p22 is a novel plasminogen fragment with antiangiogenic activity
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M Kwon1, C S Yoon, S Fitzpatrick
1Cancer Biology Research Group, Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
Abstract:
Tumor or tumor-associated cells cleave circulating plasminogen into three or four kringle-containing antiangiogenic fragments, collectively referred to as angiostatin. Angiostatin blocks tumor growth and metastasis by preventing the growth of endothelial cells that are critical for tumor vascularization. Here, we show that cancer and normal cells convert plasminogen into a novel 22 kDa fragment (p22). Production of this plasminogen fragment in a cell-free system has allowed characterization of the structure and activity of the protein. p22 consists of amino acid residues 78-180 of plasminogen and therefore embodies the first plasminogen kringle (residues 84-162) as well as additional N- and C-terminal residues. Circular dichroism and intrinsic fluorescence spectrum analysis have defined structural differences between p22 and recombinant plasminogen kringle 1 (rK1), therefore suggesting a unique conformation for kringle 1 within p22. Proliferation of capillary endothelial cells but not cells of other lineages was selectively inhibited by p22 in vitro. In addition, p22 prevented vascular growth of chick chorioallantoic membranes (CAMs) in vivo. Furthermore, administration of p22 at low dose suppressed the growth of murine Lewis lung carcinoma (LLC) metastatic foci in vivo. This is the first identification of a single kringle-containing antiangiogenic plasminogen fragment produced under physiological conditions.
Insights
Researchers discovered a novel antiangiogenic fragment, p22, derived from plasminogen. This fragment selectively inhibits endothelial cell proliferation, blocking tumor growth and metastasis.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Tumor cells cleave plasminogen into antiangiogenic fragments called angiostatin.
- Angiostatin inhibits endothelial cell growth, crucial for tumor vascularization and metastasis.
Purpose of the Study:
- To identify and characterize novel plasminogen fragments with antiangiogenic properties.
- To investigate the structure, function, and therapeutic potential of a newly identified 22 kDa plasminogen fragment (p22).
Main Methods:
- Cell-free production of the p22 fragment from plasminogen.
- Structural analysis using circular dichroism and fluorescence spectroscopy.
- In vitro endothelial cell proliferation assays and in vivo chick chorioallantoic membrane assays.
- In vivo studies using murine Lewis lung carcinoma (LLC) model.
Main Results:
- Identified and produced a novel 22 kDa plasminogen fragment (p22) comprising plasminogen kringle 1 and flanking residues.
- p22 exhibits a unique conformation distinct from recombinant kringle 1.
- p22 selectively inhibited capillary endothelial cell proliferation in vitro.
- p22 demonstrated antiangiogenic activity in vivo, suppressing CAM vascularization and LLC metastasis.
Conclusions:
- p22 is a novel, physiologically produced antiangiogenic plasminogen fragment.
- p22 selectively targets endothelial cells, offering a potential therapeutic strategy against angiogenesis-dependent diseases.
- This finding represents the first identification of a single kringle-containing antiangiogenic fragment produced under physiological conditions.
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