chondroitin-sulfates and Adenocarcinoma

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Chondroitin Sulfates; Docetaxel; Drug Carriers; Half-Life; Humans; Hyaluronan Receptors; Inhibitory Concentration 50; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Nanoparticles; NIH 3T3 Cells; Particle Size; PC-3 Cells; Prostatic Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays; Zein

Glycans play a critical role in physiological and pathological processes through interaction with a variety of ligands. Altered expression and dysregulation of these molecules can cause aberrant cellular function such as malignancy. Glycomics provide information of the structure and function of glycans, glycolipids, and glycoproteins such as proteoglycans, and may help to predict cancer development and progression as biomarkers. In this report, we compared the expression of proteoglycans, the content and structure of glycosaminoglycans and glycolipids between patient-matched normal and cancer tissues obtained from colon cancer patients. Tumor-related proteoglycans, glypican-3, and syndecan-1 showed downregulation in cancer tissues compared to normal tissues. In cancer tissue, the total amount of chondroitin sulfate (CS)/dermatan sulfate and heparan sulfate were lower and, interestingly, the level of disaccharide units of both 4S6S (CS-E) and 6S (CS-C) were higher compared to normal tissue. Also, overall lipids including glycolipids, a major glycomics target, were analyzed by hydrophilic interaction liquid chromatography mass spectrometry. Increase of lyso-phosphatidylcholine (phospholipid), sphingomyelin (sphigolipid), and four types of glycolipids (glucosylceramide, lactosylceramide, monosialic acid ganglioside, and globoside 4) in cancer tissue showed the possibility as potential biomarkers in colon cancer. While requiring the need for careful interpretation, this type of broad investigation gives us a better understanding of pathophysiological roles on glycosaminoglycans and glycolipids and might be a powerful tool for colon cancer diagnosis.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antigens, CD; Biomarkers; Carbohydrate Sequence; Case-Control Studies; Chondroitin Sulfates; Colonic Neoplasms; Dermatan Sulfate; Female; Gangliosides; Gene Expression Regulation, Neoplastic; Globosides; Glucosylceramides; Glypicans; Heparitin Sulfate; Humans; Lactosylceramides; Lysophosphatidylcholines; Male; Middle Aged; Molecular Sequence Data; Sphingomyelins; Syndecan-1

Heparin is an excellent inhibitor of P- and L-selectin binding to the carbohydrate determinant, sialyl Lewis(x). As a consequence of its anti-selectin activity, heparin attenuates metastasis and inflammation. Here we show that fucosylated chondroitin sulfate (FucCS), a polysaccharide isolated from sea cucumber composed of a chondroitin sulfate backbone substituted at the 3-position of the beta-D-glucuronic acid residues with 2,4-disulfated alpha-L-fucopyranosyl branches, is a potent inhibitor of P- and L-selectin binding to immobilized sialyl Lewis(x) and LS180 carcinoma cell attachment to immobilized P- and L-selectins. Inhibition occurs in a concentration-dependent manner. Furthermore, FucCS was 4-8-fold more potent than heparin in the inhibition of the P- and L-selectin-sialyl Lewis(x) interactions. No inhibition of E-selectin was observed. FucCS also inhibited lung colonization by adenocarcinoma MC-38 cells in an experimental metastasis model in mice, as well as neutrophil recruitment in two models of inflammation (thioglycollate-induced peritonitis and lipopolysaccharide-induced lung inflammation). Inhibition occurred at a dose that produces no significant change in plasma activated partial thromboplastin time. Removal of the sulfated fucose branches on the FucCS abolished the inhibitory effect in vitro and in vivo. Overall, the results suggest that invertebrate FucCS may be a potential alternative to heparin for blocking metastasis and inflammatory reactions without the undesirable side effects of anticoagulant heparin.

Topics: Adenocarcinoma; Animals; Anticoagulants; Carbohydrate Conformation; Cell Adhesion; Chondroitin Sulfates; Disease Models, Animal; Dose-Response Relationship, Drug; Heparin; L-Selectin; Lipopolysaccharides; Lung Neoplasms; Mice; Neoplasm Metastasis; Neoplasms, Experimental; Neutrophil Infiltration; P-Selectin; Partial Thromboplastin Time; Peritonitis; Pneumonia; Sea Cucumbers; Thioglycolates

Chondroitin sulfate (CS) is abundantly present in the tumor stroma, and tumor-specific CS modifications might be potential targets to influence tumor development. We applied the phage display technology to select antibodies that identify these tumor-specific CS modifications. Antibody GD3G7 was selected against embryonic glycosaminoglycans, and it reacted strongly with CS-E (rich in GlcA-GalNAc4S6S units). In ovarian adenocarcinomas, strong expression of this CS-E epitope was found in the extracellular matrix, and occasionally on tumor cells. No expression was found in normal ovary and cystadenomas. Differential expression was found in ovarian carcinoma cell lines, which correlated with the gene expression of the GalNAc4S-6st enzyme, involved in biosynthesis of CS-E. Vascular endothelial growth factor (VEGF)-sensitive fenestrated (in normal tissues) and tumor blood vessels were both identified by antibody GD3G7, which might implicate a role for CS-E in VEGF biology. VEGF bound to CS-E and antibody GD3G7 could compete for binding of VEGF to CS-E. In conclusion, antibody GD3G7 identified rare CS-E-like structures that were strongly expressed in ovarian adenocarcinomas. This antibody might therefore be instrumental for identifying tumor-related CS alterations.

Topics: Adenocarcinoma; Animals; Antibodies, Neoplasm; Cell Line, Tumor; Chondroitin Sulfates; Epitopes; Female; Gene Expression; Glycosaminoglycans; Humans; Membrane Glycoproteins; Mice; Ovarian Neoplasms; Peptide Library; Rats; Sulfotransferases; Up-Regulation; Vascular Endothelial Growth Factor A

The disease course of localized prostate cancer is highly variable, and patients potentially curable by aggressive management are not readily identified by current clinical practice. Chondroitin sulfate (CS) glycosaminoglycan is a candidate biomarker as elevated levels of CS in peritumoral stroma of prostate cancer have been associated with prostate-specific antigen (PSA) failure. Immunoreactive CS was measured using image analysis of archived radical prostatectomy tissues, obtained from 157 men with a median of 47 months (range, 16-111 months) clinical follow-up. CS level, Gleason score, and preoperative serum PSA levels were independent predictors of PSA failure by Cox's multivariate analysis. Patients with low CS levels had significantly fewer PSA failures after radical prostatectomy than patients with high levels of CS (Kaplan-Meier plot; 32% PSA failures at 5 years for CS mean integrated absorbance cut point < 7.0 versus 50% for CS > or = 7.0, P = 0.0001). In the subgroup of patients with preoperative serum PSA levels < 10 ng/ml, CS was particularly useful in discriminating retrospectively those patients most suited for surgery (Kaplan-Meier plot; 14% PSA failures at 5 years for CS mean integrated absorbance cut point < 7.0 versus 47% for CS > or = 7.0, P = 0.0001). We conclude that measurements of CS level can assist in predicting patient outcome after surgery. Additionally, our data suggest that the combination of CS and PSA measurements may improve outcome prediction for patients with intermediate Gleason scores.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; Chondroitin Sulfates; Cohort Studies; Disease Progression; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Life Tables; Male; Middle Aged; Neoplasm Staging; Prognosis; Proportional Hazards Models; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Severity of Illness Index; Survival Analysis

To follow the biodistribution of exogenous hyaluronan in tumor-bearing animals, a total of seventeen inbred rats with hepatic metastases from a colonic adenocarcinoma received 125I-labelled hyaluronan by intravenous injections. Group I received only labeled hyaluronan (25 microg), whereas group II received 2.5 mg chondroitin sulphate prior to labeled hyaluronan, to block receptor uptake in normal liver endothelial cells. Animals in group III received intravenous, as well as intraperitoneal chondroitin sulphate (2.5 mg), to see if a better and prolonged blocking could be achieved. Radioactivity was visualized by whole body autoradiography, using phosphorimaging and the average radioactivity determined as phosphoimaging density units of the total area of hepatic metastases, normal liver, and skeletal muscle by computer-based image analysis. At 5 h, tumors in groups II and III showed higher uptake (4.8+/-1.8, P = .01 and 3.6+/-1.1, P = .01, respectively), in comparison to group I (1.8+/-0.6), and the mean normal liver/tumor concentration ratio was reduced from 21.4+/-10.1 in group I to 5.7+/-2.7 in group II and 3.5+/-1.1 in group III (P = .008 and P = .01, respectively). Our study shows that hyaluronan targets liver metastases of a colon adenocarcinoma. Furthermore, chondroitin sulphate pretreatment increases tumor uptake, while uptake at normal receptor sites is significantly reduced. The results also suggest that after blocking of normal hyaluronan/chondroitin sulphate receptors in healthy tissue, hyaluronan may be used to deliver drugs to specific hyaluronan receptor-positive sites of pathology.

Topics: Adenocarcinoma; Animals; Autoradiography; Chondroitin Sulfates; Colonic Neoplasms; Female; Hyaluronan Receptors; Hyaluronic Acid; Image Processing, Computer-Assisted; Iodine Radioisotopes; Liver Neoplasms, Experimental; Neoplasm Metastasis; Rats; Rats, Wistar; Tissue Distribution; Tumor Cells, Cultured

Topics: Adenocarcinoma; Basement Membrane; Cell Differentiation; Chondroitin Sulfates; Eccrine Glands; Fluorescent Antibody Technique; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Proteoglycans; Sweat Gland Neoplasms

In order to elucidate the gross composition of fibrous stroma and to better understand the obstructive nature of advanced human colonic cancers the extracellular matrix components of its stroma were analyzed immunohistologically, emphasizing the process of fibrosis and possible tissue constriction. Collagenous material, identified by Masson's trichrome stain, was distributed mainly in the invasive area, where type I and III collagens and chondroitin 4-sulfate stained intensely in the periacinar area, and further, fibronectin stained. Conversely, in the invasive area away from tumor acini type III collagen stained weakly and fibronectin not at all. Type V collagen and myofibroblasts stained in the periacinar area and did not stain in the invasive area away from tumor acini, the findings of myofibroblasts being prominent in cases with obstructive type carcinomas. In conclusion, the invasive area, especially the periacinar area, displayed signs of active ongoing fibrosis and tissue contraction, which may be responsible for the genesis of obstructing type colonic carcinomas.

Topics: Adenocarcinoma; Chondroitin Sulfates; Collagen; Colon; Colonic Neoplasms; Extracellular Matrix; Fibronectins; Fibrosis; Humans; Immunoenzyme Techniques

We report a case of a secretory carcinoma of the breast in a 72-year-old woman with a long history of a left breast mass. Rapid growth and skin invasion of the tumor was noticed three months before a radical mastectomy was performed and a lung metastasis was found one month after the operation. A metastasis to the axillary nodes was noted in 6 of 9 resected specimens and a receptor assay of the estrogen and progesterone proved to be negative. This patient is the oldest case of a secretory carcinoma of the breast reported in Japan.

Topics: Adenocarcinoma; Aged; Breast Neoplasms; Chondroitin Sulfates; Female; Humans; Hyaluronic Acid; Lung Neoplasms; Lymphatic Metastasis; Mastectomy, Radical; Neoplasm Invasiveness; Skin

The proteoglycans secreted by a malignant human breast cell line (MDA-MB-231) were compared with the corresponding proteoglycans from a normal human breast cell line (HBL-100). The physicochemical characteristics of these proteoglycans were established by hexosamine analysis, chemical and enzymatic degradations, and dissociative cesium chloride density gradient centrifugation, and by gel filtration before and after alkaline beta-elimination. Both cell lines secreted approximately 70% of the synthesized proteoglycans, which were composed of 20% heparan sulfate and 80% chondroitin sulfate proteoglycans. The MDA cell line secreted large hydrodynamic size (major) and small hydrodynamic size heparan sulfate proteoglycan. In contrast HBL cells secreted only one species having a hydrodynamic size intermediate to the above two. The chondroitin sulfate proteoglycans from MDA medium were slightly larger than the corresponding polymers from HBL medium. All proteoglycans except the small hydrodynamic size heparan sulfate proteoglycan from MDA medium were of high buoyant density. The proteoglycans of both cell lines contained significant proportions of disulfide-linked lower molecular weight components which were more pronounced in the proteoheparan sulfate polymers, particularly those from MDA medium, than in chondroitin sulfate proteoglycans. The glycosaminoglycans of heparan sulfate proteoglycans from MDA medium were more heterogeneous than those from HBL medium. The glycosaminoglycan chains of large hydrodynamic size heparan sulfate proteoglycans from MDA medium were larger in size than those from HBL medium while small hydrodynamic size heparan sulfate proteoglycans contained shorter glycosaminoglycan chains. In contrast to the glycosaminoglycans derived from chondroitin sulfate proteoglycans of both MDA and HBL medium were comparable in size. The heparan sulfate as well as chondroitin sulfate proteoglycans of both cell lines contained both neutral (di- and tetrasaccharides) and sialylated (tri- to hexasaccharides) O-linked oligosaccharides.

Topics: Adenocarcinoma; Breast; Breast Neoplasms; Carbohydrate Conformation; Cell Line; Centrifugation, Density Gradient; Chondroitin Sulfates; Chromatography, Gel; Disulfides; Epithelium; Female; Galactosamine; Glucosamine; Glycosaminoglycans; Heparitin Sulfate; Humans; Molecular Weight; Oligosaccharides; Proteoglycans

The sulfated glycosaminoglycan (SGAG) composition of gastric mucosa from 24 patients with chronic superficial gastritis, 2 patients with adenocarcinoma and 36 normal subjects is reported. The mucosa was obtained by endoscopic biopsy and after histopathological examination the SGAG were extracted and characterized. Three different SGAG were isolated: chondroitin 4,6-sulfate, dermatan sulfate and heparan sulfate. Their relative concentrations for the different groups were submitted to analysis of variance by Scheffe's method. Different SGAG compositions were observed in two gastric regions (antrum and body), in chronic superficial gastritis, in adenocarcinoma and in two age groups (less than 40 years and greater than 40 years). These and other results suggest that these macromolecules might be involved in the processes of cell division and aging.

Topics: Adenocarcinoma; Adult; Aging; Chondroitin Sulfates; Dermatan Sulfate; Gastric Mucosa; Gastritis; Glycosaminoglycans; Heparitin Sulfate; Humans; Stomach Neoplasms

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

The influence of fixed fibroblasts on the glycosaminoglycan (GAG) synthesis of gastric carcinoma cells was examined by incubation along with [3H]glucosamine. In well-differentiated adenocarcinoma cells, the amount of 3H-GAG in the interface material between the carcinoma cells and the fixed fibroblasts was much larger (about twenty times) than in the interface between the carcinoma cells and the bare culture plates, and 3H-GAG consisted mainly of heparan sulfate, with a small amount of dermatan sulfate and chondroitin sulfate. On the other hand, in poorly differentiated carcinoma cells, the amount of 3H-GAG in the interface material produced by the carcinoma cells on the fibroblast was almost the same as on the bare culture dish. In a conventional monolayer culture, well-differentiated adenocarcinoma cells produced a much greater amount of GAG, consisting mainly of dermatan sulfate, chondroitin sulfate and heparan sulfate, than poorly differentiated carcinoma cells. Almost the same amount of hyaluronic acid was secreted into the medium by both types of carcinoma cells.

Topics: Adenocarcinoma; Cell Adhesion; Cell Communication; Cell Differentiation; Cell Division; Cell Line; Chondroitin Sulfates; Dermatan Sulfate; Fibroblasts; Glycosaminoglycans; Heparitin Sulfate; Humans; Stomach Neoplasms

A transplantable colorectal adenocarcinoma and the normal colonic mucosa derived from rats of ACI/N strain were digested with pronase, and the glycosaminoglycan fractions were obtained by fractionation with cetylpyridinium chloride. The glycosaminoglycan fraction derived from the adenocarcinoma contained substantial amounts of chondroitin sulfate A/C, dermatan sulfate, heparan sulfate, and hyaluronic acid, whereas chondroitin sulfate A/C and dermatan sulfate were undetectable in that derived from the normal colonic mucosa. An increment in the heparan sulfate content was also apparent in the adenocarcinoma, while the level of hyaluronic acid appeared to be unchanged. Analyses of the extract of the tumor tissue with 5mM ethylenediaminetetraacetate (pH 7.0) indicated that heparan sulfate was present largely, if not completely, in the form of proteoglycan.

Topics: Adenocarcinoma; Animals; Chemical Fractionation; Chondroitin Sulfates; Colon; Colonic Neoplasms; Dermatan Sulfate; Glycosaminoglycans; Heparitin Sulfate; Hyaluronic Acid; Mucous Membrane; Neoplasms, Experimental; Rats; Rats, Inbred ACI; Rectal Neoplasms

The quantitative changes of glycosaminoglycans in tumor tissue of human lung cancers (2 squamous cell carcinomas, 4 adenocarcinomas and 5 small cell carcinomas) were studied. The total amount of glycosaminoglycans in human lung cancer tissues increased 1.4 to 4 times in comparison with that in normal lung tissues. The increase in tissue content of glycosaminoglycans was accompanied by an increase in the chondroitin sulfate level in every histologic type of lung cancer, as well as by a marked increase in hyaluronic acid level in squamous cell carcinomas, and a moderate increase in its level in small cell carcinomas. The concentrations of dermatan sulfate and heparan sulfate in lung cancer tissues did not show any significant changes compared with those in normal lung tissues. The increase in total amount and changes in the composition of glycosaminoglycans in human lung cancer tissue were closely related to the histologic type of the tumor.

Topics: Adenocarcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chondroitin Sulfates; Dermatan Sulfate; Electrophoresis, Cellulose Acetate; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Lung Neoplasms

The glycosaminoglycans from normal colonic mucosa and colons with a variety of inflammatory diseases, as well as benign and malignant neoplasms were analyzed. Normal colonic mucosa contains predominantly chondroitin sulfates and dermatan sulfate. Increases in the levels of hyaluronic acid and heparan sulfate, as well as substantial increases in the amount of total glycosaminoglycans were characteristic of invasive colonic adenocarcinoma. Lesser elevations in the amount of total glycosaminoglycans and hyaluronic acid and heparan sulfate were present in neonatal colonic mucosa, villous adenoma, ulcerative colitis, and mucosa adjacent to carcinoma. The degree of elevation was proportional to the dysplastic potential. Since dysplastic lesions have scant connective tissue, the epithelial component of colonic neoplasms may contribute to these neoplasm-related alterations in glycosaminoglycan composition.

Topics: Adenocarcinoma; Adult; Aged; Chondroitin Sulfates; Colitis; Colon; Colonic Neoplasms; Dermatan Sulfate; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Intestinal Mucosa; Male; Middle Aged

Normal, transitional, and carcinoma areas of five colons resected for carcinoma were examined morphologically, histochemically, and biochemically. The transitional area contained a larger amount of non-sulphated acid mucin than the normal mucosa as verified histochemically. Normal mucosa contained mainly sulphated mucin. The hexosamine-containing macromolecules present in different areas were isolated and characterized. They were divided into the following groups: 1) acid glycosaminoglycans, 2) high-molecular-weight glycopeptides, and 3) low-molecular weight glycopeptides. The concentration of the total hexosamine-containing material was in the carcinoma area twice as high as in normal areas. Acid glycosaminoglycans were identified as hyaluronate, heparan sulphate, dermatan sulphate, and chondroitin 4-(6)-sulphate. Their concentraitons were found to increase from normal to transitional and from transitional to carcinoma areas. The high-molecular-weight glycopeptide was composed of fucose, galactose, glucosamine, galactosamine, sialic acid, and variable amounts of sulphate. The sulphation degree of the glycopeptide was higher in normal mucosa than in transitional or carcinoma areas: The low-molecular-weight glycopeptides consisted of about a half of the total hexosamine-containing substances. The concentration of saline-insoluble fraction of the low-molecular-weight glycopeptides was in transitional areas about two times, and in carcinoma areas about four times, higher than in normal mucosa.

Topics: Adenocarcinoma; Chondroitin Sulfates; Colonic Neoplasms; Dermatan Sulfate; Fucose; Galactosamine; Galactose; Glucosamine; Glycopeptides; Glycosaminoglycans; Heparitin Sulfate; Hexosamines; Histocytochemistry; Humans; Hyaluronic Acid; Intestinal Mucosa; Macromolecular Substances; Molecular Weight; Mucins; Sialic Acids; Sulfates

The glycosaminoglycans were prepared by exhaustive Pronase digestion and alkaline treatment of squamous cell carcinoma and adenocarcinoma tissues of human lung, and of tissues taken at a site distant from the tumor as a control. The glycosaminoglycan classes were characterized by chemical enzymic, and electrophoretic methods. The presence of oversulfated chondroitin-and/or dermatan-sulfates which have not up till now been found in lung tissues was also demonstrated in carcinoma and control tissues, their contents being higher in the carcinoma tissues. The levels of whole glycosaminoglycans were markedly increased in carcinoma tissue. The classes of glycosaminoglycans which increased in lung carcinoma tissue were predominatly chondroitin-4-and/or-6-sulfates and hyauronic acid.

Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Chondroitin Sulfates; Glycopeptides; Glycosaminoglycans; Heparitin Sulfate; Hexosamines; Humans; Hyaluronic Acid; Lung; Lung Neoplasms; Sulfates