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Full kringles of plasminogen (aa 1–566) mediate complete regression of human MDA-MB-231 breast tumor xenografted in nude mice

Gene Therapy volume 12, pages 831–842 (2005)Cite this article

Abstract

Since kringle (K)5, not present in the angiostatin molecule, was shown to be a key functional domain possessing potent antiangiogenic activity, we have evaluated a new plasminogen-derived fragment, consisting of the N-terminal part of human plasminogen, that included the complete secondary structure of K1–5 (aa 1–566). In contrast to other fragments described to date, K1–5 includes cysteine residues at positions 543, 555 and 560 allowing the formation of the three disulfide bonds lying within K5. Vascular endothelial cell proliferation and migration assays revealed that a replication-defective adenovirus (AdK1–5(1–566)), expressing K1–5 (aa 1–566), was dose dependently more potent that AdK1–3(1–354), an adenovirus that expresses only the first three kringles. In contrast to AdK1–3(1–354), a single intratumoral injection of AdK1–5(1–566) into MDA-MB-231 breast human carcinoma tumors was followed by a total regression of 40% of the tumor and by significant arrest of tumor growth (90%), which was correlated with a drastic decrease of functional neovascularization into the tumors. Furthermore, systemic delivery of AdK1–5(1–566) in mice inhibited the lung invasion of melanoma B16-F10 cells by 87%. Our findings provide evidence that the full kringles of plasminogen (aa 1–566) may be much more potent than K1–3 (aa 1–354), for the suppression of angiogenesis, tumor growth and metastatic dissemination.

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Acknowledgements

We sincerely thank the SCEA and specially M Stanciu, D Challuau and P Ardouin for animal care, E Connault for technical assistance, I Chawi for echography analysis, C Bouquet for the kind gift of pMP13 plasmid and N Lamandé (Inserm U36 – Collège de France) for the kind gift of HUVECs. We warmly acknowledge B Mullan and M Mackenthun for critical reading. Le Centre National de la Santé et de la Recherche Scientifique (CNRS), la ligue nationale contre le cancer and l'Association pour la Recherche sur le Cancer (ARC) are acknowledged for financial support.

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Authors and Affiliations

  1. Le Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 8121, Institut Gustave Roussy, Villejuif Cedex, France

    A Galaup, C Magnon, P Opolon, D Opolon, M Perricaudet & F Griscelli

  2. Laboratoire d'Imagerie du Petit Animal (LIPA), Institut Gustave Roussy, Villejuif Cedex, France

    V Rouffiac

  3. Imaging Department, Institut Gustave Roussy, Villejuif Cedex, France

    N Lassau

  4. Department of Medical Oncology, Institut Gustave Roussy, Villejuif Cedex, France

    T Tursz

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  1. A Galaup
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Galaup, A., Magnon, C., Rouffiac, V. et al. Full kringles of plasminogen (aa 1–566) mediate complete regression of human MDA-MB-231 breast tumor xenografted in nude mice. Gene Ther 12, 831–842 (2005). https://doi.org/10.1038/sj.gt.3302474

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