chondroitin-sulfates and Carcinoma

The malaria protein VAR2CSA binds oncofetal chondroitin sulfate (ofCS), a unique chondroitin sulfate, expressed on almost all mammalian cancer cells. Previously, we produced a bispecific construct targeting ofCS and human T cells based on VAR2CSA and anti-CD3 (V-aCD3. We produced a bispecific construct consisting of a recombinant version of VAR2CSA coupled to an anti-murine CD3 single-chain variable fragment. Flow cytometry and ELISA were used to check cell binding capabilities and the therapeutic effect was evaluated in vitro in a killing assay. The in vivo efficacy of V-aCD3. V-aCD3. Our findings suggest that V-aCD3

Topics: Animals; Antibodies, Bispecific; Carcinoma; Cell Line, Tumor; Chondroitin Sulfates; Humans; Immune Checkpoint Inhibitors; Immunologic Memory; Mammals; Melanoma, Experimental; Mice

Topics: Adult; Autografts; Bone Neoplasms; Carcinoma; Chondroitin Sulfates; Humans; Hydroxyapatites; Liposarcoma; Male; Middle Aged; Nitrogen; Osteosarcoma; Succinates; Tibia; Ulna

Topics: Carcinoma; Chondroitin Sulfates; Collagen; Female; Head and Neck Neoplasms; Humans; Middle Aged; Plastic Surgery Procedures

The extracellular matrix (ECM) of ovarian cancer may provide a number of potential biomarkers. Chondroitin sulfate (CS), a class of sulfated polysaccharides, is abundantly present in the ECM of ovarian cancer. Structural alterations of CS chains (i.e. sulfation pattern) have been demonstrated to play a role in cancer development and progression. In this study we investigate the potential of highly sulfated CS as a biomarker in ovarian cancer using the single chain antibody GD3A11 selected by the phage display technology.. The specificity of the antibody was determined by an indirect ELISA. GD3A11 epitope expression was assessed by immunohistochemistry in healthy organs, benign and malignant ovarian tumors (N=359) and correlated to clinical parameters. The CHST15 gene, responsible for the biosynthesis of highly sulfated CS was evaluated for mutation and methylation status.. The GD3A11 epitope was minimally expressed in normal organs. Intense expression was observed in the ECM of different ovarian cancer subtypes, in contrast to benign ovarian tumors. Expression was independent of tumor grade, FIGO stage, and the use chemotherapy. For the aggressive ovarian cancer phenotype, intense expression was identified as an independent predictor for poor prognosis. CHST15 gene analysis showed no mutations nor an altered methylation status.. Specific highly sulfated CS motifs expressed in the tumoral ECM hold biomarker potential in ovarian cancer patients. These matrix motifs constitute a novel class of biomarkers with prognostic significance and may be instrumental for innovative diagnostic and therapeutic applications (e.g. targeted therapy) in management of ovarian cancer.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibody Specificity; Biomarkers, Tumor; Carcinoma; Chondroitin Sulfates; Disease-Free Survival; DNA Methylation; DNA Mutational Analysis; Epitopes; Extracellular Matrix; Female; Humans; Membrane Glycoproteins; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Ovary; Phenotype; Single-Chain Antibodies; Sulfotransferases; Survival Rate; Young Adult

Changes in the production and structure of glycosaminoglycans and proteoglycans have been reported in many neoplastic tissues, and versican and hyaluronan (extracellular matrix components) are frequently increased in tumours and promote tumour progression. The distribution of chondroitin sulphate, versican and hyaluronan in normal canine colonic wall (n=10), and normal colonic lymph nodes (n=10), colonic adenomas (n=22), colonic adenocarcinomas (n=28), colonic undifferentiated carcinomas (n=7), and colonic lymph node metastases (n=8), was examined, with antibodies against chondroitin sulphate and versican, and a specific biotinylated probe for hyaluronan. The epithelial cells of the normal colonic mucosa were negative for all three substances, whereas the stromal tissue and lamina propria were moderately positive for chondroitin sulphate and hyaluronan, and weakly positive for versican. Chondroitin sulphate expression was increased in adenomas and carcinomas. However, there was no significant correlation between grade of tumour and degree of chondroitin sulphate expression. Versican expression was increased in the peritumoral stroma of adenocarcinomas and reduced in adenomas. A significant correlation was observed between grade of tumour and degree of versican expression. In 13 adenocarcinomas and undifferentiated carcinomas with invasion into all layers of the colorectum, the intensity of stromal versican expression was significantly related to the depth of invasion; the intensity was increased in the stroma of tumour islands in deep layers of the colonic wall. Unlike versican expression, hyaluronan expression was increased in the stromal tissue of both adenomas and carcinomas. However, the degree of stromal hyaluronan expression was unrelated to tumour grade and depth of tumour invasion. Hyaluronan was also expressed in the membrane and in the cytoplasm of tumour cells in 3/22 (14%) adenomas, 18/28 (64%) adenocarcinomas and 2/7 (29%) undifferentiated carcinomas. These results suggest that altered levels of both versican and hyaluronan in canine colonic tumours affect tumour progression.

Topics: Adenoma; Animals; Biomarkers, Tumor; Carcinoma; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Colonic Neoplasms; Dog Diseases; Dogs; Hyaluronic Acid; Immunoenzyme Techniques; Lectins, C-Type; Lymph Nodes; Lymphatic Metastasis; Neoplasm Invasiveness; Versicans

The expression of increased amounts of versican, a chondroitin sulphate proteoglycan, in neoplastic tissues may play a role in promoting tumour cell proliferation and migration. This study investigated the immunolocalization of versican in normal and neoplastic canine mammary tissues, using antibodies 12C5 and 2B1, against different epitopes of the protein core of versican. Antibody CS56, recognising chondroitin sulphate (CS), was used to investigate the relation between versican and CS, which accumulates in canine mammary tumours. We found enhanced versican expression in both benign and malignant tumours, appearing in three main patterns: in periductal tissues, probably in association with basement membranes of ducts; in peripheral invasive areas of malignant tumours; and in spindle cell proliferations and myxoid areas of complex and mixed tumours. The 12C5 and 2B1 immunoreactivities co-localised in all types of tumours, and could be improved by chondroitinase digestion. The only exception was the abundant extracellular matrix (ECM) of spindle cell proliferations, particularly in myxoid areas of complex and mixed tumours, which displayed intense and diffuse 12C5 immunoreactivity and patchy or absent 2B1 and CS56 immunoreactivities; versican immunoreactivity could not be enhanced by chondroitinase digestion. The results indicate that versican is one of the extracellular matrix components characteristic of canine mammary tumours. It appears likely that in complex and mixed tumours versican exists in at least two forms, one of them lacking the CS attachment domain and the 2B1 epitope. Furthermore, the enhanced versican expression in the invasive areas of malignant tumours indicates the involvement of this proteoglycan in tumour cell invasion.

Topics: Animals; Antibodies, Monoclonal; Carcinoma; Carcinoma, Papillary; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Connective Tissue; Dogs; Female; Immunohistochemistry; Lectins, C-Type; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mixed Tumor, Malignant; Neoplasm Invasiveness; Skin; Versicans

Mammary tumours are the most common neoplasias of female dogs and may have a complex histological pattern with both epithelial and spindle cells participating in the transformation process. A frequent feature of these tumours is chondroid or bone metaplasia of the extracellular matrix, which mainly occurs in areas of proliferated spindle-shaped cells, probably of myoepithelial origin. The present study evaluates immunohistochemically the expression of tenascin in 186 surgical samples of canine mammary tissues, ranging from normality to neoplasia. Tenascin was present in all mammary tissues studied, with an increased expression in remodelling situations and in neoplastic lesions. Basement membrane was the most frequently labelled structure, but stromal tissue was more often and widely labelled in neoplastic lesions. The extracellular matrix was positive in solid and anaplastic carcinomas as well as in spindle cell proliferation areas. Tenascin expression in extracellular matrix was also abundant in areas of initial chondroid metaplasia and, with variable extension, in almost all cartilage islands of mixed tumours. In well differentiated secretory areas only apical granules of luminal cells were positive, suggesting a different pattern of tenascin expression during secretory differentiation. The digestion of chondroitin sulphate significantly improved the labelling for tenascin when a co-expression of these two molecules was present. Although our results suggest that tenascin cannot be used as a marker of transformation or of malignancy in canine mammary oncology, it is clear that this molecule plays an important role in proliferation and differentiation processes in the canine mammary gland.

Topics: Adenoma; Animals; Basement Membrane; Carcinoma; Chondroitin Sulfates; Dog Diseases; Dogs; Extracellular Matrix; Female; Hyperplasia; Immunohistochemistry; Mammary Glands, Animal; Mammary Neoplasms, Animal; Precancerous Conditions; Tenascin

The chondroitin sulfate excreted in the urine of 10 patients with cancer of the head and neck and 27 healthy subjects was analyzed. The disaccharide products formed from chondroitin sulfate excreted by these 10 patients by action of chondroitinase ABC show a significant (P < 0.0001) relative increase of nonsulfated disaccharide (35.6% +/- 5.7%) when compared with the nonsulfated disaccharide (10.0% +/- 0.9%) present in the chondroitin sulfate of 27 healthy subjects. In 6 patients the structure of the excreted compound was analyzed up to 4 months after surgery. After removal of the cancer, the percent amounts of the nonsulfated disaccharide tend to approach the values found for the chondroitin sulfate of healthy subjects. A significant (P < 0.0001) change in the ratio of urinary chondroitin sulfate and heparan sulfate and a decrease in the electrophoretic migration of chondroitin sulfate were also observed. All of the patients with head and neck cancer analyzed so far have shown this structural anomaly of urinary chondroitin sulfate. This assay may be useful in the diagnosis and follow-up of cancer therapy.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma; Chondroitin Sulfates; Chromatography; Electrophoresis; Head and Neck Neoplasms; Heparitin Sulfate; Humans; Middle Aged

Human carcinoma cells cultured in serum free medium produced an enzyme present as two different isoforms of 62 and 59 kDa which was found to degrade hyaluronan and chondroitin sulfate, with optimum activity at pH 4.0 and 0.03 M NaCl. The activity was suppressed by treatment with 250 mM apigenin and 1 mM DTT. The one-dimensional and two-dimensional gel patterns of tumor hyaluronidase differed from those of human serum hyaluronidase. Deglycosylation of tumor hyaluronidase caused nearly complete elimination of activity, suggesting the importance of sugar chains in enzymatic function. The results of treatment with neuraminidase, in addition to the findings for the enzyme mentioned above, suggest hyaluronidase from carcinoma cells and serum hyaluronidase to differ in sugar chains and/or the core protein. Tumor hyaluronidase was shown to be endo-beta-N-acetyl-D-hexosaminidase and tetrasaccharide was identified as the major product, thus indicating the tumor hyaluronidase to be a testis-type hyaluronidase.

Topics: Blood Proteins; Carcinoma; Chondroitin Sulfates; Electrophoresis, Gel, Two-Dimensional; Female; Humans; Hyaluronic Acid; Hyaluronoglucosaminidase; Isoenzymes; Lung Neoplasms; Neoplasm Proteins; Substrate Specificity; Tumor Cells, Cultured; Uterine Cervical Neoplasms

We investigated changes in the glycosaminoglycans (GAGs) during progression of a human gingival carcinoma xenograft line, GK -1, in nude mice. The GAGs extracted from cancers 3, 5, 7, 10 and 15 weeks after transplantation consisted of hyaluronic acid (HA), chondroitin sulfate (CS) and heparan sulfate (HS) as major components, and dermatan sulfate (DS) as a trace component for all cancers. HPLC analysis revealed that the HA content per defatted tissue dry weight increased in the cancers 5 weeks after transplantation compared to those of 3 weeks (p < 0.05), while CS for cancers at 10 weeks decreased compared with 7 weeks (p < 0.05). However, HS showed no significant change. Both the CS and DS contained primarily 4-sulfated disaccharide units. Immunohistochemical staining with antibody 2-B-6 for the PGs having delta DI-4S produced by chondroitinase ABC digestion showed that CS is located in the tissue surrounding the cancer nests and mass. These results indicate that the location of accumulation of CS, which primarily contains 4-sulfated disaccharide units, plays an important role in cancer progression.

Topics: Animals; Carcinoma; Chondroitin Sulfates; Chromatography, High Pressure Liquid; Dermatan Sulfate; Disaccharides; Disease Progression; Female; Gingival Neoplasms; Glycosaminoglycans; Heparitin Sulfate; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Neoplasm Transplantation; Tumor Cells, Cultured

Using a modified papain digestion cetylpyridinium salt precipitation method, glycosaminoglycans were isolated from 21 mesotheliomas, 34 primary lung carcinomas, 12 carcinomas of other sites, and 7 soft tissue sarcomas. Qualitatively, hyaluronic acid (HA) was present in 20 of 21 mesotheliomas, about half of the primary lung adenocarcinomas, and all of the soft tissue sarcomas. On the average, HA constituted 45% of the total glycosaminoglycans in the mesotheliomas and 28% of the total in the lung cancers. Quantitatively, mesotheliomas contained statistically greater amounts (mean value, 0.74 mg/g) of HA than primary lung adenocarcinomas (mean value, 0.08 mg/g), but were not statistically different from soft tissue sarcomas (mean value, 2.01 mg/g) or primary ovarian serous neoplasms (mean value, 0.92 mg/g). The study concludes that, contrary to previous reports, HA is neither the sole nor the predominant glycosaminoglycan in most mesotheliomas, but, given the proper clinical and histologic setting, the finding of sufficiently high levels (greater than 0.4 mg/g dry tissue extract) supports the diagnosis of mesothelioma when the alternative diagnosis is primary adenocarcinoma of lung.

Topics: Adenocarcinoma; Carcinoma; Chondroitin Sulfates; Dermatan Sulfate; Diagnosis, Differential; Electrophoresis, Cellulose Acetate; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Lung Neoplasms; Mesothelioma; Ovarian Neoplasms; Sarcoma