Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium

Abstract

We previously showed that endothelial cells (EC) from the vasculature of human solid tumors have a decreased expression of intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 as compared with normal tissue EC. This effect is explained by EC exposure to angiogenic factors. It is known that upregulation of endothelial adhesion molecules (EAM) is a sign of EC activation in inflammatory responses. We therefore tested the effect of angiogenic factors on upregulation of EAM on tumor EC and human umbilical vein EC (HUVEC) by proinflammatory cytokines. Incubation of tumor-derived EC in tumor necrosis factor alpha (TNF alpha) did result in expression levels of only 20% of the level of similarly treated normal tissue-derived EC. Pretreatment of HUVEC with 10 ng/ml basic fibroblast growth factor (bFGF) for 3 days, before TNF alpha- or interleukin-1 alpha (IL-1 alpha) stimulation, resulted in ICAM-1 levels of only 30% to 60% of cells without pretreatment. Also, the induction of vascular EC adhesion molecule-1 (VCAM-1) and E- selectin by TNF alpha was significantly inhibited by prior exposure to bFGF. Vascular endothelial growth factor had similar but less prominent effects. The effect of transforming growth factor-beta and IL-8 was studied as well. The functional relevance of the finding of a decreased EC inflammatory response was confirmed by adhesion assays. Our results show that tumor angiogenesis induces EC anergy. This may serve as a tumor-protecting mechanism by impairing the development of an efficient leukocyte infiltrate in tumors.

Anti‐angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte‐endothelium interactions and infiltration in tumors

“…The bFGF-mediated down-regulation of ICAM-1 was observed in HUVEC ( Fig. 3C), which is in agreement with previous observations (6,7). Culture in the presence of anginex completely prevented the bFGF-mediated down-regulation of both ICAM-1 and VCAM-1 at the protein level ( Fig.…”

“…It is known that tumors have the capacity to prevent the formation of a proper anti-tumor immune response by down-regulation of endothelial adhesion molecules that are necessary for leukocyte-vessel wall interactions (11,12,31). This regulation is mediated by angiogenic growth factors (6,7). It was recently demonstrated in ovarian carcinoma patients that the expression of VEGF in tumor tissue is negatively correlated with the presence of infiltrating T lymphocytes, which was found to be the strongest prognostic factor in ovarian carcinoma (13).…”

Vascular cell adhesion molecule‐1 (VCAM‐1)—An increasing insight into its role in tumorigenicity and metastasis

“…The downregulation of VCAM-1, first described for melanoma and carcinoma, 93,94 serves most probably as a tumor protecting mechanism by attenuating the immune response for leukocyte infiltration. 95 The reduced adhesion molecule expression on tumor microvessels is related to the TC secretion of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). 96,97 Also the in vitro treatment of endothelial cells with proinflammatory TNFa or IL-1a could not compensate a bFGF or VEGF pretreatment to recover VCAM-1 expression completely.…”

“…96,97 Also the in vitro treatment of endothelial cells with proinflammatory TNFa or IL-1a could not compensate a bFGF or VEGF pretreatment to recover VCAM-1 expression completely. 95,96 Recently, Egfl7 (also known as VE-statin) expressed by many carcinomas was shown to promote a tumor escape by hampering VCAM-1 expression on tumor endothelial cells. 98 On the contrary to the above mentioned observations, other studies report on an upregulation of VCAM-1 after VEGF stimulation of endothelial cells.…”

Synergistic Effect of Avemar on Proinflammatory Cytokine Production and Ras-Mediated Cell Activation

“…These results indicate that signaling pathways usually triggered by inflammatory cytokines 18 might be involved in the effects of Avemar. To learn more about the molecular events elicited by Avemar, HeLa cells were transiently transfected with signaling pathway-specific reporters and treated with increasing doses of Avemar.…”