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 alpha-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 alpha-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.