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ADAM8 is a negative regulator of retinal neovascularization and of the growth of heterotopically injected tumor cells in mice

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Abstract

ADAM8 is a member of the “a disintegrin and metalloproteinase” (ADAM) family of membrane-anchored metalloproteinases. ADAM8-deficient mice have no evident spontaneous developmental or pathological defects, and little is currently known about the role of ADAM8 in disease. Here, we investigated the contribution of ADAM8 to pathological neovascularization in mice using an oxygen-induced retinopathy (OIR) model and heterotopical injection of tumor cells. We found an increase in retinal re-vascularization but fewer neovascular tufts in the OIR model and increased growth of heterotopically injected tumor cells in Adam8-/- mice compared with wild-type controls. These results suggest that ADAM8 functions to limit both of these processes in wild-type mice. In cell-based assays, overexpression of ADAM8 increased the ectodomain shedding of several co-expressed membrane proteins with roles in angiogenesis (CD31, Tie-2, Flk-1, Flt-1, EphrinB2, EphB4, VE-cadherin, KL-1, E-selectin, and neuregulin-1β2). Thus, dysregulated expression of ADAM8 in endothelial cells in vivo could potentially increase the processing of these and other substrate proteins. Taken together, our findings suggest that inhibiting ADAM8 could be useful for promoting re-vascularization and thereby preventing formation of neovascular tufts in proliferative retinopathies. On the other hand, blocking ADAM8 could be detrimental in the context of rapidly growing tumors.

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Acknowledgements

This work was supported by NIH/NEI grant EY015758 to CPB. We thank Dr. Andrew Docherty from UCB NewMedicines for providing Adam8-/- mice and Mrs. Elin Mogollon, Mr. Arash Shirazi, and Mr. Joshua Namm as well as the staff of the Center for Laboratory Animal Services of the Hospital for Special Surgery for excellent technical assistance.

Conflict of interest

The authors reported no conflict of interest.

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Authors and Affiliations

  1. Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, Caspary Research Building, Room 426, 535 East 70th street, New York, NY, 10021, USA

    Victor H. Guaiquil, Steven Swendeman, Wenhui Zhou, Patricio Guaiquil, Gisela Weskamp & Carl P. Blobel

  2. Gateways to the Laboratory Program, Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY, USA

    Wenhui Zhou

  3. Pharmaceutical Science Research Division, King’s College London, London, SE1 9NH, UK

    Jörg W. Bartsch

  4. Departments of Medicine and of Physiology, Biophysics and Systems Biology, Weill Medical College of Cornell University, New York, NY, 10021, USA

    Carl P. Blobel

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  1. Victor H. Guaiquil
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  2. Steven Swendeman
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  4. Patricio Guaiquil
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  7. Carl P. Blobel
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Correspondence to Carl P. Blobel.

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Guaiquil, V.H., Swendeman, S., Zhou, W. et al. ADAM8 is a negative regulator of retinal neovascularization and of the growth of heterotopically injected tumor cells in mice. J Mol Med 88, 497–505 (2010). https://doi.org/10.1007/s00109-010-0591-8

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  • DOI: https://doi.org/10.1007/s00109-010-0591-8

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