Modulation of tumor-host interactions, angiogenesis, and tumor growth by tissue inhibitor of metalloproteinase 2 via a novel mechanism.
Solid tumors depend on angiogenesis for sustained growth. Tissue inhibitor of metalloproteinase 2 (TIMP-2) is an angiogenesis inhibitor initially characterized for its ability to block matrix metalloproteinases; however, recent data suggest that the antiangiogenic action of TIMP-2 may rely on matrix metalloproteinase-independent mechanisms. The aim of this study was to identify molecular pathways involved in the effects of TIMP-2 on processes dependent on tumor-host interactions such as angiogenesis. Using in vitro cell culture and a syngeneic murine tumor model, we compared the effects of TIMP-2 overexpression on gene expression profiles in vitro to those observed in vivo. Validating these findings by real-time quantitative PCR and layered protein scanning, we identified up-regulation of mitogen-activated protein kinase phosphatase 1 as an effector of the antiangiogenic function of TIMP-2. Up-regulation of mitogen-activated protein kinase phosphatase 1 in tumors overexpressing TIMP-2 leads to dephosphorylation of p38 mitogen-activated protein kinase and inhibition of tumor growth and angiogenesis. Phosphatase activity appears important in regulating tumor angiogenesis, offering a promising direction for the identification of novel molecular targets and antiangiogenic compounds for the treatment of cancer.
Feldman
Andrew L
AL
Metabolism Section, Surgery Branch, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
Stetler-Stevenson
William G
WG
Costouros
Nick G
NG
Knezevic
Vladimir
V
Baibakov
Galina
G
Alexander
H Richard
HR
Lorang
Dominique
D
Hewitt
Stephen M
SM
Seo
Dong-Wan
DW
Miller
Marshall S
MS
O'Connor
Sarah
S
Libutti
Steven K
SK
D000818:Animals; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000502:physiology; D003110:Colonic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D054638:Dual Specificity Phosphatase 1; D004790:Enzyme Induction; D005260:Female; D020869:Gene Expression Profiling; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic; D048051:p38 Mitogen-Activated Protein Kinases
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases