Abstract
We recently reported that uPARAP/Endo180 can mediate the cellular uptake and lysosomal degradation of collagen by cultured fibroblasts. Here, we show that uPARAP/Endo180 has a key role in the degradation of collagen during mammary carcinoma progression. In the normal murine mammary gland, uPARAP/Endo180 is widely expressed in periductal fibroblast-like mesenchymal cells that line mammary epithelial cells. This pattern of uPARAP/Endo180 expression is preserved during polyomavirus middle T-induced mammary carcinogenesis, with strong uPARAP/Endo180 expression by mesenchymal cells embedded within the collagenous stroma surrounding nests of uPARAP/Endo180-negative tumor cells. Genetic ablation of uPARAP/Endo180 impaired collagen turnover that is critical to tumor expansion, as evidenced by the abrogation of cellular collagen uptake, tumor fibrosis, and blunted tumor growth. These studies identify uPARAP/Endo180 as a key mediator of collagen turnover in a pathophysiological context.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Carcinoma / genetics
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Carcinoma / metabolism*
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Carcinoma / ultrastructure
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / ultrastructure
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Cells, Cultured
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Collagen / metabolism*
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Disease Models, Animal
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Extracellular Matrix / metabolism*
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Extracellular Matrix / ultrastructure
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Female
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Mammary Glands, Animal / metabolism
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Mammary Glands, Animal / pathology
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Mammary Glands, Animal / ultrastructure
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism*
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Mammary Neoplasms, Experimental / ultrastructure
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Mesoderm / metabolism*
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Mesoderm / pathology
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Mesoderm / ultrastructure
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Mice
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Mice, Knockout
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Microscopy, Electron, Transmission
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Molecular Sequence Data
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Neoplasm Invasiveness
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Polyomavirus
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism*
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Stromal Cells / metabolism
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Stromal Cells / pathology
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Stromal Cells / ultrastructure
Substances
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Membrane Glycoproteins
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Mrc2 protein, mouse
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Receptors, Cell Surface
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Collagen
Associated data
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GENBANK/BC072650
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GENBANK/X66473
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GENBANK/X83536