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  • Original Paper
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Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells

Oncogene volume 21, pages 2504–2512 (2002)Cite this article

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-β 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-β 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.

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Acknowledgements

We thank Dr RZ Florkiewicz (Ciblex Corporation, San Diego, CA, USA) for the pF2.1 CAT plasmid, and Dr RD Schreiber (Washington University School of Medicine) for RAD-105 cell line and pcDNA3.MuStat1 plasmid. This work was supported in part by Cancer Center Support Core grant CA16672 and grant R35-CA42107 (IJ Fidler) from the National Cancer Institute, National Institutes of Health, and by a grant from the Vivian L Smith Foundation. The authors are grateful to Walter Pagel for his critical editorial comments, and Lola López for expert assistance in the preparation of this manuscript.

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  1. Department of Cancer Biology, Box 173, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Texas, 77030, Houston, TX, USA

    Suyun Huang, Corazon D Bucana, Melissa Van Arsdall & Isaiah J Fidler

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  1. Suyun Huang
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Correspondence to Isaiah J Fidler.

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Huang, S., Bucana, C., Arsdall, M. et al. Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells. Oncogene 21, 2504–2512 (2002). https://doi.org/10.1038/sj.onc.1205341

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