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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