Modulation of tumor-host interactions, angiogenesis, and tumor growth by tissue inhibitor of metalloproteinase 2 via a novel mechanism.

Abstract

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.

• Authors: Andrew L Feldman, William G Stetler-Stevenson, Nick G Costouros, Vladimir Knezevic, Galina Baibakov, H Richard Alexander Jr, Dominique Lorang, Stephen M Hewitt, Dong-Wan Seo, Marshall S Miller, Sarah O'Connor, Steven K Libutti
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 13 Pg. 4481-6 (Jul 01 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15231657 (Publication Type: Journal Article)

Chemical References

• Cell Cycle Proteins
• Immediate-Early Proteins
• Tissue Inhibitor of Metalloproteinase-2
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Phosphoprotein Phosphatases
• Protein Phosphatase 1
• Dual Specificity Phosphatase 1
• Dusp1 protein, mouse
• Protein Tyrosine Phosphatases

Topics

• Animals
• Cell Cycle Proteins
• Cell Division (physiology)
• Colonic Neoplasms (blood supply, genetics, metabolism, pathology)
• Dual Specificity Phosphatase 1
• Enzyme Induction
• Female
• Gene Expression Profiling
• Immediate-Early Proteins (biosynthesis)
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinases (metabolism)
• Neovascularization, Pathologic (genetics, metabolism, pathology)
• Phosphoprotein Phosphatases
• Phosphorylation
• Protein Phosphatase 1
• Protein Tyrosine Phosphatases (biosynthesis)
• Retroviridae (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Tissue Inhibitor of Metalloproteinase-2 (biosynthesis, genetics, physiology)
• Transduction, Genetic
• p38 Mitogen-Activated Protein Kinases