alpha-Neup5Ac-(2--3)-beta-D-Galp-(1--4)-[alpha-L-Fucp-(1--3)]-D-GlcpNAc and Cell-Transformation--Neoplastic

Malignant transformation is associated with abnormal glycosylation, resulting in the synthesis and expression of altered carbohydrate determinants including sialyl Lewisa and sialyl Lewisx. The sialyl Lewisa and sialyl Lewisx determinants appear in the sera of patients with cancer, and are extensively utilized for serum diagnosis of cancers in Japan. Sialyl Lewisa and sialyl Lewisx are involved in selectin-mediated adhesion of cancer cells to vascular endothelium, and these determinants are thought to be closely associated with hematogenous metastasis of cancers. Recent progress in this area includes the following: 1. Substantial increases in solid clinical statistics that further confirm the contribution of these determinants in the progression of a wide variety of cancers; 2. Elucidation of the ligand specificity of the three family members of selectins and evaluation of the roles of these molecules in cancer cell adhesion; and 3. Advances in the study of the mechanism that leads to the enhanced expression of the sialyl Lewis(a/x) determinants in malignant cells. These recent results have confirmed that these determinants are not merely markers for cancers, but are functionally implicated in the malignant behavior of cancer cells. The results also suggested that the increase of these determinants in malignant cells is an inevitable consequence of the malignant transformation of cells. Considerable new knowledge has also been accumulated regarding the therapeutic implications for suppression of hematogenous metastasis targeting this cell adhesion system.

Topics: Antigens, Tumor-Associated, Carbohydrate; Biomarkers, Tumor; CA-19-9 Antigen; Carbohydrate Metabolism; Cell Adhesion; Cell Transformation, Neoplastic; Endothelium; Gangliosides; Humans; Lewis Blood Group Antigens; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Oligosaccharides; Selectins; Sialyl Lewis X Antigen

Cell adhesion mediated by selectins and their carbohydrate ligands, sialyl Lewis X and sialyl Lewis A, figures heavily in cancer metastasis. Expression of these carbohydrate determinants is markedly enhanced in cancer cells, but the molecular mechanism that leads to cancer-associated expression of sialyl Lewis X/A has not been well understood. Results of recent studies indicated involvement of two principal mechanisms in the accelerated expression of sialyl Lewis X/A in cancers; 'incomplete synthesis' and ' neo synthesis.' As to 'incomplete synthesis,' we have recently found further modified forms of sialyl Lewis X and sialyl Lewis A in non-malignant colonic epithelium, which have additional 6-sulfation or 2 --> 6 sialylation. The impairment of GlcNAc 6-sulfation and 2 --> 6 sialylation upon malignant transformation leads to accumulation of sialyl Lewis X/A in colon cancer cells. Epigenetic changes such as DNA methylation and/or histone deacetylation are suggested to lie behind such incomplete synthesis. As to the mechanism called ' neo synthesis,' recent studies have indicated that cancer-associated alterations in the sugar transportation and intermediate carbohydrate metabolism play important roles. Cancer cells are known to exhibit a metabolic shift from oxidative to elevated anaerobic glycolysis (Warburg effect), which is correlated with the increased gene expression of sugar transporters and glycolytic enzymes induced by common cancer-specific genetic alterations. The increased sialyl Lewis X/A expression in cancer is a link in the chains of these events because our recent results indicated that these events accompany transcriptional induction of a set of genes closely related to its expression.

Topics: Animals; Biomarkers, Tumor; CA-19-9 Antigen; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Oligosaccharides; Sialyl Lewis X Antigen

In patients with chronic Helicobacter pylori (H pylori) infection, parietal and chief cell atrophy in the gastric corpus, a process known as spasmolytic polypeptide-expressing metaplasia (SPEM), increases the risk for progression to cancer. The relation between H pylori and these metaplastic changes is unclear. We investigated whether H pylori localizes to regions of SPEM.. We developed an in situ adherence assay in which we incubated H pylori with free-floating tissue sections from the gastric corpora of mice; we assessed H pylori distribution along the gastric unit by immunofluorescence. We analyzed the interactions of H pylori with tissue collected from mice with acute SPEM, induced by high-dose tamoxifen. We also evaluated how adhesin-deficient H pylori strains, chemical competition assays, and epithelial glycosylation affected H pylori adhesion to SPEM glands. Mice colonized with the mouse-adapted PMSS1 strain were analyzed for H pylori colonization in vivo during tamoxifen-induced SPEM or after decrease of stomach acid with omeprazole.. Compared with uninjured glands, H pylori penetrated deep within SPEM glands, in situ, through interaction of its adhesin, SabA, with sialyl-Lewis X, which expanded in SPEM. H pylori markedly increased gastric corpus colonization when SPEM was induced, but this proximal spread reversed in mice allowed to recover from SPEM. Decreasing corpus acidity also promoted proximal spread. However, H pylori penetrated deep within corpus glands in vivo only when sialyl-Lewis X expanded during SPEM.. Helicobacter pylori differentially binds SPEM glands in situ and in mice, in large part by interacting with sialyl-Lewis X. Our findings indicate that H pylori expands its niche into the gastric corpus by promoting and exploiting epithelial metaplastic changes that can lead to tumorigenesis.

Topics: Adhesins, Bacterial; Animals; Bacterial Adhesion; Cell Transformation, Neoplastic; Disease Models, Animal; Female; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Host-Pathogen Interactions; Humans; Intercellular Signaling Peptides and Proteins; Lewis X Antigen; Male; Metaplasia; Mice; Peptides; Sialyl Lewis X Antigen

The risk of progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is low and difficult to calculate. Accurate tools to determine risk are needed to optimize surveillance and intervention. We assessed the ability of candidate biomarkers to predict which cases of BE will progress to EAC or high-grade dysplasia and identified those that can be measured in formalin-fixed tissues.. We analyzed data from a nested case-control study performed using the population-based Northern Ireland BE Register (1993-2005). Cases who progressed to EAC (n = 89) or high-grade dysplasia ≥ 6 months after diagnosis with BE were matched to controls (nonprogressors, n = 291), for age, sex, and year of BE diagnosis. Established biomarkers (abnormal DNA content, p53, and cyclin A expression) and new biomarkers (levels of sialyl Lewis(a), Lewis(x), and Aspergillus oryzae lectin [AOL] and binding of wheat germ agglutinin) were assessed in paraffin-embedded tissue samples from patients with a first diagnosis of BE. Conditional logistic regression analysis was applied to assess odds of progression for patients with dysplastic and nondysplastic BE, based on biomarker status.. Low-grade dysplasia and all biomarkers tested, other than Lewis(x), were associated with risk of EAC or high-grade dysplasia. In backward selection, a panel comprising low-grade dysplasia, abnormal DNA ploidy, and AOL most accurately identified progressors and nonprogressors. The adjusted odds ratio for progression of patients with BE with low-grade dysplasia was 3.74 (95% confidence interval, 2.43-5.79) for each additional biomarker and the risk increased by 2.99 for each additional factor (95% confidence interval, 1.72-5.20) in patients without dysplasia.. Low-grade dysplasia, abnormal DNA ploidy, and AOL can be used to identify patients with BE most likely to develop EAC or high-grade dysplasia.

Topics: Adenocarcinoma; Aged; Aneuploidy; Barrett Esophagus; Biomarkers; CA-19-9 Antigen; Case-Control Studies; Cell Transformation, Neoplastic; Cyclin A; Esophageal Neoplasms; Female; Humans; Immunohistochemistry; Lectins; Logistic Models; Male; Middle Aged; Multivariate Analysis; Northern Ireland; Oligosaccharides; Precancerous Conditions; Registries; Risk Assessment; ROC Curve; Sialyl Lewis X Antigen; Tumor Suppressor Protein p53; Wheat Germ Agglutinins

The glycoconjugates expressed by cancer cells frequently contain sialylated oligosaccharide chains. Among these oligosaccharides the sialyl Lewis a (sLe(a)) and sialyl Lewis x (sLe(x)) antigens are found to be overexpressed in tumours of different origin. The current study assesses sLe(a) and sLe(x) expression in different colorectal specimens in order to establish the correlation of these biomarkers with both malignant transformation of colorectal mucosa and the progression of colorectal cancer (CRC). Healthy disease-free and inflammatory mucosa specimens showed no presence of the antigens. sLe(a) was expressed in 6.7% of the healthy tissue from CRC patients, in 20.8% of the adenomas, and in 33.3% and 42.6% of the transitional tissue and tumour tissue, respectively. sLe(x) expression was observed in 6.7% of the healthy tissue from CRC patients, in 27.0% of the adenomas, and in 25.6% and 74.8% of the transitional and the tumour tissue, respectively. The expression of the sLe(a) and sLe(x) antigens was correlated in adenomas, as well as in healthy and tumour tissue from CRC. Moreover, the high expression of sLe(x) in adenomas was correlated with a high degree of dysplasia (p=0.042). Finally, the survival analysis suggested that sLe(a) expression may be a prognostic factor for predicting disease-free survival in colorectal cancer (p=0.012).

Topics: Adenocarcinoma; Adenoma; Biomarkers, Tumor; CA-19-9 Antigen; Cell Transformation, Neoplastic; Colorectal Neoplasms; Disease-Free Survival; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Neoplasm Staging; Oligosaccharides; Prognosis; Sialyl Lewis X Antigen

The process of metastasis involves a series of steps and interactions between the tumor embolus and the microenvironment. Key alterations in adhesion molecules are known to dictate progression from the invasive to malignant phenotype followed by colonization at a distant site. The invasive phenotype results from the loss of expression of the E-cadherin adhesion molecule, whereas the malignant phenotype is associated with an increased expression of the carbohydrate ligand-binding epitopes, (e.g. Sialyl Lewis (x/a)) that bind endothelial E-selectin of the lymphatics and vasculature.. Our study analyzed the expression of two adhesion molecules, E-cadherin and Sialyl Lewis x (sLe(x)), in both a canine mammary carcinoma and human inflammatory breast cancer (IBC) model, using double labelled immunofluorescence staining.. Our results demonstrate that canine mammary carcinoma and human IBC exhibit an inversely correlated cellular expression of E-cadherin and sLe(x) within the same tumor embolus.. Our results in these two comparative models (canine and human) suggest the existence of a biologically coordinated mechanism of E-cadherin and sLe(x) expression (i.e. molecular plasticity) essential for tumor establishment and metastatic progression.

Topics: Animals; Cadherins; Cell Line, Tumor; Cell Transformation, Neoplastic; Disease Models, Animal; Dogs; Female; Humans; Mammary Neoplasms, Experimental; Oligosaccharides; Sialyl Lewis X Antigen

Sialyl Lewis x (sLex) antigen is a carbohydrate antigen that is considered not only a marker for cancer but also implicated functionally in the malignant behaviour of cancer cells. Overexpression of sLex is associated with enhanced progression and metastases of many types of cancer including those of the mammary gland. Canine mammary tumours can invade and give rise to metastases via either lymphatic or blood vessels.E-Cadherin is specifically involved in epithelial cell-to-cell adhesion. In cancer, E-Cadherin underexpression is one of the alterations that characterizes the invasive phenotype and is considered an invasion/tumour suppressor gene. Partial or complete loss of E-Cadherin expression correlates with poor prognosis in canine malignant mammary cancer. The aim of this study was to analyse the sLex expression in canine malignant mammary tumours and to evaluate if the presence of sLex correlates with the expression of E-Cadherin and with clinicopathological features.. Fifty-three cases of canine mammary carcinomas were analysed immunohistochemically using monoclonal antibodies against sLex (IgM) and E-Cadherin (IgG). The clinicopathological data were then assessed to determine whether there was a correlation with sLex tumour expression. Double labelled immunofluorescence staining was performed to analyse the combined expression of sLex and E-Cadherin.. sLex expression was consistently demonstrated in all cases of canine mammary carcinomas with different levels of expression. We found a significant relationship between the levels of sLex expression and the presence of lymph node metastases. We also demonstrated that when E-Cadherin expression was increased sLex was reduced and vice-versa. The combined analysis of both adhesion molecules revealed an inverse relationship.. In the present study we demonstrate the importance of sLex in the malignant phenotype of canine malignant mammary tumours. Our results support the use of sLex as a prognostic tumour marker in canine mammary carcinomas. Furthermore, we showed that sLex and E-Cadherin expression were inversely correlated. Future studies are warranted to clarify the molecular mechanism underlying the relation between sLex and E-Cadherin in canine mammary carcinoma cells which represents an important comparative model to woman breast cancer.

Topics: Animals; Biomarkers, Tumor; Biopsy, Needle; Cadherins; Cell Transformation, Neoplastic; Dogs; Female; Gene Expression Regulation, Neoplastic; Immunohistochemistry; Mammary Neoplasms, Animal; Models, Animal; Neoplasm Invasiveness; Neoplasm Staging; Oligosaccharides; Probability; Random Allocation; Reference Values; Sensitivity and Specificity; Sialyl Lewis X Antigen

Increased expression of sialyl Lewis antigens, sLe(a) and sLe(x), is frequent during malignant transformation and tumor progression of gastrointestinal cancers and it is assumed to be correlated with the increased metastatic potential of tumor cells and, consequently, with poor patient survival. To determine the influence of the increased expression of these antigens in disease progression of ductal carcinoma of the pancreas, immunohistochemical expressions of sLe(x) and sLe(a) in 51 ductal carcinomas of the pancreas were examined. We also examined the expression of glycosyltransferase genes, which are involved in the synthetic pathways of these antigens to understand the molecular mechanism involved in the increased expression of these antigens. Of the 51 primary ductal carcinomas of the pancreas, 40 (78.4%) were sLe(a)-positive and 11 (21.6%) were sLe(a)-negative; 16 (31.4%) were sLe(x)-positive and 35 (68.6%) were sLe(x)-negative. Although there were no significant differences in any examined clinicopathological factors such as age, sex, histological type, tumor size, presence of lymph node metastasis, or presence of vessel invasion between the positive and negative groups with both the sLe(a) and sLe(x) antigens, patient survival tended to be worse in the antigens-positive group than in the antigens-negative group. Increased expression, however, was not dependent on the increased expression of a single glycosyltransferase gene examined among five such genes, which are postulated to be responsible for the synthesis of the sLe(a) and sLe(x) epitopes in the glycosylation pathway. Furthermore, the increased expression of these antigens was not closely associated with mutations status of the K-ras or p53 genes. These findings suggested that increased expression of sialyl Lewis antigens are involved in pancreatic tumorigenesis and that the accumulation of genetic alterations or epigenetic changes is responsible for the molecular mechanisms of increased expression of the sLe(a) and sLe(x) antigens in ductal carcinomas of pancreas.

Topics: Adenocarcinoma; Adult; Aged; Antigens, Neoplasm; CA-19-9 Antigen; Cell Transformation, Neoplastic; DNA Mutational Analysis; Female; Gangliosides; Gene Expression Regulation, Neoplastic; Genes, p53; Genes, ras; Glycosylation; Glycosyltransferases; Humans; Male; Middle Aged; Neoplasm Proteins; Pancreatic Neoplasms; Prognosis; Protein Processing, Post-Translational; Sialyl Lewis X Antigen; Survival Analysis

Sialyl Lewis(x) (sLe(x)) and sialyl Lewis(a) (sLe(a)), the endothelial-selectin ligands involved in extravasation of neutrophils and carcinomas, have been identified in human melanoma. This study explored the following issue: If these ligands are immunogenic tumor-differentiation antigens, they would be potential targets for immunotherapy because of their putative roles in extravasation and metastasis.. Using a cell-suspension enzyme-linked immunosorbent assay (ELISA), the expression of sLe(x) and sLe(a) on the surface of normal melanocytes, melanoma cells from biopsies, and cell lines (M10-v, M24, and M101) constituting melanoma cell vaccine (MCV) were quantitated. Melanoma patients were immunized with the MCV expressing these antigens. Sera of normal individuals, sera of patients, and sera that adsorbed to sLe(x) and sLe(a) were titrated for anti-sLe antibodies by ELISA to verify the immunogenicity of the ligands.. The normal melanocytes did not express sLe(x) and poorly expressed sLe(a). Melanoma cells from tumor biopsies and MCV lines expressed both sLe(x) and sLe(a). Sialyl Le(x) was associated with glycoprotein(s) in M10-v, and sLe(a) occurred as a glycolipid moiety in M24. MCV recipients developed high titers for immunoglobulin (Ig)M but not IgG to both ligands. IgM titers to these ligands were low in normal subjects. In some of the preimmune sera of patients, the titers were threefold above normal. Six of 13 MCV recipients developed at least a twofold increase in anti-sLe titers above preimmune level after the second or third immunization. Adsorption studies suggested that both ligands were immunogenic.. The melanoma-associated sLe(x) and sLe(a) are immunogenic neoplasm-differentiation antigens and are therefore potential targets for passive and active specific immunotherapy in the treatment of melanoma.

Topics: Animals; Antibodies, Neoplasm; Antigens, Differentiation; Antigens, Neoplasm; Biopsy; CA-19-9 Antigen; Cancer Vaccines; Cell Transformation, Neoplastic; Endothelium, Vascular; Gangliosides; Humans; Ligands; Melanocytes; Melanoma; Mice; Oligosaccharides; Selectins; Sialyl Lewis X Antigen; Tumor Cells, Cultured