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

Andrew L. Feldman, William G. Stetler-Stevenson, Nick G. Costouros, Vladimir Knezevic, Galina Baibakov, H. Richard Alexander, Dominique Lorang, Stephen M. Hewitt, Dong Wan Seo, Marshall S. Miller, Sarah O'Connor, Steven K. Libutti

Research output: Contribution to journalArticle

31 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4481-4486
Number of pages6
JournalCancer research
Volume64
Issue number13
DOIs
StatePublished - Jul 1 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Feldman, A. L., Stetler-Stevenson, W. G., Costouros, N. G., Knezevic, V., Baibakov, G., Alexander, H. R., Lorang, D., Hewitt, S. M., Seo, D. W., Miller, M. S., O'Connor, S., & Libutti, S. K. (2004). Modulation of tumor-host interactions, angiogenesis, and tumor growth by tissue inhibitor of metalloproteinase 2 via a novel mechanism. Cancer research, 64(13), 4481-4486. https://doi.org/10.1158/0008-5472.CAN-03-2929