Neutralizing Monoclonal Antibodies to Hepatocyte Growth Factor/Scatter Factor (HGF/SF) Display Antitumor Activity in Animal Models
The hepatocyte growth factor (HGF/SF) receptor, Met, regulates mitogenesis, motility, and morphogenesis in a cell type-dependent fashion. Activation of Met via autocrine, paracrine, or mutational mechanisms can lead to tumorigenesis and metastasis and numerous studies have linked inappropriate expression of this ligand-receptor pair to most types of human solid tumors. To prepare mAbs to human HGF/SF, mice were immunized with native and denatured preparations of the ligand. Recloned mAbs were tested in vitro for blocking activity against scattering and branching morphogenesis. Our results show that no single mAb was capable of neutralizing the in vitro activity of HGF/SF, and that the ligand possesses a minimum of three epitopes that must be blocked to prevent Met tyrosine kinase activation. In vivo, the neutralizing mAb combination inhibited s.c. growth in athymic nu/nu mice of tumors dependent on an autocrine Met-HGF/SF loop. Importantly, growth of human glioblastoma multiforme xenografts expressing Met and HGF/SF were markedly reduced in the presence of HGF/SF-neutralizing mAbs. These results suggest interrupting autocrine and/or paracrine Met-HGF/SF signaling in tumors dependent on this pathway is a possible intervention strategy..
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2001 |
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Erschienen: |
2001 |
Enthalten in: |
Zur Gesamtaufnahme - volume:98 |
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Sprache: |
Englisch |
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Beteiligte Personen: |
Cao, Brian [VerfasserIn] |
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Links: |
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Themen: |
Biological sciences |
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PPN (Katalog-ID): |
JST069579725 |
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520 | |a The hepatocyte growth factor (HGF/SF) receptor, Met, regulates mitogenesis, motility, and morphogenesis in a cell type-dependent fashion. Activation of Met via autocrine, paracrine, or mutational mechanisms can lead to tumorigenesis and metastasis and numerous studies have linked inappropriate expression of this ligand-receptor pair to most types of human solid tumors. To prepare mAbs to human HGF/SF, mice were immunized with native and denatured preparations of the ligand. Recloned mAbs were tested in vitro for blocking activity against scattering and branching morphogenesis. Our results show that no single mAb was capable of neutralizing the in vitro activity of HGF/SF, and that the ligand possesses a minimum of three epitopes that must be blocked to prevent Met tyrosine kinase activation. In vivo, the neutralizing mAb combination inhibited s.c. growth in athymic nu/nu mice of tumors dependent on an autocrine Met-HGF/SF loop. Importantly, growth of human glioblastoma multiforme xenografts expressing Met and HGF/SF were markedly reduced in the presence of HGF/SF-neutralizing mAbs. These results suggest interrupting autocrine and/or paracrine Met-HGF/SF signaling in tumors dependent on this pathway is a possible intervention strategy. | ||
540 | |a Copyright 1993-2001 National Academy of Sciences of the United States of America | ||
650 | 4 | |a Immunology | |
650 | 4 | |a Health sciences |x Medical conditions |x Diseases |x Neoplasia |x Tumors | |
650 | 4 | |a Biological sciences |x Biology |x Cytology |x Cell biology |x Cells |x Epithelial cells |x Hepatocytes | |
650 | 4 | |a Physical sciences |x Chemistry |x Chemical compounds |x Chemicals |x Polymers |x Biopolymers |x Proteins |x Receptors | |
650 | 4 | |a Physical sciences |x Chemistry |x Chemical compounds |x Chemicals |x Ligands | |
650 | 4 | |a Physical sciences |x Chemistry |x Chemical compounds |x Chemicals |x Polymers |x Biopolymers |x Proteins |x Signaling proteins |x Fibroblast growth factors | |
650 | 4 | |a Biological sciences |x Biology |x Cytology |x Cell biology |x Cell physiology |x Cell growth | |
650 | 4 | |a Biological sciences |x Biology |x Developmental biology |x Growth and development |x Biological development |x Morphogenesis | |
650 | 4 | |a Health sciences |x Medical sciences |x Immunology |x Immune system |x Immune response |x Adaptive immunity |x Active immunity |x Humoral immunity |x Antigens |x Epitopes | |
650 | 4 | |a Biological sciences |x Biology |x Zoology |x Animals |x Mammals |x Primates |x Humans | |
650 | 4 | |a Biological sciences |x Biology |x Developmental biology |x Embryology |x Organogenesis |x Angiogenesis |x Biological Sciences | |
655 | 4 | |a research-article | |
700 | 1 | |a Su, Yanli |e verfasserin |4 aut | |
700 | 1 | |a Oskarsson, Marianne |e verfasserin |4 aut | |
700 | 1 | |a Zhao, Ping |e verfasserin |4 aut | |
700 | 1 | |a Kort, Eric J. |e verfasserin |4 aut | |
700 | 1 | |a Fisher, Robert J. |e verfasserin |4 aut | |
700 | 1 | |a Wang, Ling-Mei |e verfasserin |4 aut | |
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856 | 4 | 0 | |u https://www.jstor.org/stable/3056008 |3 Volltext |
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