Abstract
Carcinoma cells initiate the metastatic cascade by inserting invasive pseudopodia through breaches in the basement membrane (BM), a specialized barrier of cross-linked, extracellular matrix macromolecules that underlies epithelial cells and ensheaths blood vessels. While BM invasion is the sine qua non of the malignant phenotype, the molecular programs that underlie this process remain undefined. To identify genes that direct BM remodeling and transmigration, we coupled high-resolution electron microscopy with an ex vivo model of invasion that phenocopies the major steps observed during the transition of carcinoma in situ to frank malignancy. Herein, a triad of membrane-anchored proteases, termed membrane type-1, type-2, and type-3 metalloproteinases, are identified as the triggering agents that independently confer cancer cells with the ability to proteolytically efface the BM scaffolding, initiate the assembly of invasive pseudopodia, and propagate transmigration. These studies characterize the first series of gene products capable of orchestrating the entire BM remodeling program that distinguishes the carcinomatous phenotype.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Basement Membrane / enzymology
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Basement Membrane / physiology*
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Basement Membrane / ultrastructure
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COS Cells
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Cell Line
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Cell Line, Tumor
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Cell Movement / physiology
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Chlorocebus aethiops
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Collagen Type IV / metabolism
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Extracellular Matrix / metabolism
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Extracellular Matrix / ultrastructure
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Humans
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Matrix Metalloproteinase 14 / genetics
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Matrix Metalloproteinase 14 / metabolism
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Matrix Metalloproteinase 15 / genetics
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Matrix Metalloproteinase 15 / metabolism
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Matrix Metalloproteinase 16 / genetics
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Matrix Metalloproteinase 16 / metabolism
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Matrix Metalloproteinases, Membrane-Associated / genetics
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Matrix Metalloproteinases, Membrane-Associated / metabolism*
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Mice
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Microscopy, Electron, Scanning
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Microscopy, Electron, Transmission
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Mutation / genetics
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Neoplasm Invasiveness
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Neoplasms / metabolism
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Neoplasms / pathology
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Neoplasms / physiopathology
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RNA, Small Interfering / genetics
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Rats
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Tissue Inhibitor of Metalloproteinases / metabolism
Substances
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Collagen Type IV
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RNA, Small Interfering
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Tissue Inhibitor of Metalloproteinases
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Matrix Metalloproteinase 15
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Matrix Metalloproteinase 16
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Matrix Metalloproteinases, Membrane-Associated
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Matrix Metalloproteinase 14