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

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

Oral & Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland (JS,RAW-M,JS,AM,THB), and Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (DHM,LHE,NB)

Correspondence to: Thomas H. Bugge, PhD, Proteases and Tissue Remodeling Unit, Oral & Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Room 211, Bethesda, MD 20892. E-mail: thomas.bugge{at}nih.gov

	Summary

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Local growth, invasion, and metastasis of malignancies of the head and neck involve extensive degradation and remodeling of the underlying, collagen-rich connective tissue. Urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180 is an endocytic receptor recently shown to play a critical role in the uptake and intracellular degradation of collagen by mesenchymal cells. As a step toward determining the putative function of uPARAP/Endo180 in head and neck cancer progression, we used immunohistochemistry to determine the expression of this collagen internalization receptor in 112 human squamous cell carcinomas and 19 normal or tumor-adjacent head and neck tissue samples from the tongue, gingiva, cheek, tonsils, palate, floor of mouth, larynx, maxillary sinus, upper jaw, nasopharynx/nasal cavity, and lymph nodes. Specificity of detection was verified by staining of serial sections with two different monoclonal antibodies against two non-overlapping epitopes on uPARAP/Endo180 and by the use of isotype-matched non-immune antibodies. uPARAP/Endo180 expression was observed in stromal fibroblast-like, vimentin-positive cells. Furthermore, expression of the collagen internalization receptor was increased in tumor stroma compared with tumor-adjacent connective tissue or normal submucosal connective tissue and was most prominent in poorly differentiated tumors. These data suggest that uPARAP/Endo180 participates in the connective tissue destruction during head and neck squamous cell carcinoma progression by mediating cellular uptake and lysosomal degradation of collagen. (J Histochem Cytochem 55:347–353, 2007)

Key Words: collagen degradation • Endo180 • head and neck cancer • invasion • squamous cell carcinoma • urokinase plasminogen activator receptor-associated protein

	Introduction

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DEGRADATION OF COLLAGEN-RICH extracellular matrix (ECM) is believed to be essential for the dissemination of malignancies of the head and neck from the site of origin to local and distant anatomic sites. In addition to clearing a path for malignant cells, ECM degradation liberates latent tumor growth factors embedded within the ECM, enables the formation of a neovasculature within the expanding tumor mass, and subverts the proliferative restrictions imposed on tumor cells by ECM confinement (Hotary et al. 2003; Mott and Werb 2004). Inhibition of ECM degradation, therefore, is a well-recognized target for therapeutic intervention aimed at limiting tumor growth (Coussens et al. 2002). To date, head and neck cancer-associated ECM turnover has been investigated primarily in the context of extracellular/pericellular degradation, which is executed by proteolytic systems such as the plasminogen activation system, matrix metalloproteinases, and cathepsins (Kusukawa et al. 1993; Muller et al. 1993; Okada et al. 1995; Kawada et al. 1996; Yasuda et al. 1997; Schmidt et al. 1999,2000; Birkedal-Hansen et al. 2000; Bugge 2003; Curino et al. 2004). However, a significant proportion of interstitial collagen is turned over by a little-studied intracellular pathway that involves the binding of collagen fibrils to mesenchymal cells via specific cell surface receptors, followed by cellular uptake and proteolytic degradation of the internalized collagen in the lysosomal compartment (Everts et al. 1996).

Urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180 is a recently identified member of the macrophage mannose receptor family of endocytic transmembrane glycoproteins (Behrendt et al. 2000; Sheikh et al. 2000). Little is known about the expression of uPARAP/Endo180 in vivo, but the receptor has been reported to be present on a subset of mesenchymal cells at sites of active tissue remodeling. These include bone-forming cells, activated hepatic stellate cells, and mammary tumor myoepithelial cells and fibroblasts (Engelholm et al. 2001; Schnack Nielsen et al. 2002; Mousavi et al. 2005). Gene-targeting studies in mice unexpectedly uncovered a near-complete requirement of uPARAP/Endo180 for cellular uptake and subsequent lysosomal degradation of a wide range of collagen species (East et al. 2003; Engelholm et al. 2003; Wienke et al. 2003; Kjoller et al. 2004). Furthermore, our recent study showed that uPARAP/Endo180 impaired collagen turnover critical to tumor expansion in a murine model of mammary adenocarcinoma, as evidenced by the abrogation of cellular collagen uptake, tumor fibrosis, and blunted tumor growth (Curino et al. 2005). Together these studies suggest that uPARAP/Endo180 could have a key function in collagen turnover during tumor dissemination.

In this study we investigated the expression of uPARAP/Endo180 in a panel of human head and neck squamous cell carcinomas presenting at a wide spectrum of anatomic locations and representing different histological grades. We report that stromal expression of uPARAP/Endo180 is a consistent feature of head and neck squamous cell carcinoma, suggesting that intracellular collagen degradation contributes to the devastating connective tissue destruction associated with this disease.

	Materials and Methods

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Tissue Samples
The "OR601, Oral squamous cancer tissue array with normal oral control tissue" (http://www.biomax.us/tissue-arrays/Oral/OR601) was obtained from US Biomax, Inc. (Rockville, MD). The "CC34-01-001, Head and neck squamous carcinoma (multisites, grade I– III) tissue array (http://www.cybrdi.com/viewproduct.php) was obtained from Cybrdi Inc. (Frederick, MD). Additionally, 49 oral squamous cell carcinomas were obtained from the Oral & Pharyngeal Cancer Branch Tissue Repository, National Institute of Dental and Craniofacial Research, Bethesda, MD.

Generation of Monoclonal Antibodies
A uPARAP/Endo180 fusion protein, including the third domain of the urokinase receptor as a purification tag, was produced and isolated as described previously for the C4.4A antigen (Hansen et al. 2004). uPARAP/Endo180-deficient mice (backcrossed >10 times in the mouse FVB strain) were immunized with the soluble human uPARAP/Endo180 fusion protein after which cell fusion, cloning of hybridomas, and generation of monoclonal antibodies (MAbs) were performed using routine techniques (Ronne et al. 1991).

Western Blotting
Specificity of the isolated antibodies was tested by Western blotting analysis using the Western Breeze kit (Invitrogen; Carlsbad, CA) according to the manufacturer's protocol. MAbs were diluted to 2 µg/ml. Procedures for the generation of uPARAP/Endo180-sufficient and -deficient dermal fibroblasts from newborn mice have been described previously (Engelholm et al. 2003). Detergent lysates of U937 cells and fibroblasts were prepared as described (Behrendt et al. 2000).

Immunohistochemistry
Tissue sections (5 µm) were deparaffinized in xylene (Mallinckrodt Baker; Phillipsburg, NJ), and the tissue was rehydrated in graded ethanol (100%, 95%, 70%, and H₂O). Antigen retrieval was performed using proteinase-K (Fisher Scientific; Pittsburgh, PA) treatment (5 µg/ml in 50 mM Tris–HCl, pH 8.0; Quality Biologicals, Gaithersburg, MD), 5 mM EDTA (Quality Biologicals) at 37C for 10 min for detection of uPARAP/Endo180, or using 10 mM sodium citrate, pH 6.0, for 15 min for detection of vimentin. Endogenous peroxidase activity was quenched by treatment with 1% hydrogen peroxide (Fisher Scientific) in H₂O for 15 min, after which the sections were washed in tap water and transferred to 1X TBS buffer (Quality Biologicals) with 0.5% Triton X-100 (Sigma-Aldrich; St Louis, MO). Mouse MAbs against uPARAP/Endo180 described above (2.h.9:F12 at 1.8 µg/ml and 5.f.4:D7 at 1.4 µg/ml, both IgG1), vimentin (1:500; DakoCytomation, Carpinteria, CA), or a non-immune mouse IgG1 control antibody (1.5 µg/ml; eBiosciences, San Diego, CA) in 1X TBS with 0.25% BSA (Sigma-Aldrich) were incubated overnight at 4C. Slides were removed the following day from the cold and incubated for an additional 30 min at room temperature. Slides were then washed twice with 0.05% Tween-20 (Bio-Rad Laboratories; Hercules, CA) in 1X TBS. EnVision+ peroxidase anti-mouse antibody (DakoCytomation) was applied to the slides for 45 min at room temperature, followed by two washes with TBS–Tween-20 buffer. Slides were developed for 22 min for uPARAP/Endo180 and 4 min for vimentin using SIGMA FAST 3,3'-diaminobenzidine tablet sets (Sigma-Aldrich) according to the manufacturer's instructions. The staining reaction was stopped with tap water and the tissue was counterstained in Mayer's hematoxylin (Sigma-Aldrich) for 30 sec, blued using 1X TBS, and rinsed in tap water. Slides were dehydrated through graded ethanol and xylene. Coverslips were mounted with permount (Fisher Scientific) and the slides examined for uPARAP/Endo180 expression as described below.

Evaluation of Staining Intensities and Statistical Analysis
Assessment of staining intensities of tissue samples was performed by an investigator unaware of sample identity using a modification of procedures used previously to quantitatively assess expression of stromal antigens in oral squamous cell carcinomas (de Vicente et al. 2005; Mathe et al. 2006; Piattelli et al. 2006). Scores were assigned on the basis of the intensity and extent of stromal staining in random x20 microscopic fields using an arbitrary scale from zero to four where 0 = three or fewer stromal cells stain weakly, 1 = four or more stromal cells stain weakly, 2 = many stromal cells stain moderately or the majority of stromal cells stain weakly, 3 = the majority of stromal cells stain strongly, and 4 = almost all stromal cells stain at great intensity.

Two-tailed ² analysis was used to determine statistical significance of differences in the frequency of uPARAP/Endo180 staining between groups. Statistical significance of the intensity of uPARAP/Endo180 staining between groups was determined by the two-tailed Mann–Whitney U test.

	Results

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uPARAP/Endo180 expression was studied by immunohistochemical (IHC) analysis of a panel of human squamous cell carcinomas of the head and neck area, as well as a number of tumor-adjacent head and neck and normal head and neck tissues. The combined material successfully analyzed included 112 squamous cell carcinomas derived from the tongue (n=39), gingiva (n=15), larynx (n=8), cheek (n=9), tonsils (n=4), nasopharynx/nasal cavity (n=4), palatal surface of maxilla and mandible (n=7), lymph node metastases (n=2), maxillary sinus (n=2), ethmoid sinus (n=1), or from an unknown location in the oral cavity (n=21). The normal or tumor-adjacent tissues analyzed included tongue (n=11), gingiva (n=5), palate (n=1), cheek (n=1), or from an unknown location in the oral cavity (n=1). The material was derived from the Biomax array (43 tumor samples and 13 normal or tumor-adjacent samples) and the Cybrdi array (20 tumor samples in triplicate and six normal or tumor-adjacent samples in duplicate), and 49 oral squamous cell carcinomas from the Oral & Pharyngeal Cancer Branch Tissue Repository. For IHC analysis, we used mouse MAbs (2.h.9:F12 and 5.f.4:D7) that recognize species-conserved, non-overlapping epitopes on uPARAP/Endo180 (unpublished data). Both MAbs were specific for uPARAP/Endo180, as demonstrated by Western blotting (Figure 1 ). Thus, in protein extracts of human U937 cells, which are known to express uPARAP/Endo180 (Behrendt et al. 2000), both MAbs recognized exclusively one band representing a protein with the molecular mass of uPARAP/Endo180 (180,000) (Sheikh et al. 2000) (Figure 1A, Lanes 1 and 2). No protein was recognized by an irrelevant control MAb of the same isotype (anti-TNP; Figure 1A, Lane 3). Utilization of uPARAP/Endo180-deficient mice for immunization led to the generation of MAbs (including the two MAbs of this study) that are reactive against both human and murine uPARAP/Endo180. As evident in Figure 1B, both antibodies reacted with a single protein (molecular mass 180,000) in lysates of wild-type mouse fibroblasts known to express uPARAP/Endo180 (Engelholm et al. 2003), whereas no protein was recognized in lysates of fibroblasts from littermate uPARAP/Endo180-deficient mice.

View larger version (24K): [in this window] [in a new window]   Figure 1 Monoclonal antibodies (MAbs) 2.h.9:F12 and 5.f.4:D7 specifically recognize uPARAP/Endo180. (A) Western blot of protein lysates from uPARAP/Endo180-expressing human U937 cells using MAb 2.h.9:F12 (Lane 1), MAb 5.f.4:D7 (Lane 2), and an irrelevant isotype-matched anti-TNP MAb (Lane 3). MAbs 2.h.9:F12 and 5.f.4:D7, but not an isotype-matched irrelevant MAb, recognize a single 180,000 molecular mass protein compatible with uPARAP/Endo180 (arrow, right). (B) Western blot of fibroblasts from newborn uPARAP/Endo180-sufficient (U+/+; Lanes 1 and 3) mice and littermate uPARAP/Endo180-deficient (U–/–; Lanes 2 and 4) mice. Both MAbs 2.h.9:F12 and 5.f.4:D7A recognize a single 180,000 molecular mass protein (arrow, right), which is present in uPARAP/Endo180-sufficient fibroblast lysates but absent in uPARAP/Endo180-deficient fibroblast lysates. Molecular mass marker (kD) is shown at left.

View larger version (112K): [in this window] [in a new window]   Figure 2 uPARAP/Endo180 can be detected in head and neck squamous cell carcinoma by immunohistochemistry (IHC). Representative examples of IHC staining of serial sections of normal (A,E,I,M), well-differentiated (W-D) (B,F,J,N), moderately differentiated (M-D) (C,G,K,O), and poorly differentiated (P-D) (D,H,L,P) head and neck squamous cell carcinomas with MAb 2.h.9:F12 (A–D), 5.f.4:D7 MAb (E–H), or isotype-matched, non-immune IgG1 (I–L). Hematoxylin/eosin-stained sections are shown in M–P. MAbs 2.h.9:F12 and 5.f.4:D7 (which recognize non-overlapping epitopes on uPARAP/Endo180), but not isotype-matched, non-immune IgG1k, stain tumor stromal cells (arrows in B–D,F–H) and display a polarized intracellular or membrane-confined staining compatible with an endocytic recycling receptor. The location of tumor cells is shown with stars. Bar = 50 µm.

View larger version (89K): [in this window] [in a new window]   Figure 3 uPARAP/Endo180 is located in stromal cells of head and neck squamous cell carcinoma. Representative examples of low magnification (A–C) and high magnification (D–F) photomicrographs of IHC staining of serial sections of head and neck squamous cell carcinoma with uPARAP/Endo180 MAb 2.h.9:F12 (A,D), a MAb against vimentin (B,E), or an isotype-matched, non-immune IgG1 (C,F). uPARAP/Endo180 is expressed by vimentin-positive fibroblast-like cells within streaks of tumor stroma surrounding nests of tumor cells. Examples of tumor cells are indicated with stars, and examples of uPARAP/Endo180- and vimentin-expressing stromal cells are indicated with arrows. Bars: A–C = 100 µm; D–F = 50 µm.

View larger version (12K): [in this window] [in a new window]   Figure 4 Increased expression of uPARAP/Endo180 in head and neck squamous cell carcinoma. Scatterplot of the intensity of IHC staining of uPARAP/Endo180 in tissue sections represented on the Biomax (A) and Cybrdi (B) tissue arrays, and of 49 archived head and neck squamous cell carcinomas from the Oral & Pharyngeal Cancer Branch Tissue Repository (C). Horizontal bars show median values. Tumor samples in the Cybrdi tissue array were represented in triplicate and normal and tumor-adjacent samples in duplicate. Staining intensities were determined as described in Materials and Methods. Average values for each tumor and normal tissue are shown in the plot.

	Discussion

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Intracellular collagen degradation mediated by uPARAP/Endo180 is emerging as a quantitatively important pathway for ECM degradation in the context of malignant tissue remodeling (East et al. 2003; Engelholm et al. 2003; Curino et al. 2005). Recent studies have established that uPARAP/Endo180 expression by tumor stromal cells is critical to tumor expansion by limiting the deposition of collagen within the tumor stroma (Curino et al. 2005). However, studies of the expression and localization of the collagen internalization receptor in human malignancies are still very limited (St Croix et al. 2000; Schnack Nielsen et al. 2002). Here we performed a detailed IHC study of the expression of uPARAP/Endo180 in human head and neck squamous cell carcinomas of diverse origin and variable histological grades. Use of independently derived MAbs defining non-overlapping epitopes on uPARAP/Endo180, as well as the use of isotype-matched control antibodies, allowed the unambiguous identification of uPARAP/Endo180-expressing cells in these head and neck malignancies. Our analysis revealed that the collagen internalization receptor is frequently expressed by fibroblast-like, vimentin-positive cells embedded in collagen-rich stroma adjacent to nests of tumor cells. Furthermore, uPARAP/Endo180 expression was increased in the tumor stroma as compared with tumor-adjacent connective tissue or normal submucosal connective tissue, and the receptor displayed the most prominent expression in the stroma of poorly differentiated tumors. These data strongly suggest that uPARAP/Endo180 contributes to the pathological destruction of connective tissue during head and neck squamous cell carcinoma progression by facilitating cellular uptake and intracellular degradation of collagen by tumor stromal cells. In addition to its role in collagen catabolism, uPARAP/Endo180 forms a trimolecular complex with urokinase plasminogen activator and the urokinase plasminogen activator receptor (Behrendt et al. 2000). Interestingly, expression of the urokinase plasminogen activator receptor is also strongly upregulated in stromal fibroblasts of oral squamous cell carcinoma (Lindberg et al. 2006), suggesting that uPARAP/Endo180 may also promote oral squamous cell carcinoma progression by modulating the activity of the plasminogen activation system.

Many mechanistic aspects of intracellular collagen degradation remain poorly understood. However, extra- and intracellular collagen degradation pathways appear to operate at least partially independently of each other (Everts et al. 1989; Holmbeck et al. 1999). This property of the intracellular collagen degradation pathway, when combined with the findings in this paper, suggests that uPARAP/Endo180 could represent a new therapeutic target for the clinical management of head and neck malignancies.

	Acknowledgments

 
The work was supported by the National Institute of Dental and Craniofacial Research Intramural Research Program and by a grant from the Department of Defense (DAMD-17-02-0693 to THB). J. Shireman was supported by the Howard Hughes Medical Research–NIH Research Scholars Program. L.H.E, N.B., and D.H.M were supported by EU contract LSHC-CT-2003-503297 and by grants from the Danish Cancer Society, the Danish Cancer Research Foundation, and the Danish Medical Research Council.

We thank Drs. Mary Jo Danton and J. Silvio Gutkind for carefully reading this manuscript.

	Footnotes

 
Received for publication October 27, 2006; accepted December 4, 2006

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