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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

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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 (2005) 12, 831–842 & 2005 Nature Publishing Group All rights reserved 0969-7128/05 $30.00 www.nature.com/gt RESEARCH ARTICLE Full kringles of plasminogen (aa 1–566) mediate complete regression of human MDA-MB-231 breast tumor xenografted in nude mice A Galaup1, C Magnon1, V Rouffiac2, P Opolon1, D Opolon1, N Lassau3, T Tursz4, M Perricaudet1 and F Griscelli1 1Le Centre National de la Recherche Scientifique, Unite´ Mixte de Recherche (UMR) 8121, Institut Gustave Roussy, Villejuif Cedex, France; 2Laboratoire d’Imagerie du Petit Animal (LIPA), Institut Gustave Roussy, Villejuif Cedex, France; 3Imaging Department, Institut Gustave Roussy, Villejuif Cedex, France; and 4Department of Medical Oncology, Institut Gustave Roussy, Villejuif Cedex, France Since kringle (K)5, not present in the angiostatin molecule, intratumoral injection of AdK1–5(1–566) into MDA-MB-231 was shown to be a key functional domain possessing potent breast human carcinoma tumors was followed by a total antiangiogenic activity, we have evaluated a new plasmino- regression of 40% of the tumor and by significant arrest of gen-derived fragment, consisting of the N-terminal part of tumor growth (90%), which was correlated with a drastic human plasminogen, that included the complete secondary decrease of functional neovascularization into the tumors. structure of K1–5 (aa 1–566). In contrast to other fragments Furthermore, systemic delivery of AdK1–5(1–566) in mice described to date, K1–5 includes cysteine residues at inhibited the lung invasion of melanoma B16-F10 cells by positions 543, 555 and 560 allowing the formation of the 87%. Our findings provide evidence that the full kringles three disulfide bonds lying within K5. Vascular endothelial of plasminogen (aa 1–566) may be much more potent than cell proliferation and migration assays revealed that a K1–3 (aa 1–354), for the suppression of angiogenesis, tumor replication-defective adenovirus (AdK1–5(1–566)), expres- growth and metastatic dissemination. sing K1–5 (aa 1–566), was dose dependently more potent Gene Therapy (2005) 12, 831–842. doi:10.1038/ that AdK1–3(1–354), an adenovirus that expresses only the sj.gt.3302474; Published online 24 March 2005 first three kringles. In contrast to AdK1–3(1–354), a single Keywords: antiangiogenesis; K1–5 (aa 1–566); adenovirus; cancer Introduction constitutes a new strategy to suppress tumor growth. Some angiogenic inhibitors are fragments, or cryptic Angiogenesis is defined as the formation of new blood domains, of larger proteins. This is the case for vessels that sprout from pre-existing ones. The different angiostatin,3 endostatin,4 and canstatin,5 which are steps of this process respond to stimuli that promote the proteolytic fragments of plasminogen, collagen XVIII proliferation, migration, and differentiation of endo- and collagen IV, respectively, and for the 16 kDa N- thelial cells, and the degradation of the blood vessel terminal fragment-derived prolactin6 or the N-terminal basement membrane and extracellular matrix.1 This fragment-derived platelet factor 4.7 process leads to the sprouting of new microtubes and The different fragments derived from the five kringles implies the presence of multiple controls, which can be (K) of plasminogen that are known to inhibit angiogen- turned on and off within a short period of time. esis have been characterized. Human angiostatin K1–4 Angiogenesis is required for physiological processes (aa 97–454), containing the first four disulfide-linked such as embryonic development, wound healing, tissue structures of plasminogen, which was the first protein and organ regeneration, and for pathological processes described, is generated following hydrolysis of plasmi- such as tumor growth, metastatic dissemination, cardio- nogen by a metalloelastase.3,8–10 In vitro, angiostatin K1–4 2 vascular diseases and diabetic retinopathy. (aa 97–454) inhibits endothelial cell growth with an ED50 The angiogenic switch depends upon the balance of 135 nM,11 and endothelial cell migration in a specific between angiogenic stimulators and inhibitors.2 There- manner.12 In vivo, angiostatin K1–4 (aa 97–454) inhibits fore, blocking the action of angiogenic factors, or neovascularization in chick chorioallantoic membrane utilizing angiogenic suppressors to inhibit angiogenesis, and mouse corneal assays, and suppresses subsequent tumor growth in different murine models.13 On the other hand, a smaller fragment of plasminogen, containing the Correspondence: Dr A Galaup, Le Centre National de la Recherche first three kringles (K1–3 (aa 97–354)), inhibits endothe- Scientifique, Unite´ Mixte de Recherche (UMR) 8121 PR2, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France lial cell proliferation with an ED50 of 70 nM, but does not Received 1 April 2004; accepted 16 November 2004; published display an inhibitory effect on cell migration. In vivo online 24 March 2005 studies have shown that K1–3 (aa 97–354) inhibits tumor K1–5 (aa 1–566) gene transfer A Galaup et al 832 growth in different murine models.14 Another fragment observed from the AdK1–3(1–354)- and AdK1–5(1–566)- of plasminogen containing only the K5 (aa 481–566) infected cell supernatants (Figure 1c), whereas no signal displays distinct inhibitory functions on endothelial cell could be detected following the infection with AdCO1. proliferation with an ED50 of 50 nM, and on endothelial The immunoreactive peptides appeared with a molecu- cell migration.15,16 Furthermore, K5 (aa 481–566) and lar weight of 40.5 kDa for the K1–3 (aa 1–354) molecule K1–3 (aa 97–354) were shown to cause cell cycle arrest and 63.8 kDa for the K1–5 (aa 1–566) molecule. and apoptosis of endothelial cells.13,14 It was recently To assess in vitro the antiangiogenic effect of AdK1– shown that plasminogen can be converted by plasmin 5(1–566), and to compare its activity to AdK1–3(1–354), (a fibrinolytic serine protease)17 or by glioma cell BT325- human umbilical vein endothelial cells (HUVECs) were derived proteinase,18 into a new angiogenic inhibitor, infected for 96 h at various MOI (100–800 PFU/cell), and called K1–5 (aa 97–549), which contains the K1–4 and a then incubated in the presence of MTT reagent to part of K5 domains of plasminogen. The inhibitory effect determine the percentage of surviving cells. In this assay, of K1–5 (aa 97–549), also called angiostatin 4.5 by other transduction of HUVEC by AdK1–5(1–566) resulted in authors,17 on endothelial cell proliferation appears to be a strong and dose-dependent inhibition of endothelial at least 50-fold greater than that of angiostatin cell surviving (Figure 2a). AdK1–5(1–566) infection of K1–4. In vivo, low doses of K1–5 (aa 97–549) suppress HUVEC led to a significantly higher inhibitory effect angiogenesis in chicken embryo and in mouse corneal (Po0.001) as compared with cells that had been infected assays, whereas angiostatin has no effect at the same by AdK1–3(1–354). At an MOI of 100 PFU/cell, HUVEC dose. Furthermore, daily systemic injections of mice with survival of 46720.6 and 88711.9% was observed after low doses of K1–5 (aa 97–549) (2 mg/kg) over 18 days, infection of HUVEC with AdK1–5(1–566) and AdK1– during which K1–4 (aa 97–454) was ineffective, inhibited 3(1–354), respectively. Thus, compared to the infection of the growth of, and angiogenesis within, murine T241 HUVEC with AdK1–3(1–354), cells were found to be fibrosarcomas in mice. Thus, K1–5 (aa 97–549) appears to systematically more sensitive to infection with AdK1– be a naturally occurring human isoform that is more 5(1–566), with an ED50 (defined as the MOI leading to potent than K1–4 (aa 97–454) in inhibiting the prolifera- 50% inhibition) in the range of 100 PFU/cell, whereas tion and migration of endothelial cells in vitro and the AdK1–3(1–354) was ineffective at this dose. The infection T241 fibrosarcoma in vivo.17 Furthermore, it was recently of HUVEC with 800 PFU/cell of AdK1–3(1–354) and demonstrated that K1–5 (aa 97–549) mediates apoptosis AdK1–5(1–566) resulted in cell survival of 5972.8 and of vascular endothelial cells by the activation of caspase- 1178.8%, respectively. 3, -8, and -9 activity.19 The quantities of K1–3 (aa 1–354) and K1–5 (aa 1–566) Interestingly, the K1–5 (aa 97–549) fragment lacks produced in supernatant of HUVECs 48 h or 96 h cysteine residues in positions 555 and 560, thus prevent- postinfection (p.i.) with AdK1–3(1–354) or AdK1–5(1– ing the formation of two out of three disulfide bonds 566) were evaluated with a specific ELISA. The levels of lying within K5. In order to optimize the antitumor proteins expressed by both adenoviruses were identical, effects associated with the secondary structures of showing that the higher inhibitory effect of AdK1–5(1– kringle domains, we chose to evaluate the antitumor 566) was related to the specific activity of the K1–5 (aa properties of a fragment that encompasses the first 566 1–566) molecule and not to a difference in transgene amino acids of plasminogen, allowing the complete production (Figure 2b). In contrast, infection of HUVEC secondary structure of the K5. with the control empty virus had only a marginal effect, We constructed a replication-defective adenovirus even at the highest tested dose of 800 PFU/cell. The directing the expression and secretion of the N-terminal dose-dependent inhibitory effect specifically observed fragment of human plasminogen, including K1–5 after HUVEC infection with AdK1–5(1–566) is thus a (AdK1–5(1–566)), and assessed its in vitro and in vivo direct consequence of peptide expression, and not due activity in different murine tumor models.
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