Endothelial-Monocyte Activating Polypeptide Ii, a Novel Antitumor Cytokine That Suppresses Primary and Metastatic Tumor Growth and Induces Apoptosis in Growing Endothelial Cells
| Autor: | Olivier N Chappey, John A. Chabot, Roderich E. Schwarz, Joanne Hayward, Margaret A. Schwarz, Jerald Brett, Jean Luc Wautier, Paul Lo Gerfo, Jun Li, David M. Stern, Jessica J. Kandel |
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| Rok vydání: | 1999 |
| Předmět: |
tumor
medicine.medical_specialty Programmed cell death Endothelium Angiogenesis medicine.medical_treatment Immunology Mice Nude Neovascularization Physiologic Apoptosis capillary endothelium Biology Proinflammatory cytokine blood vessels Carcinoma Lewis Lung Mice Tissue factor Internal medicine Tumor Cells Cultured medicine Animals Humans Immunology and Allergy Tissue Distribution Infusions Intravenous programmed cell death Cells Cultured Mice Inbred BALB C RNA-Binding Proteins Cell migration Growth Inhibitors Recombinant Proteins Neoplasm Proteins Cell biology Endocrinology medicine.anatomical_structure Cytokine cell growth inhibitors Cytokines Cattle Fibroblast Growth Factor 2 Original Article Tumor necrosis factor alpha Endothelium Vascular Cell Division |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Murine methylcholanthrene A–induced (meth A)1 fibrosarcomas, which exhibit spontaneous vascular insufficiency manifested by a heterogeneous pattern of thrombohemorrhage and central necrosis, as well as a failure to form metastatic lesions 12, provide an ideal starting point for isolation of tumor-derived mediators that perturb the vasculature 3456. We purified a novel cytokine-like molecule, endothelial-monocyte activating polypeptide (EMAP) II, from meth A–conditioned medium based on its capacity to induce activation of endothelial cells (ECs) and mononuclear phagocytes 56. This single chain polypeptide, devoid of a signal sequence, is initially synthesized as an ≈34-kD intracellular precursor, which is processed to the mature ≈20-kD form and released extracellularly by an as yet unidentified pathway. EMAP II showed no significant homology to other known proteins such as cytokines or growth factors. However, an aspartic acid residue is present in the P-1 position in both murine and human EMAP II, suggesting that a cysteine protease in the IL-1β–converting enzyme family might be responsible for producing mature EMAP II from its pro-form. Our initial characterization of EMAP II suggested that its properties resembled those of proinflammatory mediators. For example, EMAP II induced endothelial release of von Willebrand factor, translocation of P-selectin to the cell surface, and synthesis and expression of E-selectin and procoagulant tissue factor 56; these, and EMAP II–mediated activation of cultured monocytes, resulting in production of cytokines and stimulation of cell migration, suggested phlogogenic properties. However, EMAP II administered in vivo, locally or systemically, gave rise to, at most, mild and transient inflammation 6, suggesting that its effects were quite different from those of TNF or IL-1 278. In this study we report that EMAP II has antiangiogenic properties preventing blood vessel ingrowth in two experimental angiogenesis models, and suppressing the growth of primary and metastatic tumors without toxicity in normal organs. Consistent with this hypothesis, EMAP II appears to target growing ECs; exposure of growing cultured capillary endothelium to EMAP II induces apoptosis, which is magnified by concomitant hypoxia. These data suggest that EMAP II is a polypeptide with antiangiogenic properties that targets rapidly growing vascular beds. |
| Databáze: | OpenAIRE |
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