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Differential effects of angiostatin, endostatin and interferon-α1 gene transfer on in vivo growth of human breast cancer cells

Gene Therapy volume 9, pages 867–878 (2002)Cite this article

Abstract

The administration of different angiogenesis inhibitors by gene transfer has been shown to result in inhibition of tumor growth in animal tumor models, but the potency of these genes has been only partially evaluated in comparative studies to date. To identify the most effective anti-angiogenic molecule for delivery by retroviral vectors, we investigated the effects of angiostatin, endostatin and interferon(IFN)-α1 gene transfer in in vivo models of breast cancer induced neovascularization and tumor growth. Moloney leukemia virus-based retroviral vectors for expression of murine angiostatin, endostatin and IFN-α1 were generated, characterized, and used to transduce human breast cancer cell lines (MCF7 and MDA-MB435). Secretion of the recombinant proteins was confirmed by biological and Western blotting assays. Their production did not impair in vitro growth of these breast cancer cells nor their viability, and did not interfere with the expression of angiogenic factors. However, primary endothelial cell proliferation and migration in vitro were inhibited by supernatants of the transduced cells containing angiostatin, endostatin, and IFN-α1. Stable gene transfer of the IFN-α1 cDNA by retroviral vectors in both MCF7 and MDA-MB435 cells resulted in a marked and long-lasting inhibition of tumor growth in nude mice that was associated with reduced vascularization. Endostatin reduced the in vivo growth of MDA-MB435, but not MCF7 cells, despite similar levels of in vivo production, and angiostatin did not impair the in vivo growth of either cell line. These findings indicate heterogeneity in the therapeutic efficacy of angiostatic molecules delivered by viral vectors and suggest that gene therapy with IFN-α1 and endostatin might be useful for treatment of breast cancer.

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Acknowledgements

We thank Dr E Lechman for the MFG retroviral vector; Dr E Shewach for the anti-Ly-6C antibody; Dr V Tosello for cytofluorimetric analysis; Mr P Gallo for artwork and Ms P Segato for help in the preparation of the manuscript. This work was supported by grants from the MURST 40% and 60%, the Italian Association for Cancer Research (AIRC), the Ministero della Sanità Programma Nazionale Ricerca sull'AIDS, the Italian Foundation for Cancer Research (FIRC), the Fondazione Cassa di Risparmio di Padova e Rovigo, the CNR PF Biotecnologie.

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Authors and Affiliations

  1. IST-Viral and Molecular Oncology Section-Padova, Padova, Italy

    S Indraccolo

  2. Department of Oncology and Surgical Sciences, University of Padova, Padova, Italy

    S Indraccolo, E Gola, A Rosato, S Minuzzo, W Habeler, V Tisato, V Roni, G Esposito, A Amadori & L Chieco-Bianchi

  3. IST-Modulo di Progressione Neoplastica, Genova, Italy

    M Morini & DM Noonan

  4. IST-Laboratorio di Biologia Molecolare, Genova, Italy

    A Albini

  5. Laboratory of Virology, Istituto Superiore di Sanità, Roma, Italy

    M Ferrantini

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  1. S Indraccolo
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  2. E Gola
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Indraccolo, S., Gola, E., Rosato, A. et al. Differential effects of angiostatin, endostatin and interferon-α1 gene transfer on in vivo growth of human breast cancer cells. Gene Ther 9, 867–878 (2002). https://doi.org/10.1038/sj.gt.3301703

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