Raised Serum Chondroitin Sulfate Epitope Level in Ovarian Epithelial Cancer

Pothacharoen, Peraphan; Siriaunkgul, Sumalee; Ongchai, Siriwan; Supabandhu, Jitwadee; Kumja, Prayoon; Wanaphirak, Chanane; Sugahara, Kazuyuki; Hardingham, Timothy E.; Kongtawelert, Prachya

doi:10.1093/jb/mvj181

Cited by 58 publications

(43 citation statements)

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“…Studies of experimental canine osteoarthritis cartilage revealed that early in diseases there were distinctive changes in the CS epitopes long before there was any cartilage destruction (20). Changes in the sulfation of CS were also reported in the PG fragments found in synovial fluid following joint trauma (21).…”

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confidence: 99%

“…It is reactive with shark CS-PGs, and the epitope was also detected in commercial CS preparations (CS-C and CS-D) from shark cartilage, but the antibody is unreactive with other glycosaminoglycans (GAGs) (25). An enzyme-linked immunosorbent assay (ELISA) has shown that this mAb detected an increased level of WF6 epitope in serum samples from patients of osteoarthritis and rheumatoid arthritis (19) and in those of ovarian cancer (20). The established specificity of the antibody and its restricted distribution among CS chains has suggested that the epitope is a specific sequence found in some but not all CS chains and is composed of sulfated disaccharides, including A unit (GlcUA␤1-3GalNAc(4-O-sulfate)), C unit (GlcUA␤1-3GalNAc(6-O-sulfate)), and D unit (GlcUA(2-O-sulfate)␤1-3GalNAc(6-O-sulfate)).…”

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confidence: 99%

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Two Related but Distinct Chondroitin Sulfate Mimetope Octasaccharide Sequences Recognized by Monoclonal Antibody WF6

Pothacharoen

Kalayanamitra

Deepa

et al. 2007

Journal of Biological Chemistry

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Chondroitin sulfate (CS) proteoglycans are major components of cartilage and other connective tissues. The monoclonal antibody WF6, developed against embryonic shark cartilage CS, recognizes an epitope in CS chains, which is expressed in ovarian cancer and variably in joint diseases. To elucidate the structure of the epitope, we isolated oligosaccharide fractions from a partial chondroitinase ABC digest of shark cartilage CS-C and established their chain length, disaccharide composition, sulfate content, and sulfation pattern. These structurally defined oligosaccharide fractions were characterized for binding to WF6 by enzyme-linked immunosorbent assay using an oligosaccharide microarray prepared with CS oligosaccharides derivatized with a fluorescent aminolipid. The lowest molecular weight fraction recognized by WF6 contained octasaccharides, which were split into five subfractions. The most reactive subfraction contained several distinct octasaccharide sequences. Two octasaccharides, ⌬D-C-C-C and ⌬C-C-A-D (where A represents GlcUA␤1-3GalNAc(4-O-sulfate), C is GlcUA␤1-3Gal-NAc(6-O-sulfate), D is GlcUA(2-O-sulfate)␤1-3GalNAc(6-Osulfate), ⌬C is ⌬ 4,5 HexUA␣1-3GalNAc(6-O-sulfate), and ⌬D is ⌬ 4,5 HexUA(2-O-sulfate)␣1-3GalNAc(6-O-sulfate)), were recognized by WF6, but other related octasaccharides, ⌬C-A-D-C and ⌬C-C-C-C, were not. The structure and sequences of both the binding and nonbinding octasaccharides were compared by computer modeling, which revealed a remarkable similarity between the shape and distribution of the electrostatic potential in the two different octasaccharide sequences that bound to WF6 and that differed from the nonbinding octasaccharides. The strong similarity in structure predicted for the two binding CS octasaccharides (⌬D-C-C-C and ⌬C-C-A-D) provided a possible explanation for their similar affinity for WF6, although they differed in sequence and thus form two specific mimetopes for the antibody. Chondroitin sulfate proteoglycans (CS-PGs)5 are expressed on the surface of most cells and in extracellular matrices in vertebrates, where CS is linked to a wide range of core protein families. They are increasingly implicated as important regulators of many biological processes, contributing in various ways to the physical strength of tissues, cell adhesion, and signal transduction (1-4).CS chains have a considerable structural variability, the biological functions of which are not well understood. The structure is an unbranched polymer linked through a unique tetrasaccharide (GlcUA-Gal-Gal-Xyl) to a serine residue in a PG and is composed of repeating disaccharides (-4GlcUA␤1-3GalNAc␤1-) n , which can be modified by O-sulfation reactions at various positions, where GlcUA and GalNAc represent *

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confidence: 99%

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confidence: 99%

Two Related but Distinct Chondroitin Sulfate Mimetope Octasaccharide Sequences Recognized by Monoclonal Antibody WF6

Pothacharoen

Kalayanamitra

Deepa

et al. 2007

Journal of Biological Chemistry

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“…Chondroitin sulfate as part of the tumor microenvironment accumulates in the stromal compartment of many solid tumors, including breast tumors (Olsen et al, 1988;Kovalszky et al, 1990;Alini and Losa, 1991;Ricciardelli et al, 1997Ricciardelli et al, , 1999Ricciardelli et al, , 2009Vijayagopal et al, 1998;Suwiwat et al, 2004;Pothacharoen et al, 2006;Sakko et al, 2008;Teng et al, 2008;Kalathas et al, 2009), the functional relevance of which had not been analyzed so far. Here, we utilized intra-tumor injections of ChABC in an orthotopic mouse model to demonstrate that enzymatic elimination of endogenous breast cancer-associated chondroitin sulfate leads to an increased metastatic burden.…”

Section: Discussionmentioning

confidence: 99%

“…Several laboratories have also begun to elucidate potential roles for chondroitin sulfates and CSPGs in tumor biology. Strikingly increased levels of chondroitin sulfates and CSPGs have been observed in the microenvironment of a number of human solid tumors, including melanoma, ovarian adenocarcinomas, hepatocarcinoma, prostate tumors, colon adenocarcinoma, and breast cancer (Olsen et al, 1988;Kovalszky et al, 1990;Alini and Losa, 1991;Ricciardelli et al, 1997Ricciardelli et al, , 1999Ricciardelli et al, , 2009Vijayagopal et al, 1998;Suwiwat et al, 2004;Pothacharoen et al, 2006;Sakko et al, 2008;Teng et al, 2008;Kalathas et al, 2009). The functional significance of this observation for cancer progression is unknown, but increased deposition of chondroitin sulfates within malignant tissues raises the possibility of a cancer therapy targeted towards tumor-associated chondroitin sulfates.…”

Section: Introductionmentioning

confidence: 99%

Elimination of breast tumor-associated chondroitin sulfate promotes metastasis

Prinz¹,

Willis²,

Viloria-Petit³

et al. 2011

Genet. Mol. Res.

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ABSTRACT. Breast cancer is one of the leading causes of cancer-related deaths amongst women in the USA. The tumor microenvironment has been suggested to be an attractive therapeutic target for treatment of cancers. The glycosaminoglycan chondroitin sulfate, as part of the cellular microenvironment, consists of long linear chains of repeating disaccharide units, which are covalently attached to core proteins to form chondroitin sulfate-proteoglycans. In vitro studies have implicated chondroitin sulfate in various aspects of carcinogenesis, whereas the in vivo roles of chondroitin sulfate are less clear. Drastically elevated levels of chondroitin sulfate have been observed within the stromal compartment of many solid tumors, including human breast carcinomas, the significance of which is unknown. We examined the role of tumor-associated chondroitin sulfate in breast cancer progression. Enzymatic elimination of endogenous chondroitin sulfate by intra-tumor injections of chondroitinase ABC leads to the development of secondary tumors and increased lung metastases, while primary orthotopic tumor growth was not affected. These results establish a metastasis-inhibiting effect of primary breast tumor-associated chondroitin sulfate, which may open novel carbohydrate-based therapeutic strategies to combat breast cancer.

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“…Monoclonal antibodies (mAbs) that recognize specific features of the repeating disaccharide region of CS chains have been generated, and epitopes of some of them have been characterized [12][13][14][15][16]. Studies using anti-CS mAbs have revealed restricted spatiotemporal patterns of the expression of specific CS structures in various tissues during growth and development, and in pathological conditions [16][17][18][19]. However, so far, no antibodies have been reported which recognize the GAG-protein linkage region.…”

Section: Introductionmentioning

confidence: 99%

Development of a mouse monoclonal antibody against the chondroitin sulfate-protein linkage region derived from shark cartilage

et al. 2010

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Glycosaminoglycans (GAGs) like chondroitin sulfate (CS) and heparan sulfate (HS) are synthesized on the tetrasaccharide linkage region, GlcA1-3Gal1-3Gal1-4Xyl1-O-Ser, of proteoglycans. The Xyl can be modified by 2-O-phosphate in both CS and HS, whereas the Gal residues can be sulfated at C-4 and/or C-6 in CS but not in HS. To study the roles of these modifications, monoclonal antibodies were developed against linkage glycopeptides of shark cartilage CS proteoglycans, and one was characterized in detail. This antibody bound hexa-and pentasaccharide-peptides more strongly than tetrasaccharide-peptides, suggesting the importance of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Xyl-Ser linkage completely abolished the binding activity, suggesting the importance of the Xy-Ser linkage for the binding. Furthermore, the antibody stained wild-type CHO cells, but not mutant cells deficient in xylosyltransferase required for the synthesis of the linkage region. These results suggest that the antibody recognizes the structure GalNAc-GlcA-Gal-Gal-Xyl-Ser that is modified by 6-O-sulfation on GalNAc and/or Gal. The antibody will be a useful tool for investigating the significance of the linkage region in the biosynthesis and/or intracellular transport of different GAG chains.

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Raised Serum Chondroitin Sulfate Epitope Level in Ovarian Epithelial Cancer

Cited by 58 publications

References 34 publications

Two Related but Distinct Chondroitin Sulfate Mimetope Octasaccharide Sequences Recognized by Monoclonal Antibody WF6

Two Related but Distinct Chondroitin Sulfate Mimetope Octasaccharide Sequences Recognized by Monoclonal Antibody WF6

Elimination of breast tumor-associated chondroitin sulfate promotes metastasis

Development of a mouse monoclonal antibody against the chondroitin sulfate-protein linkage region derived from shark cartilage

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