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Clinical Cancer Research Vol. 11, 2969-2973, April 15, 2005
© 2005 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

ß1,6-Branched Oligosaccharides Are Increased in Lymph Node Metastases and Predict Poor Outcome in Breast Carcinoma

Tamara Handerson1, Robert Camp2,4, Malini Harigopal2,4, David Rimm2,4 and John Pawelek3,4

Authors' Affiliations: 1 Department of Pathology, University of Massachusetts School of Medicine, Worchester, Massachusetts; Departments of 2 Pathology and 3 Dermatology, and 4 Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: John M. Pawelek, Department of Dermatology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8059. Phone: 203-785-4411; Fax: 203-785-7637; E-mail: john.pawelek{at}yale.edu.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
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Purpose: This study was designed to provide a comprehensive assessment on the role of ß1,6-branched oligosaccharides in the metastasis and outcome of breast carcinoma. Generation of these structures on N-glycans is initiated by ß1,6-N-acetylglucosaminyltransferase V and used by both myeloid cells and cancer cells in systemic migration.

Experimental Design: Tissue microarrays of >700 tumors (>400 patients; 30-year follow-up data) were stained through lectin histochemistry with leukocytic phytohemagglutinin (LPHA), a selective marker for ß1,6-branched oligosaccharides. Node-negative and node-positive primary tumors and patient-matched lymph node metastases were scored by blinded observers.

Results: Metastases stained at significantly greater intensities than did the patient-matched primary tumors (P < 0.0001), demonstrating for the first time that the abundance of ß1,6-branched oligosaccharides was directly associated with breast carcinoma nodal metastasis. Multivariate analyses revealed that ß1,6-branched oligosaccharides in primary tumors were a predictor of poor outcome, most notably in node-negative tumors, where an LPHA staining score of 3+ gave a risk factor of 3.3, independent of tumor size, nuclear grade, or patient age (P = 0.007).

Conclusions: The data firmly establish a role for ß1,6-N-acetylglucosaminyltransferase V activity and ß1,6-branched oligosaccharides in breast carcinoma metastasis, and reemphasize the involvement, although poorly understood, of aberrant glycosylation in tumor progression.

Key Words: N-glycosylation • GnT-V • tumor progression • Kaplan-Meier analyses • vesicular phenotype

ß1,6-N-acetylglucosaminyltransferase V (GnT-V, E.C.2.4.1.155) is a key enzyme in the production of tri- or tetra-antennary glycans, and catalyzes the transfer of N-acetylglucosamine to {alpha}-1,6-mannose in the pentasaccharide core of acceptor glycans (1–3). This forms a ß1,6 branch point, whose branches typically consist of polylactosamine antennae, carriers of the fucosyl-based antigens, Lewisx and Lewisa. These are used by both normal leukocytes and tumor cells in selectin binding (4–9). ß1,6 branching also affects numerous cellular pathways for adhesion, motility, angiogenesis, and apoptosis (see Discussion). Thus, the ß1,6 branch point represents a potential rate-limiting step in systemic migration. This branch point can be identified through lectin histochemistry with the plant lectin, leukocytic phytohemagglutinin (LPHA), which exhibits high specificity for ß1,6 branching on N-glycans (10, 11) and can be used in formalin-fixed, paraffin-embedded tissues (12). LPHA binding to histologic sections of melanomas was resistant to the strong oxidative bleaching procedures necessary to decolorize melanin (12), indicating the ß1,6 branches were stable to oxidation, a major cause of antigen loss on long-term storage of paraffin-embedded tissues (13). LPHA binding was markedly reduced when histologic sections of renal cell carcinomas, melanomas, and breast carcinomas were preincubated with glycosidase F, indicating that the ß1,6 branch points were associated with N-glycans (asparagine linked) in these tissues (12).

Earlier studies showed a role for GnT-V and ß1,6-branched oligosaccharides in tumor progression (8, 14). In one study of primary invasive breast carcinomas, the intensity of LPHA staining was higher in the carcinomas compared with either normal breast tissue or regions of hyperplasia (15). In primary colorectal carcinoma, a risk factor of 2.5 was associated with high-intensity LPHA staining (16). GnT-V expression correlated inversely with survival in both primary colorectal and non–small cell lung cancers (17, 18). In melanoma, the number of LPHA-positive tumor cells varied widely in primaries, ranging from 0% to 100% for a given tumor, whereas metastases were more homogeneous, suggesting that LPHA-positive cells in the primary tumor were a source of metastases (12).

Here, LPHA staining was analyzed for the first time in large-cohort breast carcinoma microarrays, with 30-year patient follow-up data. Data show that the abundance of ß1,6-branched oligosaccharides was increased in lymph node metastases compared with patient-matched primary tumors, and that the presence of ß1,6-branched oligosaccharides in primary tumors was an independent risk factor for poor outcome, particularly when present in node-negative tumors.


   Materials and Methods
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Tissue microarrays. Microarrays of human breast carcinomas were constructed as previously described (19–20) and were provided by the Yale Cancer Center Critical Technologies group. Four microarrays were used for these studies: YTMA 10 A1, consisting of node-positive primary tumors; YTMA 10 B1, consisting of tumor-positive lymph nodes patient-matched to the primary tumors in YTMA 10 A1; YTMA 49, consisting of node-negative and node-positive primary tumors; and YTMA 50, consisting of patient-matched node-positive primaries and tumor-positive lymph nodes (combining YTMA 10: A1 and B1 onto a single slide). Paraffin-embedded, formalin-fixed specimens of breast carcinoma were identified from the archives of the Yale University Department of Pathology, as available from 1962 to 1980. Complete treatment information was unavailable; however, most of the node-positive patients were treated with local radiation and ~15% were given chemotherapy primarily consisting of Adriamycin, cytoxan, and 5-fluorouracil. The node-negative patients were routinely treated with surgery and/or local radiation alone. About one fourth of the patients subsequently received tamoxifen (post-1978). Representative regions of invasive carcinoma were selected for coring by a pathologist (R. Camp). Prior studies by us and others have shown that, in general, a single tissue core adequately represents the staining pattern of an entire section (19, 20). Therefore, all studies were done using a single sample of each tumor. All patients were followed until death or for a minimum of 30 years. Patients were deemed "uncensored" if they died of breast cancer within 30 years of their initial date of diagnosis.

Leukocytic phytohemagglutinin lectin histochemistry. Antigen retrieval was done by pressure cooking slides [10 mmol/L sodium citrate (pH 6.5), 20 minutes, 100°C]. Slides were then stained with biotinylated LPHA (Vector Laboratories, Burlingame, CA) through immunoperoxidase techniques and counterstained with hematoxylin. Arrays were scored blinded on scales of 0 to 3+. As a control for staining specificity, when LPHA was preincubated with porcine thyroglobulin (7.5 µmol/L; Sigma-Aldrich, Inc., St. Louis, MO) 30 minutes before addition to tissue microarrays, LPHA binding was completely inhibited (not shown). Data represent the average of at least two independent observer scores with agreement correlation coefficients of r > 0.80.

Statistical analyses. All analyses were done using Statview 5.0.1 (SAS Institute, Inc., Cary, NC). Prognostic significance was assessed using multivariate Cox proportional hazards model with 30-year follow-up data. Survival curves were calculated using the Kaplan-Meier method with significance evaluated using the log-rank test.


   Results
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The relative LPHA staining intensity was compared between primary tumors and their patient-matched nodal metastases (n = 323 patients). All tumor sections were on the same slide, and LPHA staining intensity for each section was scored blinded on a 0 to 3+ scale (Fig. 1A). LPHA staining, whether primaries or metastases, was always, but not exclusively, associated with coarse vesicles (Fig. 1B). The abundance of coarse vesicles seemed to increase with increased LPHA staining intensity, although this was not formally quantitated. LPHA staining was elevated in nodes versus primaries in 183 (56.7%) of the cases, decreased in 54 cases (16.7%), and unchanged in 86 cases (26.6%; Fig 2). The number of cases where LPHA staining was higher in the node was significantly increased compared with where staining was lower in the node or where there was no change (P < 0.0001). The mean ± SD staining intensity score for all primaries was 0.83 ± 0.8 and that for metastases 2.03 ± 0.8 (P < 0.0001). These data showed, for the first time, that the abundance of ß1,6-branched oligosaccharides is elevated in breast carcinoma metastases.



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  		Fig. 1. A, LPHA lectin histochemical staining (brown) of representative sections from breast carcinoma tumor microarray YTMA 50, showing examples of 0 to 3+ scoring. B, high-power views revealed that along with other cellular structures, LPHA stained "coarse vesicles" (arrows) thought to be phagosomes and/or autophagosomes as described in the text (12, 21). Left, primary invasive tumor; right, metastasis to a lymph node.

 


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  		Fig. 2. LPHA staining (0-3+) of patient-matched node-positive primaries and lymph node metastases on a single tumor microarray (YTMA 50). The score for the primary tumor was subtracted from that for the metastasis and the differentials plotted versus the number of cases. Black columns, positive scores (higher in node); gray columns, 0 (no change); light gray columns, negative scores (lower in node).

 
Supporting this, Kaplan-Meier curves for node-negative and node-positive primary tumors on the same microarray slide showed that LPHA staining intensity in primary tumors was inversely proportional to survival (Fig. 3). Multivariant analyses of these data indicated that for node-negative primary tumors, the risk factors for LPHA staining intensities of 1 to 3+ were all elevated, with a score of 3+ yielding a risk of 3.3 (P = 0.007), independent of tumor size, nuclear grade, or patient age (Table 1). For node-positive primary tumors, there was a smaller LPHA risk factor of 1.39 that was not significant (P = 0.226) and was less than the significant risk of 2.14 from node positivity (P = 0.001; Table 1). Thus, LPHA staining intensity was a highly significant predictor of outcome in node-negative primary carcinomas.



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  		Fig. 3. Kaplan-Meier analyses of survival versus LPHA staining intensity in breast carcinoma (microarray YTMA 49). A, node-negative tumors; B, node-positive tumors. P values are for differences between all LPHA staining categories and were obtained using a log-rank analysis.

 

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  		Table 1. Multivariate analysis of 30-year disease-related survival

 

   Discussion
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ß1,6-branched oligosaccharides have long been associated with tumor progression; however, to our knowledge, this is the first demonstration of their greater abundance in metastases compared with primary tumors (Fig. 2). These quantitative studies were aided by the use of large cohort tumor microarrays with sections of primary and metastatic tumors mounted side by side on the same slide. This allowed accurate comparison of staining intensity between sections because the tissues had been exposed to uniform processing and staining procedures. Not only was there a greater abundance in metastases, but 97% of the metastases stained with LPHA (3% were negative) compared with 66% of primaries (34% were negative). Further, even with the relatively small-bore tumor sections used in the microarrays, we noted that staining tended to be relatively homogeneous in metastases and more heterogeneous in primaries. This was observed in all four microarrays sectioned from the same core biopsies used in these studies and similar to previous results with melanoma (12).

LPHA stained both cytoplasmic and plasma membrane components. In the cytoplasm, staining was always, but not exclusively, localized to coarse vesicles. Interestingly, in earlier studies of breast and colon carcinoma, it was also noted that LPHA stained "coarse granules and globules" (15). Recently, coexpression of coarse vesicles and ß1,6-branched oligosaccharides was found to be a common phenotype in 21 different human cancers (12, 21). The significance of these structures in human cancer is as yet unknown; however, it is possible that their expression is induced by GnT-V (22). In electron microscopy studies of human and mouse melanomas, the structures seemed to be phagosomes or autophagosomes (21). Because these structures fuse with lysosomes, it is interesting that lysosome-associated membrane proteins are some of the major substrates for GnT-V (23).

We propose that the most likely reason for the greater abundance of ß1,6-branched oligosaccharides in metastases is that those cells in the primary tumor with the highest expression of ß1,6-branched oligosaccharides were also the cells with the highest metastatic potential and, thus, the principal progenitors of metastases. Another possibility could be that the microenvironment of the lymph node in some manner caused up-regulation of ß1,6-branched oligosaccharide expression. In this case, ß1,6-branched oligosaccharide expression would not necessarily have been linked with the process of metastasis, but rather have been a secondary consequence of residence in the microenvironment of the lymph node per se. However, this latter possibility would not explain why the presence of ß1,6-branched oligosaccharides in primary tumors was associated with poor outcome, a result most consistent with the former interpretation that the expressing cells in the primary tumor were the ones most likely to metastasize.

Multivariant analyses revealed that the independent risk factor associated with LPHA staining was of greater significance in node-negative compared with node-positive primary tumors (Table 1). This same trend was observed for tumor size, nuclear grade, and patient age, where the independent risks from these factors in node-negative tumors became secondary in cases where nodal spread had already occurred (Table 1). Similar results were found for macrophage colony-stimulating factor-1 in these same breast carcinoma microarrays (24). Thus, ß1,6-branched oligosaccharides and other risk factors showed less significance as independent indicators once metastasis had occurred. Perhaps this is because they were integral components of the metastatic process and/or of the metastases themselves.

GnT-V has multiple glycoprotein substrates and thereby exerts global effects on cellular phenotype. Some of the proteins affected are central for migration and adhesion, such as matriptase, ß1 integrins, cadherins, and epidermal growth factor receptor (below). Elevated GnT-V expression resulted in loss of contact inhibition and decreased substrate adhesion, increased susceptibility to apoptosis, and increased tumorigenicity (25, 26). Conversely, GnT-V–deficient mice showed suppressed tumor growth and lowered incidence of metastases (27). Increased ß1,6-branched oligosaccharides on ß1 integrins modified the interaction of S115 mammary epithelial cells with laminin-1 (28), and altered adherence to laminin and fibronectin in H7221 human hepatocarcinoma cells (29). Transfection of sense GnT-V cDNA into H7221 cells modified the signaling pathway for the epidermal growth factor receptor (30). ß1,6-branched oligosaccharides on ß1 integrin reduced clustering of {alpha}5ß1 integrin and stimulated in vitro migration of human fibrosarcoma cells and conferred resistance to cisplatin in a human squamous cell carcinoma cell line (31, 32). Addition of ß1,6-branched, polylactosamine-containing oligosaccharides to cadherin reduced cadherin-associated homotypic cell-to-cell adhesion and affected intracellular signaling pathways in human sarcoma Ht 1080 and mouse NIH3T3 cells (33). Attachment of human colon cancer cells to vascular endothelium was enhanced by GnT-V activity (34). Addition of ß1,6-branched oligosaccharides at Asn772 in the serine protease domain of matriptase played a pivotal role in its stability and resistance against trypsin (35). Matriptase plays important roles in cell migration, extracellular matrix degradation, and the activation of single-chain urokinase-plasminogen activator and hepatocyte growth factor (36). In breast carcinoma, matriptase expression was associated with poor patient outcome (37). Because matriptase is a GnT-V substrate, it is possible that ß1,6-branched oligosaccharides on matriptase contributed to metastatic progression in the breast carcinoma cases reported herein. Indeed, using redundant sections of these same microarrays, there was a strong correlation for coexpression of matriptase and ß1,6-branched oligosaccharide expression in the individual cases.(unpublished observations).5).

The cases in our study were from the 1960s and 1970s when few women were treated with systemic therapy. We have no information on local radiotherapy; however, it is generally assumed that whereas radiation therapy plays a role in local recurrence, it has little impact on overall survival. In that we are assessing disease-related survival rather than recurrence, the absence of data on local radiotherapy should have a minimal effect on our analyses.

In summary, supported by two decades of research on GnT-V, aberrant glycosylation, and tumor progression, these studies firmly establish a role for ß1,6-branched oligosaccharides in breast carcinoma metastasis and their prognostic value as indicators of outcome, notably in primary tumors with no nodal involvement. Thus, ß1,6-branched oligosaccharides, the enzymes regulating their synthesis and degradation, and their associated glycoprotein conjugates present new targets for diagnosis and therapy of this difficult and highly prevalent cancer.


   Acknowledgments
 
We thank Vincent Klump (Yale Dermatopathology Laboratories, New Haven, CT) for lectin histochemistry.


   Footnotes
 
Grant support: Vion Pharmaceuticals (J. Pawelek and T. Handerson); Breast Cancer Alliance (R. Camp and D. Rimm); NIH grants K08 ES11571 (R. Camp), R21 CA 100825 (D. Rimm), and R33 CA 106709 (D. Rimm); and U.S. Army grants DAMD-17-02-0463 and DAMD17-02-1-0634 (D. Rimm).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

5 R. Camp, unpublished observations. Back

Received 11/ 1/04; revised 1/ 5/05; accepted 1/24/05.


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Cancer Research Clinical Cancer Research
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