Intercellular adhesion molecule 1 (ICAM-1) is involved in the recirculation of blood leukocytes and, presumably, in the infiltration of cytolytic effector leukocytes into tumors. The present report describes a down-regulated expression of vascular ICAM-1 on tumor-infiltrating endothelial cells (EC) in renal cell carcinoma. This finding was obtained by flow cytometric analysis of tumor EC compared to EC obtained from healthy tissue. Since growth of solid tumors is dependent on the formation of new blood vessels (angiogenesis), we hypothesized that angiogenic factors are responsible for the down-regulation of ICAM-1. This hypothesis was investigated in vitro using human umbilical vein- and dermis-derived EC. Using flow cytometry, we found a biphasic regulation of ICAM-1 during stimulation of cultured EC with the angiogenic agent basic fibroblast growth factor (bFGF). Although 16–24 h after activation a marked up-regulation of ICAM-1 was observed, expression was significantly decreased after 48 h. The longevity of this down-regulation was at least 7 days. Northern blot analysis revealed down-regulation of the steady-state mRNA level of the gene. ICAM-2 showed similar results of initial up- and later down-regulation. Functional relevance for the changes in ICAM-1 expression was demonstrated by a corresponding biphasic regulation of EC-leukocyte adhesion after EC activation by bFGF. The described effects are specific for bFGF since other angiogenic factors (such as vascular endothelial growth factor, transforming growth factor β, and interleukin 8) did not affect adhesion molecule expression. Subsequent experiments showed that angiogenic factors decrease the sensitivity of EC to activation with tumor necrosis factor-α in regard to adhesion molecule expression. The present results reveal a tumor-derived escape mechanism from cytolytic effector leukocytes by down-regulation of vascular adhesion molecules in vivo and in vitro and decreased responsiveness to proinflammatory cytokines.
This work was supported by the Dutch Research Foundation “De Drie Lichten” and by the “Stichting de Pelgrimshoeve.”