uPARAP/Endo 180 is a key mediator of collagen turnover during mammary carcinoma progression.

CURINO A. C.; BOYE S. N.; ENGELHOLM L.H.; MOLINOLO A.A.; BEHRENDT N.; BUGGE T.H.

Bethesda, MD. USA.

Congreso; Fifth Annual Hispanic Scientist Day.; 2004

National Institutes of Health.

uPARAP is a key mediator of collagen turnover during malignant tissue remodeling   1Alejandro C. Curino, 3Boye S. Nielsen, 3Lars H. Engelholm, Lars Kjøller 2Alfredo A. Molinolo, 3Niels Behrendt, and 1Thomas H. Bugge   1Proteases and Tissue Remodeling Unit & 2Molecular Carcinogenesis Unit, Oral & Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA. 3Finsen Laboratory, Rigshospitalet, DK-2100 Copenhagen Ø, Denmark.   Abstract The urokinase plasminogen activator receptor(uPAR)-associated protein (uPARAP) is a new member of the macrophage mannose receptor family of constitutively recycling endocytic transmembrane glycoproteins that was discovered through its specific interaction with ligand-occupied uPAR.  uPARAP is a multidomain glycoprotein that consists of an N-terminal cysteine-rich domain, a fibronectin type II domain, eight C-type carbohydrate recognition domains, a transmembrane domain, and a short C-terminal cytoplasmic tail.  In situ hybridization and immunohistochemical studies revealed that uPARAP is expressed at very low levels in homeostatic tissues.  However, expression of uPARAP is dramatically increased in mesenchymal cells at sites of active tissue remodeling and rapid extracellular matrix turnover. These include both, normal developmental tissue remodeling (endochondral and intramembranous ossification) and pathophysiological tissue remodeling such as human mammary carcinoma. It has been recently reported that uPARAP can mediate the cellular uptake and lysosomal degradation of collagen by cultured fibroblasts.  Here we show that uPARAP has a key role in the remodeling of stromal collagen during mammary carcinoma progression in polyoma middle T mouse mammary cancer model. uPARAP was undetectable in the normal murine mammary gland, but became highly expressed during Polyoma virus middle T-induced mammary carcinogenesis.  uPARAP expression was strictly confined to mesenchymal cells embedded within the dense collagenous stroma surrounding nests of tumor cells.  Genetic ablation of uPARAP dramatically impaired the remodeling of stromal collagen critical to tumor expansion as it was shown by the next evidences. First, we could observe the almost complete abrogation of phagocytic collagen uptake in fibroblast-like cells of primary cultures from uPARAP-dificient Polyoma virus middle T-induced mammary tumors. Second, we could detect by immunohitochemistry a strong accumulation of fibrillar collagen species in the stroma of the tumor developed in uPARAP deficient animals. And finally, the tumor growth was severely impaired in the uPARAP deficient animals.  These studies identify uPARAP as a key regulator of collagen remodeling in a pathophysiological context.