Linked Life Data

17108113

Source:http://linkedlifedata.com/resource/pubmed/id/17108113

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
22
pubmed:dateCreated
2006-11-19
pubmed:abstractText
Tumors can escape from immunity by repressing leukocyte adhesion molecule expression on tumor endothelial cells and by rendering endothelial cells unresponsive to inflammatory activation. This endothelial cell anergy is induced by angiogenic growth factors and results in reduced leukocyte-vessel wall interactions, thereby attenuating infiltration of leukocytes into the tumor. This report describes a novel mechanism of endothelial cell anergy regulation. We recently reported that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors have angiostatic activity. Here, we studied whether epigenetic mechanisms regulate this angiogenesis-mediated escape from immunity. We found that DNMT inhibitors 5-aza-2'-deoxycytidine and zebularine, as well as HDAC inhibitor trichostatin A, reexpressed intercellular adhesion molecule-1 (ICAM-1) on tumor-conditioned endothelial cells in vitro, resulting in restored leukocyte-endothelial cell adhesion. In addition, treatment with DNMT or HDAC inhibitors in vivo also restored ICAM-1 expression on tumor endothelial cells from two different mouse tumor models. Furthermore, leukocyte-vessel wall interactions in mouse tumors were increased by these compounds, as measured by intravital microscopy, resulting in enhanced leukocyte infiltration. We show that ICAM-1 down-regulation in tumor endothelial cells is associated with ICAM-1 promoter histone H3 deacetylation and loss of histone H3 Lys(4) methylation but not with DNA hypermethylation. In conclusion, our data show that ICAM-1 is epigenetically silenced in tumor endothelial cells by promoter histone modifications, which can be overcome by DNMT and HDAC inhibitors, suggesting a new molecular mechanism based on which novel therapeutic approaches for cancer can be pursued.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
66
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
10770-7
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:17108113-Acetylation, pubmed-meshheading:17108113-Animals, pubmed-meshheading:17108113-Cell Adhesion, pubmed-meshheading:17108113-Clonal Anergy, pubmed-meshheading:17108113-Cytidine, pubmed-meshheading:17108113-DNA Modification Methylases, pubmed-meshheading:17108113-Down-Regulation, pubmed-meshheading:17108113-Endothelial Cells, pubmed-meshheading:17108113-Epigenesis, Genetic, pubmed-meshheading:17108113-Gene Silencing, pubmed-meshheading:17108113-Histone Deacetylase Inhibitors, pubmed-meshheading:17108113-Histone Deacetylases, pubmed-meshheading:17108113-Histones, pubmed-meshheading:17108113-Humans, pubmed-meshheading:17108113-Intercellular Adhesion Molecule-1, pubmed-meshheading:17108113-Leukocytes, pubmed-meshheading:17108113-Melanoma, Experimental, pubmed-meshheading:17108113-Methylation, pubmed-meshheading:17108113-Mice, pubmed-meshheading:17108113-Mice, Inbred C57BL
pubmed:year
2006
pubmed:articleTitle
Epigenetic regulation of tumor endothelial cell anergy: silencing of intercellular adhesion molecule-1 by histone modifications.
pubmed:affiliation
Angiogenesis Laboratory, Research Institute for Growth and Development, Department of Pathology, Maastricht University and University Hospital, The Netherlands.
pubmed:publicationType
Journal Article