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Tumor Angiogenesis Modulates Leukocyte-Vessel Wall Interactions in Vivo by Reducing Endothelial Adhesion Molecule Expression¹

Angiogenesis Laboratory, Research Institute for Growth and Development (GROW), Department of Internal Medicine [A. E. M. D., S. T. v. d. N., J. C. A. B-t. S., J. W.] and Department of Pathology [A. W. G.], University Hospital Maastricht and Maastricht University 6229 HX Maastricht, and Laboratory for Microcirculation, Department of Physiology, Cardiovascular Research Institute Maastricht [M. G. A. o. E., M. J. E. K., V. V. T. H.], 6202 AZ Maastricht, the Netherlands

The expression of endothelial cell (EC) adhesion molecules involved in leukocyte-vessel wall interactions is suppressed in malignancies. In the present study, we investigated in vivo the regulation of leukocyte-vessel wall interactions by the presence of a tumor. By means of intravital microscopy, tumor necrosis factor -stimulated leukocyte-vessel wall interactions were studied in ear skin microvessels of nude mice bearing small human LS174T colon carcinomas and in C57Bl/6 mice bearing murine B16F10 melanomas. Leukocyte-vessel wall interactions were studied both within and outside small tumors growing in the ear, and in ear microvessels of mice with a large tumor growing on their flank. Tumor-free mice were used as controls. Compared with values measured at the edge of the ear and in the contralateral ear, leukocyte adhesion was found to be diminished significantly in vessels inside the ear tumor in both mouse models. This reduction disappeared with increasing distance from the tumor. Surprisingly, the level of leukocyte adhesion in ear venules of mice with a large flank tumor was also reduced significantly. Leukocyte rolling, i.e., the step preceding adhesion, was not influenced by the presence of a tumor in nude mice, but was down-regulated in immune-competent C57Bl/6 mice. Treatment of mice bearing a small ear tumor with a humanized antivascular endothelial growth factor antibody prevented the down-regulation of leukocyte-vessel wall interactions inside the tumor vessels compared with the nontreated group. Fluorescence-activated cell sorter analysis showed that isolated tumor ECs have suppressed levels of intercellular adhesion molecule 1 as compared with ECs from normal mouse tissues. In cultured b.END5 cells the tumor necrosis factor -induced up-regulation of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 was reduced in ECs that were preincubated with basic fibroblast growth factor or vascular endothelial growth factor. The current results may have an impact on the effectiveness of clinical immunotherapeutic treatment protocols, because immune effector cells may not be able to enter tumor tissue.

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