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Glycosylation changes on serum glycoproteins in ovarian cancer may contribute to disease pathogenesis.

ABSTRACT: 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.

SUBMITTER: Saldova R

PROVIDER: S-EPMC3827796 | biostudies-other | 2008

REPOSITORIES: biostudies-other

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Glycosylation changes on serum glycoproteins in ovarian cancer may contribute to disease pathogenesis.

Saldova Radka R Wormald Mark R MR Dwek Raymond A RA Rudd Pauline M PM

Disease markers 20080101 4-5

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 i ...[more]

PMID: 19126966

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Project description:Epithelial ovarian cancer (EOC) was previously shown to be associated with glycosylation changes of total serum and total IgG proteins. However, as a majority of previous studies analyzed released glycan profiles, still little is known about IgG subclass-specific alterations in ovarian cancer. Hence, in this study, we investigated EOC-related glycosylation changes of the three most abundant IgG subclasses, namely, IgG1, IgG2 and IgG3 isolated from sera of 87 EOC patients and 74 age-matched healthy controls. In order to separate IgG2 and IgG3, we performed a two-step affinity purification employing Protein A and Protein G Sepharose. After tryptic digestion, IgG glycopeptides were enriched and measured by MALDI-TOF-MS. Finally, EOC-related glycosylation changes were monitored at the level of total agalactosylation, monogalactosylation, digalactosylation, sialylation, bisection and fucosylation, which were calculated separately for each IgG subclass. Interestingly, aside from an EOC-related increase in agalactosylation/decrease in monogalactosylation and digalactosylation observed in all IgG subclasses, some subclass-specific trends were detected. Glycosylation of IgG1 was found to be most strongly affected in EOC, as it exhibited the highest number of significant differences between healthy controls and EOC patients. Specifically, IgG1 was the only subclass that showed a significant decrease in sialylation and a significant increase in fucosylation in EOC patients. Interestingly, IgG2 and IgG3 that were often investigated collectively in previous studies, were found to have distinct glycosylation patterns. IgG3 displayed stronger EOC-related increase in agalactosylation/decrease in digalactosylation and was characterized by notably higher sialylation, which consequently decreased in EOC patients. In conclusion, our study indicates that IgG subclasses exhibit subtly distinct glycosylation patterns of EOC-related alterations and that IgG1 and IgG3 agalactosylation show the strongest association with CA125, the routine diagnostic marker. Additionally, our results show that simultaneous analyses of IgG2 and IgG3 might lead to wrong conclusions as these two subclasses exhibit noticeably different glycosylation phenotypes.

Dataset Information

Glycosylation changes on serum glycoproteins in ovarian cancer may contribute to disease pathogenesis.

Publications

Glycosylation changes on serum glycoproteins in ovarian cancer may contribute to disease pathogenesis.

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