Marttila-Ichihara Fumiko, Auvinen Kaisa, Elima Kati, Jalkanen Sirpa, Salmi Marko
MediCity Research Laboratory, University of Turku, Turku, Finland.
Cancer Res. 2009 Oct 1;69(19):7875-83. doi: 10.1158/0008-5472.CAN-09-1205. Epub 2009 Sep 29.
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.
癌症的生长受几种非恶性细胞类型的调控，如存在于肿瘤基质中的白细胞和内皮细胞。血管黏附蛋白-1（VAP-1）是一种胺氧化酶，在内皮细胞表面表达。它支持白细胞进入炎症组织，但对其在体内癌症生物学中的可能作用尚不清楚。在此，我们报告，在VAP-1缺陷小鼠中，B16黑色素瘤和EL-4淋巴瘤比野生型对照小鼠中的肿瘤更小。我们发现在缺乏VAP-1的情况下，肿瘤血管生成存在意外缺陷。VAP-1还选择性地增强了Gr-1⁺CD11b⁺髓样细胞向肿瘤的募集。表达无酶活性VAP-1的小鼠的生成表明，VAP-1的氧化酶活性对于支持体内新生血管生成、髓样细胞募集和肿瘤生长是必需的。这些数据将VAP-1描述为已知参与Gr-1⁺CD11b⁺髓样细胞向肿瘤募集的首个黏附分子。它们还表明，VAP-1是肿瘤免疫治疗的一种潜在新工具，可通过控制Gr-1⁺CD11b⁺髓样细胞的运输来减轻肿瘤负担。
