Stat1 Negatively Regulates Angiogenesis, Tumorigenicity and Metastasis of Tumor Cells

Oncogene. 2002 Apr 11;21(16):2504-12. doi: 10.1038/sj.onc.1205341.

Abstract

Stat1 is deficient or inactive in many types of human tumors whereas some tumors have activated Stat1. Whether Stat1 affects tumor growth and metastasis is unclear. In the present study, we used Stat1 knockout tumor cells to determine (1) whether Stat1 can regulate angiogenesis, growth, and metastasis of tumor cells; and (2) whether Stat1 is required for the inhibitory effect of IFN-beta on the expression of angiogenic factor bFGF. Highly tumorigenic and metastatic RAD-105 tumor cells derived from a fibrosarcoma of a Stat1 knockout mouse were reconstituted with a Stat1 expression vector. The reconstitution of Stat1 suppressed the tumorigenicity and metastasis of RAD-105 cells in nude mice which correlated with a decreased microvessel density and decreased expression of proangiogenic molecules bFGF, MMP-2, and MMP-9 in vivo. Moreover, noncytotoxic concentrations of IFN-beta significantly inhibited the in vitro expression of bFGF in the Stat1-reconstituted cells but not in the Stat1-deficient cells, which was consistent with decreased bFGF expression of Stat1-reconstituted tumors in vivo. Therefore, Stat1 is essential for IFN-mediated inhibition of bFGF production, suggesting that tumor-intrinsic Stat1 is an important mediator for antiangiogenic signals, such as IFN. Collectively, these data demonstrate that Stat1 expressed by tumor cells is a negative regulator of tumor angiogenesis and, hence, tumor growth and metastasis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Division
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Endothelial Growth Factors / metabolism
  • Fibroblast Growth Factor 2 / metabolism
  • Fibrosarcoma / blood
  • Fibrosarcoma / etiology
  • Fibrosarcoma / metabolism
  • Fibrosarcoma / pathology
  • Interferon-beta / pharmacology
  • Kinetics
  • Lymphokines / metabolism
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Nude
  • Neoplasm Metastasis
  • Neoplasms, Experimental* / blood
  • Neoplasms, Experimental* / etiology
  • Neoplasms, Experimental* / metabolism
  • Neoplasms, Experimental* / pathology
  • Neovascularization, Pathologic*
  • STAT1 Transcription Factor
  • Trans-Activators / genetics
  • Trans-Activators / physiology*
  • Transfection
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • DNA-Binding Proteins
  • Endothelial Growth Factors
  • Lymphokines
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Trans-Activators
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Fibroblast Growth Factor 2
  • Interferon-beta
  • Matrix Metalloproteinases