Intracellular collagen degradation mediated by uPARAP/Endo180 is a major pathway of extracellular matrix turnover during malignancy.
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.
Curino
Alejandro C
AC
Proteases and Tissue Remodeling Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Engelholm
Lars H
LH
Yamada
Susan S
SS
Holmbeck
Kenn
K
Lund
Leif R
LR
Molinolo
Alfredo A
AA
Behrendt
Niels
N
Nielsen
Boye Schnack
BS
Bugge
Thomas H
TH
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D011120:Polyomavirus; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure
D008562:Membrane Glycoproteins; C474081:Mrc2 protein, mouse; D011956:Receptors, Cell Surface; D003094:Collagen