an anti-fibrotic in lung, kidney, and liver disease models is targeting the integrin- and contractility-induced activation of TGFβ from it latent complex through the use of a monoclonal antibody to αvβ6 integrin [183-186]. This method may also be an effective therapeutic approach for blocking tumor progression, as anti-αvβ6 integrin monoclonal antibody prevents xenograft tumor growth in vivo[187]. Inhibiting TGFβ activation may present lower risk to the disruption of beneficial effects of TGFβ than targeting TGFβ itself since αvβ6 is expressed primarily within epithelial cells and is highly upregulated in diseased tissues [184]. "
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    Clinical and Translational Medicine 07/2014; 3(1):23. DOI:10.1186/2001-1326-3-23
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    • "A murine monoclonal antibody (MAb) against full length human ανβ6 (clone 6.2A1, IgG1) (Biogen Idec, Cambridge, MA, USA) was used in IHC. The specificity of the anti-ανβ6 monoclonal antibody 6.2A1 has been reported in several studies [14], [24]–[26]. All TMA sections were prepared and processed simultaneously with the same batch of primary and secondary antibodies and staining reagents, obviating the need to deploy an internal standard. "
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    ABSTRACT: Integrin ανβ6 is highly expressed in a range of human cancers and frequently correlates with patient survival. This study examines correlations between ανβ6 expression and patient clinico-pathological features in Stage B and Stage C rectal cancer, including overall survival. Expression of ανβ6 was measured in 362 Stage B or C rectal cancer tissue samples at the tumour central region, invasive tumour front and adjacent non-neoplastic mucosa using immunohistochemistry. Distribution of ανβ6 was found to be significantly higher at the invasive front compared to central regions of the tumour (p<0.001) or adjacent non-neoplastic mucosa (p<0.001) suggesting ανβ6 plays a role in tumour cell invasion. However, integrin ανβ6 expression was not associated with clinico-pathological features or overall survival indicating it is not an independent prognostic marker differentiating Stage B or C rectal cancer. Previous ανβ6 studies have suggested the expression of ανβ6 is involved in the earlier stages (i.e. Stages A/B) of tumour progression rather than the later stages (i.e. Stages C/D). However, our study has revealed that in rectal cancer ανβ6 expression does not increase between Stages B and C, but may occur earlier, namely before or during Stage B cancer.
    PLoS ONE 05/2014; 9(5):e97248. DOI:10.1371/journal.pone.0097248 · 3.23 Impact Factor
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    • "Involvement of integrin receptors in initiation and/or progression of many malicious diseases including tumour metastasis, immune dysfunction, neoplasia, inflammation, trauma and infections have been reviewed elsewhere (Arnaout et al., 2007; Hynes, 2002, 2004). Integrins are also receptors for many viruses and bacteria, and have been the target of therapeutic drugs to combat inflammation, thrombosis, fibrosis and tumourigenesis (Binder and Trepel, 2009; Hynes, 2002; Lu et al., 2008; Margadant and Sonnenberg, 2010; Van Aarsen et al., 2008). "
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    ABSTRACT: Integrin αvβ6 is an epithelially-restricted heterodimeric transmembrane glycoprotein, known to interact with the urokinase plasminogen activating receptor (uPAR), playing a critical role in cancer progression. While the X-ray crystallographic structures of segments of other integrin heterodimers are known, there is no structural information for the complete αvβ6 integrin to assess its direct interaction with uPAR. We have performed structural analysis of αvβ6•uPAR interactions using model data with docking simulations to pinpoint their interface, in accord with earlier reports of the β-propeller region of integrin α-chain interacting with uPAR. Interaction of αvβ6•uPAR was demonstrated by our previous study using immunoprecipitation coupled with proteomic analysis by mass spectrometry. Recently this interaction was validated with proximity ligation assays and peptide arrays. The data suggested that two potential peptide regions from domain II and one peptide region from domain III of uPAR, interact with αvβ6 integrin. Only the peptide region from domain III is consistent with the three-dimensional interaction site proposed in this study. The molecular basis of integrin αvβ6•uPAR binding using structural data is discussed for its implications as a potential therapeutic target in cancer management.
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