Angiogenesis inhibitors overcome tumor induced endothelial cell anergy

We report here that tumor angiogenesis‐mediated endothelial cell (EC) anergy can be overcome by inhibitors of angiogenesis. We found previously that tumor growth, known to be dependent on angiogenesis, results in down‐regulation of endothelial adhesion molecules and tumor EC anergy to inflammatory signals. We hypothesized that counteracting angiogenesis induces re‐expression of adhesion molecules and normalizes responses to inflammatory cytokines. Here, we present data to show that the angiogenesis inhibitor platelet factor‐4 (PF4) is able to prevent basic fibroblast growth factor (bFGF)‐induced down‐regulation of intercellular adhesion molecule‐1 (ICAM‐1). Furthermore, PF4 restores ICAM‐1 expression following bFGF‐induced down‐regulation of ICAM‐1. This PF4 effect occurs at the protein level and the RNA level and it has functional impact on leukocyte adhesion. In addition, PF4 overcomes the tumor‐induced EC anergy to inflammatory signals such as tumor necrosis factor α (TNFα). Our findings may be the basis of new cancer therapies by combining anti‐angiogenic therapy and immunotherapy to decrease blood vessel formation and to increase the effectiveness of inflammatory reactions against tumors. Int. J. Cancer 80:315–319, 1999. © 1999 Wiley‐Liss, Inc.