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Angiogenesis inhibitors overcome tumor induced endothelial cell anergy
A W Griffioen1, C A Damen, K H Mayo
1Department of Internal Medicine, University Hospital Maastricht, The Netherlands. a.griffioen@intmed.unimaas.nl
Abstract:
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 alpha (TNF alpha). 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.
Insights
Tumor growth causes endothelial cell anergy, but angiogenesis inhibitors like platelet factor-4 (PF4) can restore normal cell function and immune responses, offering new cancer therapy strategies.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Tumor growth relies on angiogenesis, leading to endothelial cell (EC) anergy and reduced inflammatory responses.
- Tumor-induced EC anergy involves down-regulation of adhesion molecules, impairing immune surveillance.
Purpose of the Study:
- To investigate if inhibiting angiogenesis can reverse EC anergy and restore normal endothelial cell function.
- To evaluate the effect of platelet factor-4 (PF4) on endothelial adhesion molecules and inflammatory responses in the context of tumor angiogenesis.
Main Methods:
- Assessed the impact of PF4 on intercellular adhesion molecule-1 (ICAM-1) expression, both at protein and RNA levels, following basic fibroblast growth factor (bFGF) stimulation.
- Investigated PF4's effect on leukocyte adhesion to endothelial cells.
- Examined PF4's ability to overcome EC anergy to inflammatory signals like tumor necrosis factor alpha (TNF alpha).
Main Results:
- PF4 prevented bFGF-induced down-regulation of ICAM-1 and restored ICAM-1 expression.
- PF4's effects on ICAM-1 were observed at both protein and RNA levels, with functional consequences for leukocyte adhesion.
- PF4 successfully reversed tumor-induced EC anergy to TNF alpha.
Conclusions:
- Inhibitors of angiogenesis, such as PF4, can overcome tumor angiogenesis-mediated EC anergy.
- PF4 normalizes endothelial cell responses to inflammatory signals and adhesion molecule expression.
- Combining anti-angiogenic therapy with immunotherapy holds promise for novel cancer treatment strategies.