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Vascular Adhesion Protein-1 Enhances Tumor Growth by Supporting Recruitment of Gr-1⁺CD11b⁺ Myeloid Cells into Tumors

¹ MediCity Research Laboratory, University of Turku, ² Inflammatory Mechanisms Unit, The National Institute for Health and Welfare, and Departments of ³ Medical Biochemistry and Genetics and ⁴ Medical Microbiology and Immunology, University of Turku, Turku, Finland

Requests for reprints: Marko Salmi, MediCity Research Laboratory, Tykistökatu 6A, 20520 Turku, Finland. Phone: 358-2-3337006; Fax: 358-2-3337000; E-mail: marko.salmi{at}utu.fi.

Key Words: endothelium • leukocyte traffic • oxidases • myeloid cells • adhesion molecules • angiogenesis

Cancer growth is regulated by several nonmalignant cell types, such as leukocytes and endothelial cells, which reside in the stroma of the tumor. Vascular adhesion protein-1 (VAP-1) is an amine oxidase enzyme that is expressed on the surface of endothelial cells. It supports leukocyte traffic into inflamed tissues, but nothing is known about its possible role in cancer biology in vivo. Here, we report that B16 melanoma and EL-4 lymphoma remain smaller in VAP-1–deficient mice than in wild-type controls. We found an unexpected defect in tumor angiogenesis in the absence of VAP-1. VAP-1 also selectively enhanced the recruitment of Gr-1⁺CD11b⁺ myeloid cells into the tumors. Generation of mice expressing enzymatically inactive VAP-1 showed that the oxidase activity of VAP-1 was necessary to support neoangiogenesis, myeloid cell recruitment, and tumor growth in vivo. These data describe VAP-1 as the first adhesion molecule known to be involved in the recruitment of Gr-1⁺CD11b⁺ myeloid cells into tumors. They also suggest that VAP-1 is a potential new tool for immunotherapy of tumors that could be exploited to reduce tumor burden by controlling the traffic of Gr-1⁺CD11b⁺ myeloid cells. [Cancer Res 2009;69(19):7875–83]