Antibody-mediated blockade of integrin alpha v beta 6 inhibits tumor progression in vivo by a transforming growth factor-beta-regulated mechanism.

Department of Discovery Immunology, Biogen Idec, Cambridge, Massachusetts 02142, USA.
Cancer Research (Impact Factor: 9.28). 01/2008; 68(2):561-70. DOI: 10.1158/0008-5472.CAN-07-2307
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Integrins, a family of cell adhesion molecules composed of α and β heterodimeric subunits, are involved in a wide range of cell-extracellular matrix and cell-cell interactions. The study of integrin family members as targets for molecular imaging and therapy has been generally limited with the exception of integrin αvβ3. vβ6, a member of the integrin family, is expressed at low or undetectable levels in normal tissues, but is widely upregulated during many pathological and physiological processes, especially cancer and fibrosis, making it a promising target for molecular imaging. Noninvasive and quantitative imaging of integrin vβ6 expression would be very useful for disease diagnosis, treatment monitoring, and prognosis assessment. Although various molecular probes have been developed for positron emission tomography and single-photon emission computed tomography imaging of integrin vβ6 expression in preclinical animal models, further research efforts are required to optimize integrin vβ6-targeting probes for future potential clinical applications in the fields of oncology and beyond.
    American Journal of Nuclear Medicine and Molecular Imaging 01/2014; 4(4):333-45. · 3.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer.
    JNCI Journal of the National Cancer Institute 08/2014; 106(8). · 15.16 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Fibrosis, a disease that results in loss of organ function, contributes to a significant number of deaths worldwide and sustained fibrotic activation has been suggested to increase the risk of developing cancer in a variety of tissues. Fibrogenesis and tumor progression are regulated in part through the activation and activity of myofibroblasts. Increasing evidence links myofibroblasts found within fibrotic lesions and the tumor microenvironment to a process termed epithelial-mesenchymal transition (EMT), a phenotypic change in which epithelial cells acquire mesenchymal characteristics. EMT can be stimulated by soluble signals, including transforming growth factor (TGF)-β, and recent studies have identified a role for mechanical cues in directing EMT. In this review, we describe the role that EMT plays in fibrogenesis and in the progression of cancer, with particular emphasis placed on biophysical signaling mechanisms that control the EMT program. We further describe specific TGFβ-induced intracellular signaling cascades that are affected by cell- and tissue-level mechanics. Finally, we highlight the implications of mechanical induction of EMT on the development of treatments and targeted intervention strategies for fibrosis and cancer.
    Clinical and translational medicine. 01/2014; 3:23.

Full-text (2 Sources)

Available from
Oct 9, 2014