Identification of biomarkers for tumor endothelial cell proliferation through gene expression profiling.
Extensive efforts are under way to identify antiangiogenic therapies for the treatment of human cancers. Many proposed therapeutics target vascular endothelial growth factor (VEGF) or the kinase insert domain receptor (KDR/VEGF receptor-2/FLK-1), the mitogenic VEGF receptor tyrosine kinase expressed by endothelial cells. Inhibition of KDR catalytic activity blocks tumor neoangiogenesis, reduces vascular permeability, and, in animal models, inhibits tumor growth and metastasis. Using a gene expression profiling strategy in rat tumor models, we identified a set of six genes that are selectively overexpressed in tumor endothelial cells relative to tumor cells and whose pattern of expression correlates with the rate of tumor endothelial cell proliferation. In addition to being potential targets for antiangiogenesis tumor therapy, the expression patterns of these genes or their protein products may aid the development of pharmacodynamic assays for small molecule inhibitors of the KDR kinase in human tumors.
Hardwick
James S
JS
Merck & Co., Inc., 770 Sumneytown Pike, WP26-462, West Point, PA 19486, USA. james_hardwick@merck.com
Yang
Yi
Y
Zhang
Chunsheng
C
Shi
Bin
B
McFall
Rosemary
R
Koury
Elizabeth J
EJ
Hill
Susan L
SL
Dai
Hongyue
H
Wasserman
Robert
R
Phillips
Robert L
RL
Weinstein
Edward J
EJ
Kohl
Nancy E
NE
Severino
Michael E
ME
Lamb
John R
JR
Sepp-Lorenzino
Laura
L
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017931:DNA Primers / Q000737:chemistry; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D008833:Microcirculation / Q000166:cytology; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D017931:DNA Primers; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2