This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Koopman Van Aarsen, L. A. Articles by Violette, S. M. Search for Related Content PubMed PubMed Citation Articles by Koopman Van Aarsen, L. A. Articles by Violette, S. M.

Antibody-Mediated Blockade of Integrin _vβ₆ Inhibits Tumor Progression In vivo by a Transforming Growth Factor-β–Regulated Mechanism

¹ Departments of Discovery Immunology and Discovery Oncology, Biogen Idec, Cambridge, Massachusetts; ² Phenopath Laboratories, Seattle, Washington; and ³ Centre for Tumour Biology, Institute of Cancer, Queen Mary University of London, London, United Kingdom

Requests for reprints: Shelia M. Violette, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142. Phone: 617-679-3853; Fax: 617-679-3200; E-mail: shelia.violette{at}biogenidec.com.

The _vβ₆ integrin is up-regulated on epithelial malignancies and has been implicated in various aspects of cancer progression. Immunohistochemical analysis of _vβ₆ 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 _vβ₆ in Detroit 562 human pharyngeal carcinoma cells in vitro and in vivo. Prominent _vβ₆ 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 _vβ₆ expression. Detroit 562 cells showed _vβ₆-dependent adhesion and activation of transforming growth factor-β (TGF-β) that was inhibited >90% with an _vβ₆ 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 _vβ₆ antibodies, our findings support a role for _vβ₆ in human cancer and underscore the therapeutic potential of function blocking _vβ₆ antibodies. [Cancer Res 2008;68(2):561–70]

This article has been cited by other articles:

				S. H. Hausner, C. K. Abbey, R. J. Bold, M. K. Gagnon, J. Marik, J. F. Marshall, C. E. Stanecki, and J. L. Sutcliffe Targeted In vivo Imaging of Integrin {alpha}v{beta}6 with an Improved Radiotracer and Its Relevance in a Pancreatic Tumor Model Cancer Res., July 15, 2009; 69(14): 5843 - 5850. [Abstract] [Full Text] [PDF]

				L. Coughlan, S. Vallath, A. Saha, M. Flak, I. A. McNeish, G. Vassaux, J. F. Marshall, I. R. Hart, and G. J. Thomas In Vivo Retargeting of Adenovirus Type 5 to {alpha}v{beta}6 Integrin Results in Reduced Hepatotoxicity and Improved Tumor Uptake following Systemic Delivery J. Virol., July 1, 2009; 83(13): 6416 - 6428. [Abstract] [Full Text] [PDF]

				S. Li, M. J. McGuire, M. Lin, Y.-H. Liu, T. Oyama, X. Sun, and K. C. Brown Synthesis and characterization of a high-affinity {alpha}v{beta}6-specific ligand for in vitro and in vivo applications Mol. Cancer Ther., May 1, 2009; 8(5): 1239 - 1249. [Abstract] [Full Text] [PDF]

				J. H. McCarty {alpha}v Integrins Lead the Way for Colorectal Metastases Clin. Cancer Res., October 15, 2008; 14(20): 6351 - 6353. [Abstract] [Full Text] [PDF]

				H. L. Goel, J. Li, S. Kogan, and L. R Languino Integrins in prostate cancer progression Endocr. Relat. Cancer, September 1, 2008; 15(3): 657 - 664. [Abstract] [Full Text] [PDF]

				R. A. Weinberg Mechanisms of malignant progression Carcinogenesis, June 1, 2008; 29(6): 1092 - 1095. [Full Text] [PDF]

				D. Marsh, S. Dickinson, G. W. Neill, J. F. Marshall, I. R. Hart, and G. J. Thomas {alpha}v{beta}6 Integrin Promotes the Invasion of Morphoeic Basal Cell Carcinoma through Stromal Modulation Cancer Res., May 1, 2008; 68(9): 3295 - 3303. [Abstract] [Full Text] [PDF]