alpha-Neup5Ac-(2--3)-beta-D-Galp-(1--4)-[alpha-L-Fucp-(1--3)]-D-GlcpNAc and Ovarian-Neoplasms

Sialylation (the covalent addition of sialic acid to the terminal end of glycoproteins or glycans), tightly regulated cell- and microenvironment-specific process and orchestrated by sialyltransferases and sialidases (neuraminidases) family, is one of the posttranslational modifications, which plays an important biological role in the maintenance of normal physiology and involves many pathological dysfunctions. Glycans have roles in all the cancer hallmarks, referring to capabilities acquired during all steps of cancer development to initiate malignant transformation (a driver of a malignant genotype), enable cancer cells to survive, proliferate, and metastasize (a consequence of a malignant phenotype), which includes sustaining proliferative signaling, evading growth suppressor, resisting cell apoptosis, enabling replicative immortality, inducing angiogenesis, reprogramming of energy metabolism, evading tumor destruction, accumulating inflammatory microenvironment, and activating invasion and accelerating metastases. Regarding the important role of altered sialylation of cancers, further knowledge about the initiation and the consequences of altered sialylation pattern in tumor cells is needed, because all may offer a better chance for developing novel therapeutic strategy. In this review, we would like to update alteration of sialylation in ovarian cancers.

Topics: Biomarkers, Tumor; Blood Proteins; Female; Humans; Neuraminidase; Ovarian Neoplasms; Sialic Acids; Sialyl Lewis X Antigen; Sialyltransferases

Ovarian cancer is the most lethal of all gynaecological cancers among women. Serum CA125 is the only biomarker that is used routinely and there is a need for further complementary biomarkers both in terms of sensitivity and specificity. N-glycosylation changes in ovarian cancer serum glycoproteins include a decrease in galactosylation of IgG and an increase in sialyl Lewis X (SLe(x)) on haptoglobin beta-chain, alpha1-acid glycoprotein and alpha1-antichymotrypsin. These changes are also present in chronic inflammation but not in malignant melanoma, where there are low levels of inflammatory processes. Acute phase proteins carrying increased amounts of SLe(x) have an increased half-life. Sialylation of acute phase proteins also decreases apoptosis favouring survival of cancer cells. Cancer cells produce inflammatory cytokines which influence glycosylation processing in liver parenchymal cells. Altered glycosylation of the acute phase protein transferrin plays an important role in iron homeostasis. Glycosylated transferrin and its glycans have anti-apoptotic properties and many transferrin receptors in carcinoma could play a role in development of anaemia. Decreased galactosylation and sialylation of IgG increases the cytotoxicity of natural killer cells and complement activation via mannose-binding lectin (MBL). Altered glycosylation of acute phase proteins and IgG suggests that cancer regulates certain pathways favouring cancer cells survival.

Topics: Acute-Phase Proteins; alpha 1-Antichymotrypsin; Biomarkers, Tumor; Early Detection of Cancer; Female; Galactose; Glycoproteins; Glycosylation; Humans; Immunoglobulin G; Killer Cells, Natural; Oligosaccharides; Ovarian Neoplasms; Polysaccharides; Sialyl Lewis X Antigen; Transferrin

Organ-specific colonization suggests that specific cell-cell recognition is essential. Yet, very little is known about this particular interaction. Moreover, tumor cell lodgement requires binding under shear stress, but not static, conditions. Here, we successfully isolate the metastatic populations of cancer stem/tumor-initiating cells (M-CSCs). We show that the M-CSCs tether more and roll slower than the non-metastatic (NM)-CSCs, thus resulting in the preferential binding to the peritoneal mesothelium under ascitic fluid shear stress. Mechanistically, this interaction is mediated by P-selectin expressed by the peritoneal mesothelium. Insulin-like growth factor receptor-1 carrying an uncommon non-sulfated sialyl-Lewis

Topics: Animals; Ascitic Fluid; Carcinoma; Cell Adhesion; Cell Line, Tumor; Epithelium; Female; Fucosyltransferases; HEK293 Cells; Humans; Hydrodynamics; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Stem Cells; Oligosaccharides; Ovarian Neoplasms; P-Selectin; Peritoneal Neoplasms; Peritoneum; Receptor, IGF Type 1; Sialyl Lewis X Antigen; Stress, Mechanical

Mucins are heavily glycosylated proteins overexpressed and associated with truncated or sialylated glycans upon malignant transformation. We previously identified a panel of four glyco-mucin profiles (MUC16/Tn, MUC16/STn, MUC1/Tn, and MUC1/STn) with 100 % specificity and 100 % positive predictive value for detection of borderline/malignant serous tumors of the ovary, using proximity ligation assay (PLA). In the present work, using the same method, we studied other mucin glycosylation profiles that might add relevant information for diagnostic purposes. We used PLA probes to MUC16, MUC1, sialyl Lewis(a) (SLe(a)), and sialyl Lewis(x) (SLe(x)) to study a series of 39 ovarian serous tumors (14 adenocarcinomas, 10 borderline ovarian tumors (BOTs), and 15 cystadenomas). Our results demonstrated that, in adenocarcinomas and BOTs, the major carriers of SLe(a) and SLe(x) are MUC16 and/or MUC1 (100 and 92 % for SLe(a) and 64 and 70 % for SLe(x), respectively). In cystadenomas, SLe(a) and SLe(x) are mainly carried by unidentified proteins (85 and 78 %, respectively). Our study identified, for the first time, the major protein carriers of SLe(a) and SLe(x) in ovarian adenocarcinomas and BOTs, MUC1 and MUC16, and also that distinct unidentified carriers are involved in cystadenomas. These results emphasize the relevance of multiple biomarker recognition provided by multiplex assays, such as PLA, to enhance sensitivity and specificity of serum and tissue assays.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; CA-125 Antigen; CA-19-9 Antigen; Carcinoma, Ovarian Epithelial; Cystadenoma; Female; Heterozygote; Humans; Membrane Proteins; Middle Aged; Mucin-1; Neoplasms, Glandular and Epithelial; Oligosaccharides; Ovarian Neoplasms; Sialyl Lewis X Antigen

Recent work identified L-asparaginase (L-ASP) as a putative therapeutic target for ovarian cancer. We suggest that L-ASP, a dysregulator of glycosylation, would interrupt the local microenvironment, affecting the ovarian cancer cell-endothelial cell interaction and thus angiogenesis without cytotoxic effects. Ovarian cancer cell lines and human microvascular endothelial cells (HMVEC) were exposed to L-ASP at physiologically attainable concentrations and subjected to analyses of endothelial tube formation, invasion, adhesion and the assessment of sialylated proteins involved in matrix-associated and heterotypic cell adhesion. Marked reduction in HMVEC tube formation in vitro, HMVEC and ovarian cancer cell invasion, and heterotypic cell-cell and cell-matrix adhesion was observed (P < 0.05-0.0001). These effects were associated with reduced binding to ß1integrin, activation of FAK, and cell surface sialyl Lewis(X) (sLe(x)) expression. No reduction in HMVEC E-selectin expression was seen consistent with the unidirectional inhibitory actions observed. L-ASP concentrations were non-toxic to either ovarian cancer or HMVEC lines in the time frame of the assays. However, early changes of autophagy were observed in both cell types with induction of ATG12, beclin-1, and cleavage of LC-3, indicating cell injury did occur. These data and the known mechanism of action of L-ASP on glycosylation of nascent proteins suggest that L-ASP reduces of ovarian cancer dissemination and progression through modification of its microenvironment. The reduction of ovarian cancer cell surface sLe(x) inhibits interaction with HMVEC and thus HMVEC differentiation into tubes, inhibits interaction with the local matrix reducing invasive behaviour, and causes cell injury initiating autophagy in tumour and vascular cells.

Topics: Angiogenesis Inhibitors; Asparaginase; Autophagy; Cell Adhesion; Cell Line, Tumor; Cell-Matrix Junctions; E-Selectin; Endothelial Cells; Female; Glycosylation; Humans; Integrin beta1; Neovascularization, Pathologic; Oligosaccharides; Ovarian Neoplasms; Sialyl Lewis X Antigen

Topics: Biomarkers, Tumor; Female; Humans; Lewis X Antigen; Lung Neoplasms; Male; Ovarian Neoplasms; Pancreatic Neoplasms; Sialyl Lewis X Antigen

Glycodelins (Gds) are glycoproteins with a gender specific glycosylation. Glycodelin A (GdA) is primarily produced in endometrial and decidual tissue and secreted to amniotic fluid. Glycodelins were also identified in several cancer types, including serous ovarian cancer. Gds act as a T-cell inhibitor and are involved in inactivation of human monocytes. With a Gd peptide antibody, derived from a 15 amino acid sequence of human Gd and in situ hybridization experiments, the expression of Gd in serous, mucinous, endometrioid and clear cell ovarian tumors was identified. In contrast to former investigations with antibodies against GdA, a positive immunohistochemical reaction for Gd was observed in all forms of epithelium ovarian cancer. These results were confirmed with in situ hybridization. In addition, Gd is expressed in granulose cell tumors, a non-epithelial form of ovarian cancer. Furthermore, Gd was purified from ascites fluid of ovarian cancer patients. Ascites Gd showed significant differences in its structure of sialyl Lewis-type oligosaccharides compared to GdA. Additionally, ascites Gd inhibits IL-2 stimulated proliferation of peripheral blood leucocytes and inhibits adhesion of SLe(X)-positive cells to E-selectin. Therefore, Gd could act as an inhibitor of lymphocyte activation and/or adhesion in ovarian cancer.

Topics: Cell Adhesion; Female; Glycodelin; Glycoproteins; Glycosylation; Humans; Immunohistochemistry; Immunosuppression Therapy; Lymphocyte Activation; Oligosaccharides; Ovarian Neoplasms; Pregnancy Proteins; Sialyl Lewis X Antigen

Topics: Animals; CA-19-9 Antigen; Cell Adhesion; Cell Membrane; E-Selectin; Female; Galactosides; Galectin 1; Gangliosides; Glycoconjugates; Hemagglutinins; Humans; Hyaluronan Receptors; Hyaluronic Acid; Lectins; Lewis Blood Group Antigens; Neoplasm Metastasis; Neoplasms; Oligosaccharides; Ovarian Neoplasms; Sialyl Lewis X Antigen