ENDOTHELIAL INTERCELLULAR-ADHESION MOLECULE-1 EXPRESSION IS SUPPRESSED IN HUMAN MALIGNANCIES - THE ROLE OF ANGIOGENIC FACTORS

Intercellular adhesion molecule 1 (ICAM-1) is involved in the recircul ation of blood leukocytes and, presumably, in the infiltration of cyto lytic effector leukocytes into tumors, The present report describes a downregulated expression of vascular ICAM-1 on tumor-infiltrating endo thelial cells (EC) in renal cell carcinoma, This finding was obtained by now cytometric analysis of tumor EC compared to EC obtained from he althy tissue. Since growth of solid tumors is dependent on the formati on of new blood vessels (angiogenesis), we hypothesized that angiogeni c factors are responsible for the down-regulation of ICAM-1. This hypo thesis was investigated in vitro using human umbilical vein- and dermi s-derived EC, Using flow cytometry, we found a biphasic regulation of ICAM-1 during stimulation of cultured EC with the angiogenic agent bas ic fibroblast growth factor (bFGF). Although 16-24 h after activation a marked up-regulation of ICAM-1 was observed, expression was signific antly decreased after 48 h, The longevity of this down-regulation was at least 7 days, Northern blot analysis revealed down-regulation of th e steady-state mRNA level of the gene. ICAM-2 showed similar results o f initial up- and later down-regulation. Functional relevance for the changes in ICAM-1 expression was demonstrated by a corresponding bipha sic regulation of EC-leukocyte adhesion after EC activation by bFGF, T he described effects are specific for bFGF since other angiogenic fact ors (such as vascular endothelial growth factor, transforming growth f actor beta, and interleukin 8) did not affect adhesion molecule expres sion, Subsequent experiments showed that angiogenic factors decrease t he sensitivity of EC to activation with tumor necrosis factor-alpha in regard to adhesion molecule expression, The present results reveal a tumor-derived escape mechanism from cytolytic effector leukocytes by d own-regulation of vascular adhesion molecules in vivo and in vitro and decreased responsiveness to proinflammatory cytokines.