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Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth

Nature Medicine volume 9, pages 1026–1032 (2003)Cite this article

Abstract

Current understanding of key transcription factors regulating angiogenesis is limited. Here we show that RNA-cleaving phosphodiester-linked DNA-based enzymes (DNAzymes), targeting a specific motif in the 5′ untranslated region of early growth response (Egr-1) mRNA, inhibit Egr-1 protein expression, microvascular endothelial cell replication and migration, and microtubule network formation on basement membrane matrices. Egr-1 DNAzymes blocked angiogenesis in subcutaneous Matrigel plugs in mice, an observation that was independently confirmed by plug analysis in Egr-1-deficient animals, and inhibited MCF-7 human breast carcinoma growth in nude mice. Egr-1 DNAzymes suppressed tumor growth without influencing body weight, wound healing, blood coagulation or other hematological parameters. These agents inhibited endothelial expression of fibroblast growth factor (FGF)-2, a proangiogenic factor downstream of Egr-1, but not that of vascular endothelial growth factor (VEGF). Egr-1 DNAzymes also repressed neovascularization of rat cornea. Thus, microvascular endothelial cell growth, neovascularization, tumor angiogenesis and tumor growth are processes that are critically dependent on Egr-1.

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Figure 1: DNAzyme DzF inhibits human microvascular endothelial cell proliferation, migration, microtubule formation and Egr-1 expression.
Figure 2: Egr-1 DNAzymes inhibit angiogenesis.
Figure 3: Egr-1 DNAzyme inhibits human MCF-7 breast carcinoma growth as xenografts in nude mice through suppression of angiogenesis.
Figure 4: Intratumoral administration of Egr-1 DNAzyme has no adverse effect on wound healing or hemostasis.
Figure 5: Egr-1 DNAzyme inhibition is mediated by Egr-1-dependent FGF-2 expression.
Figure 6: Solid B16 tumor growth in mice is Egr-1-independent.

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Acknowledgements

We thank L. Chalifour and J. Milbrandt for Egr-1-deficient mice, J. Hood and D. Cheresh for CAM sections, W. Gerlach and J. Pimanda for helpful comments, and H. Zreiqat and W. Lipworth for technical assistance. This work was supported by Johnson & Johnson Research Pty. Limited, a National Health and Medical Research Council (NHMRC) Program Grant and a New South Wales Health Department Research and Infrastructure Grant. L.M.K. is a Principal Research Fellow of the NHMRC.

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Authors and Affiliations

  1. Centre for Vascular Research, University of New South Wales, Sydney, 2052, NSW, Australia

    Roger G Fahmy, Colin N Chesterman & Levon M Khachigian

  2. Department of Haematology, The Prince of Wales Hospital, Sydney, 2052, NSW, Australia

    Roger G Fahmy, Colin N Chesterman & Levon M Khachigian

  3. Johnson & Johnson Research Laboratories, Sydney, Australia

    Crispin R Dass & Lun-Quan Sun

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Correspondence to Levon M Khachigian.

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Fahmy, R., Dass, C., Sun, LQ. et al. Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth. Nat Med 9, 1026–1032 (2003). https://doi.org/10.1038/nm905

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