Increased Expression of the Collagen Internalization Receptor uPARAP/Endo180 in the Stroma of Head and Neck Cancer

Sulek, Jay; Wagenaar-Miller, Rebecca A.; Shireman, Jessica; Molinolo, Alfredo A.; Madsen, Daniel H.; Engelholm, Lars H.; Behrendt, Niels; Bugge, Thomas H.

doi:10.1369/jhc.6a7133.2006

Cited by 50 publications

(54 citation statements)

References 32 publications

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“…uPARAP may also play a role in human gingival re-epithelialization and remodeling after injury (Honardoust et al 2006). In addition, uPARAP is expressed in tumor stromal cells and has a role in tumor progression (Curino et al 2005;Sulek et al 2007). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.…”

Section: Resultsmentioning

confidence: 99%

“…Immunohistochemistry was performed using mouse on mouse (MOM) detection system (Vector Labs, Burlingame, CA) according to manufacturer's protocol using uPARAP mouse monoclonal antibody (2.H.9:F12) (generous gift from Lars Engelhom, PhD, Finsen Laboratory, Copenhagen, Denmark (Sulek et al 2007)) (0.25 µg/ml) or isotype control mouse IgG1κ (eBiosciences, San Diego, CA) for 1 hour at RT. Secondary biotinylated antibody (Vector MOM Kit) was applied to samples and immunoperoxidase complexes were formed using Vectastain Elite ABC Kit (Vector).…”

Section: Immunochemistrymentioning

confidence: 99%

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uPARAP expression during murine lung development

Smith¹,

Wagner²,

Huizar³

et al. 2008

Gene Expression Patterns

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Lung remodeling requires active collagen deposition and degradation. Urokinase plasminogen activator receptor-associated protein (uPARAP), or Endo 180, is a cell surface receptor for collagens, which leads to collagen internalization and degradation. Thus, uPARAP-mediated collagen degradation is an additional pathway for matrix remodeling in addition to matrix remodeling mediated by matrix metalloproteinases and cathepsins. Using immunohistochemistry, we demonstrate extensive uPARAP expression in the mesenchyme throughout murine lung development. By immunofluorescence, we demonstrate significant overlap of uPARAP expression with collagen IV expression, but minimal overlap with collagen I expression in the developing murine lung. Finally, we compared lung development between wild-type and uPARAP −/− mice, and found no significant histologic differences, indicating the presence of alternative collagen degradation pathways during murine lung development.Keywords lung development; collagen; uPARAP; Endo 180 Results and DiscussionUrokinase plasminogen activator receptor-associated protein (uPARAP), or Endo180, is a newly described cell-surface receptor that binds and internalizes collagens, including types I, IV, and V, targeting them for lysosomal degradation (Behrendt et al. 2000;Engelholm et al. 2003;Engelholm et al. 2001;Kjoller et al. 2004). A member of the mannose receptor family, uPARAP is expressed on macrophages and mesenchymal cells, including chondrocytes and some fibroblasts (Howard et al. 2004;Sheikh et al. 2000). Mesenchymal cells that lack uPARAP are unable to internalize collagen (Curino et al. 2005;East et al. 2003;Engelholm et al. 2003;Kjoller et al. 2004;Madsen et al. 2007;Mousavi et al. 2005). In addition to its role in collagen internalization and degradation, uPARAP contributes to the adhesion and migration of collagen in vitro (Engelholm et al. 2003). uPARAP may also play a role in human gingival re-epithelialization and remodeling after injury (Honardoust et al. 2006). In addition, uPARAP is expressed in tumor stromal cells and has a role in tumor progression (Curino et al. 2005;Sulek et al. 2007). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. During lung development, the matrix undergoes active remodeling during the formation and differentiation of airways, vasculature, and mature alveoli. In particular, during the saccular stage (E17.5 to post-natal day 5 (PN5)) and alveolar stage (PN5-PN30), the lung interstitium undergoes extensive remodeling with a decrease in the interstitial space, maturation and narrowing of the blood-air barrier and t...

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Section: Resultsmentioning

confidence: 99%

Section: Immunochemistrymentioning

confidence: 99%

uPARAP expression during murine lung development

Smith¹,

Wagner²,

Huizar³

et al. 2008

Gene Expression Patterns

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“…Reagents-The monoclonal mouse anti-uPARAP/Endo180 antibodies (mAbs) 5f4 and 2h9F12 were raised against purified recombinant soluble uPARAP/Endo180 and produced as previously described (28). Isotype-matched control anti-TNP antibody was produced as described in Ref.…”

Section: Methodsmentioning

confidence: 99%

“…uPARAP/Endo180 is frequently up-regulated in invasive cancers (25)(26)(27)(28)(29), and most often expression is observed in the stromal cells. However, the total spectrum of cell types expressing uPARAP/Endo180 is not yet known and it is also unclear whether in all cases the receptor is active in and required for collagen turnover (30).…”

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confidence: 99%

The Non-phagocytic Route of Collagen Uptake

Madsen

Ingvarsen

Jürgensen

et al. 2011

Journal of Biological Chemistry

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107

100

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The degradation of collagens, the most abundant proteins of the extracellular matrix, is involved in numerous physiological and pathological conditions including cancer invasion. An important turnover pathway involves cellular internalization and degradation of large, soluble collagen fragments, generated by initial cleavage of the insoluble collagen fibers. We have previously observed that in primary mouse fibroblasts, this endocytosis of collagen fragments is dependent on the receptor urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180. Others have identified additional mechanisms of collagen uptake, with different associated receptors, in other cell types. These receptors include ␤1-integrins, being responsible for collagen phagocytosis, and the mannose receptor. We have now utilized a newly developed monoclonal antibody against uPARAP/Endo180, which down-regulates the receptor protein level on treated cells, to examine the role of uPARAP/Endo180 as a mediator of collagen internalization by a wide range of cultured cell types. With the exception of macrophages, all cells that proved capable of efficient collagen internalization were of mesenchymal origin and all of these utilized uPARAP/Endo180 for their collagen uptake process. Macrophages internalized collagen in a process mediated by the mannose receptor, a protein belonging to the same protein family as uPARAP/ Endo180. ␤1-Integrins were found not to be involved in the endocytosis of soluble collagen, irrespectively of whether this was mediated by uPARAP/Endo180 or the mannose receptor. This further distinguishes these pathways from the phagocytic uptake of particulate collagen.Remodeling of the extracellular matrix is required for a wide range of physiological and pathological conditions such as morphogenesis, organ growth, wound healing, arthritis, fibrosis and tumor growth, and metastasis (1-4). Collagens are the most abundant components of the extracellular matrix with collagen type I as the quantitatively dominating subtype. Thus, collagen constitutes about 25-30% of the dry weight of a human (5). The collagen in the body is undergoing continuous renewal and normally the collagen turnover rate is carefully controlled. Depending on the tissue type or extraneous events the collagen turnover rate can change dramatically. Therefore, highly efficient biological systems are needed in both the formation and degradation of collagen throughout life.In normal healthy tissue, collagen is fully hydroxylated and forms insoluble, cross-linked fibers and sheets of triple helical structures that are resistant to attack by most proteases (6). A number of proteases are nevertheless potentially capable of initiating the collagen degradation process through the cleavage of intact collagen fibers. These proteases are the matrix metalloproteinases (MMPs) 3 MMP-1, MMP-2, MMP-8, MMP-13, MMP-14, MMP-15, and MMP-16 and the cysteine protease cathepsin K (7-9). So far, most studies of collagen turnover have focused on the extracellular collagen degradat...

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“…18,23 Mrc2 expression by either stromal cells or malignant cells has been associated with enhanced tumor invasion and metastasis. 25,[46][47][48] This study reveals that it also serves an important role in solid organ fibrosis by reducing the rate of interstitial collagen accumulation, resulting in protection of the surrounding parenchyma from fibrosis-associated destruction.…”

Section: Mrc2 Expression Is Minimal In Normal Kidneysmentioning

confidence: 79%

Mannose Receptor 2 Attenuates Renal Fibrosis

López-Guisa

Cai

Collins

et al. 2012

Journal of the American Society of Nephrology

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Mannose receptor 2 (Mrc2) expresses an extracellular fibronectin type II domain that binds to and internalizes collagen, suggesting that it may play a role in modulating renal fibrosis. Here, we found that Mrc2 levels were very low in normal kidneys but subsets of interstitial myofibroblasts and macrophages upregulated Mrc2 after unilateral ureteral obstruction (UUO). Renal fibrosis and renal parenchymal damage were significantly worse in Mrc2-deficient mice. Similarly, Mrc2-deficient Col4a3 2/2 mice with hereditary nephritis had significantly higher levels of total kidney collagen, serum BUN, and urinary protein than Mrc2-sufficient Col4a3 2/2 mice. The more severe phenotype seemed to be the result of reduced collagen turnover, because procollagen III (a1) mRNA levels and fractional collagen synthesis in the wildtype and Mrc2-deficient kidneys were similar after UUO. Although Mrc2 associates with the urokinase receptor, differences in renal urokinase activity did not account for the increased fibrosis in the Mrc2-deficient mice. Treating wild-type mice with a cathepsin inhibitor, which blocks proteases implicated in Mrc2-mediated collagen degradation, worsened UUO-induced renal fibrosis. Cathepsin mRNA profiles were similar in Mrc2-positive fibroblasts and macrophages, and Mrc2 genotype did not alter relative cathepsin mRNA levels. Taken together, these data establish an important fibrosis-attenuating role for Mrc2-expressing renal interstitial cells and suggest the involvement of a lysosomal collagen turnover pathway.

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Increased Expression of the Collagen Internalization Receptor uPARAP/Endo180 in the Stroma of Head and Neck Cancer

Cited by 50 publications

References 32 publications

uPARAP expression during murine lung development

uPARAP expression during murine lung development

The Non-phagocytic Route of Collagen Uptake

Mannose Receptor 2 Attenuates Renal Fibrosis

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