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1.
Cancer Res ; 60(9): 2520-6, 2000 May 01.
Article in English | MEDLINE | ID: mdl-10811134

ABSTRACT

Vascular basement membrane is an important structural component of blood vessels and has been shown to interact with and modulate vascular endothelial behavior during angiogenesis. During the inductive phase of tumor angiogenesis, this membrane undergoes many degradative and structural changes and reorganizes to a native state around newly formed capillaries in the resolution phase. Such matrix changes are potentially associated with molecular modifications that include expression of matrix gene products coupled with conformational changes, which expose cryptic protein modules for interaction with the vascular endothelium. We speculate that these interactions provide important endogenous angiogenic and anti-angiogenic cues. In this report, we identify an important antiangiogenic vascular basement membrane-associated protein, the 26-kDa NC1 domain of the alpha1 chain of type IV collagen, termed arresten. Arresten was isolated from human placenta and produced as a recombinant molecule in Escherichia coli and 293 embryonic kidney cells. We demonstrate that arresten functions as an anti-angiogenic molecule by inhibiting endothelial cell proliferation, migration, tube formation, and Matrigel neovascularization. Arresten inhibits the growth of two human xenograft tumors in nude mice and the development of tumor metastases. Additionally, we show that the anti-angiogenic activity of arresten is potentially mediated via mechanisms involving cell surface proteoglycans and the alpha1beta1 integrin on endothelial cells. Collectively, our results suggest that arresten is a potent inhibitor of angiogenesis with a potential for therapeutic use.


Subject(s)
Basement Membrane/metabolism , Collagen/metabolism , Endothelium, Vascular/metabolism , Neovascularization, Pathologic/pathology , Animals , Arrestin/metabolism , Cell Cycle , Cell Line , Collagen/biosynthesis , Collagen/chemistry , Collagen Type XVIII , Dose-Response Relationship, Drug , Drug Combinations , Endostatins , Enzyme-Linked Immunosorbent Assay , Escherichia coli/metabolism , Heparan Sulfate Proteoglycans/metabolism , Humans , Immunohistochemistry , Kinetics , Laminin/metabolism , Mice , Mice, Inbred C57BL , Mice, Nude , Neoplasm Transplantation , Peptide Fragments/biosynthesis , Placenta/metabolism , Plasmids , Protein Structure, Tertiary , Proteoglycans/metabolism , Recombinant Proteins/metabolism , Tumor Cells, Cultured
2.
Transplantation ; 69(4): 679-83, 2000 Feb 27.
Article in English | MEDLINE | ID: mdl-10708133

ABSTRACT

BACKGROUND: Alport syndrome is a hereditary disorder of basement membranes especially affecting the kidneys, ears, and eyes. Some patients who undergo renal transplantation lose their kidneys as a result of posttransplant anti-glomerular basement membrane (anti-GBM) disease. METHODS: In the present study, we analyzed serum from 21 unselected Alport patients who underwent renal transplantation. Eleven samples were from patients without posttransplant anti-GBM nephritis, and 10 were from patients with this disease. RESULTS: Thirteen serum samples [10 alport posttransplant nephritis serum (APTN) and three Alport posttransplant serum (APT)] revealed linear binding to the GBM by indirect immunofluorescence. By using direct ELISA and immunoblotting with GBM constituents and type IV collagen NC1 domains from bovine, human, and recombinant sources, we detected anti-GBM antibodies in all Alport patients in varying titers. Five samples showed specific reactivity to the alpha3 chain, four to the alpha5 chain, six to both alpha3 and alpha5 chains, one to the alpha3 and alpha4 chains, and two to the alpha3, alpha4, and alpha5 chains of type IV collagen. The varied spectrum of reactivities was present equally in nephritic and non-nephritic sera. Ten control samples from non-Alport transplant patients did not exhibit specific binding to the GBM. CONCLUSIONS: These results suggest that the absence of alpha3, alpha4, and alpha5 chains of type IV collagen in the Alport kidney leads to alloantibodies in all Alport patients who receive transplants, irrespective of whether they develop nephritis or not. Although all Alport transplant patients develop this humoral response, only a select few develop anti-GBM disease. We suggest that this difference could be attributable to a genotypic effect on the ability of some individuals to launch a cell-mediated immune response.


Subject(s)
Basement Membrane/immunology , Collagen/immunology , Isoantigens/blood , Kidney Glomerulus/immunology , Kidney Transplantation/immunology , Nephritis, Hereditary/immunology , Animals , Antibodies/blood , Basement Membrane/metabolism , Cattle , Cross Reactions/immunology , Enzyme-Linked Immunosorbent Assay , Fluorescent Antibody Technique, Indirect , Humans , Immunoblotting , Immunoglobulin G/metabolism , Kidney Glomerulus/metabolism , Postoperative Complications/immunology , Protein Binding , Time Factors
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