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Suppression of Angiogenesis and Tumor Growth by the Inhibitor K1–5 Generated by Plasmin-Mediated Proteolysis (Angiostatin͞plasminogen͞antitumor)

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Suppression of Angiogenesis and Tumor Growth by the Inhibitor K1–5 Generated by Plasmin-Mediated Proteolysis (Angiostatin͞plasminogen͞antitumor) Proc. Natl. Acad. Sci. USA Vol. 96, pp. 5728–5733, May 1999 Medical Sciences Suppression of angiogenesis and tumor growth by the inhibitor K1–5 generated by plasmin-mediated proteolysis (angiostatinyplasminogenyantitumor) RENHAI CAO*, HUA-LIN WU†,NIINA VEITONMA¨KI*, PHILIP LINDEN‡,JACOB FARNEBO*, GUEY-YUEH SHI†, AND YIHAI CAO*§ *Laboratory of Angiogenesis Research, Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden; †Department of Biochemistry, National Cheng Kung University Medical College, Tainan, Taiwan, 70101, Republic of China; and ‡Department of Surgery, Brigham and Women9s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115 Edited by Judah Folkman, Harvard Medical School, Boston, MA, and approved January 28, 1999 (received for review August 21, 1998) ABSTRACT Proteolytic enzymes are involved in generation ate inhibitors of angiogenesis, including angiostatin and endosta- of a number of endogenous angiogenesis inhibitors. Previously, tin (5, 17–21). It is now believed that a switch of the angiogenic we reported that angiostatin, a potent angiogenesis inhibitor, is phenotype is dependent on a local change of the balance between a proteolytic fragment containing the first four kringle modules angiogenic stimulators and inhibitors. of plasminogen. In this report, we demonstrate that urokinase- Accumulative data from different laboratories have recently activated plasmin can process plasminogen to release an angio- shown that a number of angiogenesis inhibitors are fragments genesis inhibitor, K1–5 (protease-activated kringles 1–5). K1–5 or cryptic domains of large protein molecules (22, 23). For inhibits endothelial-cell proliferation with a half-maximal con- example, angiostatin and endostatin are proteolytic fragments centration of approximately 50 pM. This inhibitory effect is of plasminogen (Pgn) and collagen XVIII, respectively (5, 19). endothelial-cell-specific and appears to be at least approximately The 16-kDa N-terminal fragment of prolactin (24) and an 50-fold greater than that of angiostatin. A synergistic efficacy of N-terminally truncated platelet factor 4 (25) are potent an- endothelial inhibition was observed when angiostatin and krin- giogenesis inhibitors. In addition, a C-terminal fragment of gle 5 (K5) were coincubated with capillary endothelial cells. The matrix metalloprotease 2, named PEX, inhibits angiogenesis synergistic effect is comparable to that produced by K1–5 alone. and tumor growth (26). In contrast, the intact parental mol- Systemic treatment of mice with K1–5 at a low dose significantly ecules of these inhibitors lack inhibitory activity on endothelial blocked the fibroblast growth factor-induced corneal neovascu- cells and are not angiogenesis inhibitors. It is now becoming larization, whereas angiostatin had no effect at the same dose. clear that the generation of endogenous inhibitors from large K1–5 also suppressed angiogenesis in chicken embryos. Systemic precursor proteins with distinct functions is a recurrent theme administration of K1–5 at a low dose at which angiostatin was in suppression of angiogenesis. Thus, proteolytic processing ineffective significantly suppressed the growth of a murine T241 plays a critical role in control of the switch of angiogenesis. fibrosarcoma in mice. The antitumor effect correlates with the Angiostatin contains the first four disulfide-linked struc- reduced neovascularization. These findings suggest that the tures of Pgn, known as kringle structures (5, 27). Smaller plasmin-mediated proteolysis may be involved in the negative fragments of angiostatin display differential effects on sup- switch of angiogenesis. pression of endothelial cell growth (17). For example, kringle 1 (K1) exhibits greater than 50% of inhibitory activity of Angiogenesis, the outgrowth of new capillaries from preexist- angiostatin, whereas kringle 4 (K4) is an ineffective fragment ing vessels, is essential for wound healing, female reproduction, (17). We have recently discovered that the K5 domain of Pgn embryonic development, organ formation, tissue regeneration, is a specific inhibitor for endothelial-cell proliferation (23). In and tissue remodeling (1–3). Angiogenesis is a complex mul- fact, K5 appears to be more potent than angiostatin on tistep process that includes endothelial proliferation, migra- inhibition of capillary endothelial-cell proliferation. tion and differentiation, degradation of extracellular matrix, In this paper, we provide further evidence that plasmin, a tube formation, and sprouting of new capillary branches (4). fibrinolytic serine protease, can convert its precursor molecule, The complexity of the angiogenic process suggests the exis- Pgn, into an angiogenesis inhibitor, K1–5, that is structurally tence of multiple controls of the system that can be temporarily related to angiostatin. Systemic therapy with pure K1–5 dis- turned on and off. rupts tumor-induced angiogenesis and tumor growth. Under pathological conditions, a switch of the angiogenic phenotype by up-regulation of angiogenic factors and perhaps MATERIALS AND METHODS down-regulation of angiogenesis inhibitors often leads to pro- Reagents, Cells, and Animals. Bovine capillary endothelial gression of many diseases including tumor growth and diabetic (BCE) cells were kindly provided by Judah Folkman (Harvard retinopathy. Several recent studies have produced direct and Medical School) and maintained in DMEM with 10% heat- indirect evidence in proof that tumor growth and metastasis are inactivated bovine calf serum, antibiotics, and recombinant angiogenesis-dependent (5–10). To induce neovascularization, human fibroblast growth factor 2 (FGF-2 or basic fibroblast tumors often overexpress several angiogenic stimulators, includ- growth factor; Scios Nova, Mountainview, CA; 3 ngyml). ing members of the fibroblast growth factor (FGF) (11) and the Recombinant human fibroblast growth factor 1 was expressed vascular endothelial growth factoryvascular permeability factor and purified as described (28). Murine T241 fibrosarcoma families (12, 13). Tumors may produce one or more of these tumor cells were maintained in culture in DMEM supple- angiogenic peptides that can synergistically stimulate tumor an- giogenesis (14–16). Recent studies show that tumors also gener- This paper was submitted directly (Track II) to the Proceedings office. Abbreviations: K1–5, protease-activated kringle 1–5; Pgn, plasmino- The publication costs of this article were defrayed in part by page charge gen; K5, kringle 5; FGF, fibroblast growth factor; FGF-2, fibroblast growth factor 2; BCE, bovine capillary endothelial; CAM, chorioallan- payment. This article must therefore be hereby marked ‘‘advertisement’’ in toic membrane. accordance with 18 U.S.C. §1734 solely to indicate this fact. §To whom reprint requests should be addressed. e-mail: yihai.cao@ PNAS is available online at www.pnas.org. mtc.ki.se. 5728 Downloaded by guest on September 25, 2021 Medical Sciences: Cao et al. Proc. Natl. Acad. Sci. USA 96 (1999) 5729 mented with 10% fetal calf serum (HyClone) and antibiotics. maximal vessel length, clock hours, and the vascular area of Male 5- to 6-week-old C57BL6yJ mice (MTC, Karolinska corneas of all mice were measured, with a slit-lamp stereomicro- Institute) were acclimated and caged in groups of six mice or scope at a magnification of 315, on the sixth day after corneal less. Animals were anesthetized in a methoxyflurane chamber implantation. before all procedures and killed with a lethal dose of CO2.All Tumor Studies in Mice. Male 6-week-old C57BL6yJ mice animal studies were reviewed and approved by the animal care were used for tumor studies. Approximately 1 3 106 murine and use committee of the Stockholm Animal Board. T241 fibrosarcoma cells growing in logarithmic phase were Preparation of Proteolytic Fragments of Human K1–5 and harvested and resuspended in PBS, and a single cell solution Angiostatin. Intact, N-terminal Glu1-Pgn was purified from in a volume of 100 ml was implanted subcutaneously in the outdated and citrated human blood plasma by affinity chro- middle dorsum of each animal. Five mice were used in the matography on L-lysine-Sepharose, with a gradient of the treated groups and five mice were used in the control groups. ligand 6-aminohexanoic acid (17). Approximately 40 mg of Systemic treatment by subcutaneous injections with either 100 purified Glu1-Pgn in 4 ml of 0.1 M glycine buffer (pH 10.5) was ml of PBS or K1–5 (2–2.5 mgykg) and angiostatin (2–2.5 incubated at 25°C with immobilized urokinase-activated plas- mgykg) in PBS was begun shortly after implantation of tumor min (10 M Pgn in 1 M plasmin) for 14 h (29). After incubation, cells and continued once daily for a total of 18–20 treatments. 3 the sample was applied to a lysine-Sepharose column (1.0 30 Visible tumors were present 72 h after implantation. Primary cm) preequilibrated and washed with 1.0 M sodium phosphate tumors were measured with digital calipers on the days indi- buffer (pH 8.0). A peak containing micro-Pgn was detected in cated. Tumor volumes were calculated according to the for- the flow-through fraction. K1–5 was eluted from the column mula: width2 3 length 3 0.52 as reported (27). with a 0–25 mM linear gradient of 6-aminocapronic acid Histology. Tumor-bearing C57BL6yJ animals were killed by an (Sigma). The protein fraction containing K1–5 was further 3 overdose of methoxyflurane on day 20 after tumor cell implan- purified with a Sephadex G-75 column (2.6 90 cm).
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