Despite recent progress in understanding the cancer genome, there is still a relative delay in understanding the full aspects of the glycome and glycoproteome of cancer. Glycobiology has been instrumental in relevant discoveries in various biological and medical fields, and has contributed to the deciphering of several human diseases. Glycans are involved in fundamental molecular and cell biology processes occurring in cancer, such as cell signalling and communication, tumour cell dissociation and invasion, cell-matrix interactions, tumour angiogenesis, immune modulation and metastasis formation. The roles of glycans in cancer have been highlighted by the fact that alterations in glycosylation regulate the development and progression of cancer, serving as important biomarkers and providing a set of specific targets for therapeutic intervention. This Review discusses the role of glycans in fundamental mechanisms controlling cancer development and progression, and their applications in oncology.

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Glycosylation in cancer: mechanisms and clinical implications

The glycome describes the complete repertoire of glycoconjugates composed of carbohydrate chains, or glycans, that are covalently linked to lipid or protein molecules. Glycoconjugates are formed through a process called glycosylation and can differ in their glycan sequences, the connections between them and their length. Glycoconjugate synthesis is a dynamic process that depends on the local milieu of enzymes, sugar precursors and organelle structures as well as the cell types involved and cellular signals. Studies of rare genetic disorders that affect glycosylation first highlighted the biological importance of the glycome, and technological advances have improved our understanding of its heterogeneity and complexity. Researchers can now routinely assess how the secreted and cell-surface glycomes reflect overall cellular status in health and disease. In fact, changes in glycosylation can modulate inflammatory responses, enable viral immune escape, promote cancer cell metastasis or regulate apoptosis; the composition of the glycome also affects kidney function in health and disease. New insights into the structure and function of the glycome can now be applied to therapy development and could improve our ability to fine-tune immunological responses and inflammation, optimize the performance of therapeutic antibodies and boost immune responses to cancer. These examples illustrate the potential of the emerging field of ‘glycomedicine’. Glycosylation refers to the addition of carbohydrate chains to proteins and lipids. In this Review, the authors discuss the broad role of glycans in immunity, cancer, xenotransplantation and glomerular filtration and the potential of ‘glycomedicine’.

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Glycosylation in health and disease.

We examined plasma microRNA (miRNA) concentrations from patients with gastric cancers (GCs) to assess their clinical application for diagnosing and monitoring diseases. We initially investigated the appropriateness of plasma miRNA assay, and then compared plasma miRNA results with the expressions in cancer tissues from eight GC patients, and also compared plasma miRNAs between pre- and post-operative paired samples from 10 GC patients. Then, plasma miRNAs (miR-17-5p, miR-21, miR-106a, miR-106b and let-7a) were analysed in 69 GC patients and 30 healthy volunteers in total. The initial analysis showed that miRNAs were stable and detectable in all plasma samples, and the plasma miRNA levels reflected the tumour miRNAs in most cases. The levels of these miRNAs were significantly reduced in post-operative samples. In large-scale analysis, the plasma concentrations of miRNAs (miR-17-5p, miR-21, miR-106a, miR-106b) were significantly higher in GC patients than controls (P=0.05, 0.006, 0.008 and <0.001 respectively), whereas let-7a was lower in GC patients (P=0.002). The values of the area under the receiver-operating characteristic curve were 0.721 for the miR-106b assay and 0.879 for the miR-106a/let-7a ratio assay. Detection of circulating miRNAs might provide new complementary tumour markers for GC.

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Circulating microRNAs in plasma of patients with gastric cancers

Glycoconjugates constitute a major class of biomolecules which include glycoproteins, glycosphingolipids and proteoglycans. Glycans are involved in several physiological and pathological conditions, such as host-pathogen interactions, cell differentiation, migration, tumour invasion and metastisation, cell trafficking and signalling. Cancer is associated with glycosylation alterations in glycoproteins and glycolipids. This review describes various aspects of protein glycosylation with the focus on alterations associated with human cancer. The application of these glycosylation modifications as biomarkers for cancer detection in tumour tissues and serological assays is summarised.

Alterations in glycosylation as biomarkers for cancer detection

Biomarkers are measurable indicators of a biological state. As our understanding of diseases meliorates, it is generally accepted that early diagnosis renders the best chance to cure a disease. In the context of proteomics, the discovery phase of identifying bonafide biomarkers and the ensuing validation phase involving large cohort of patient samples are impeded by the complexity of bodily fluid samples. High abundant proteins found in blood plasma make it difficult for the detection of low abundant proteins that may be potential biomarkers. Extracellular vesicles (EVs) have reignited interest in the field of biomarker discovery. EVs contain a tissue-type signature wherein a rich cargo of proteins and RNA are selectively packaged. In addition, as EVs are membranous structures, the luminal contents are protected from degradation by extracellular proteases and are highly stable in storage conditions. Interestingly, an appealing feature of EV-based biomarker analysis is the significant reduction in the sample complexity compared to whole bodily fluids. With these prescribed attributes, which are the rate-limiting factors of traditional biomarker analysis, there is immense potential for the use of EVs for biomarker detection in clinical settings. This review will discuss the current issues with biomarker analysis and the potential use of EVs as reservoirs of disease biomarkers.

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Exosomes in bodily fluids are a highly stable resource of disease biomarkers.

The prognostic value of preoperative serum levels of CEA, CA 19-9 and CA 72-4 tumor markers was investigated in 153 patients resected for gastric cancer. The positivity rates for CEA, CA 19-9 and CA 7

Prognostic significance of CEA, CA 19-9 and CA 72-4 preoperative serum levels in gastric carcinoma.

Background: The aim of this longitudinal study was to evaluate the effectiveness of the serum tumor markers CEA, CA 19-9, and CA 72-4 in the early diagnosis of recurrence of gastric cancer. Methods: One hundred and thirty-three patients who had undergone potentially curative surgery were considered. Serum samples were obtained preoperatively, 1 week after surgery, and at every follow-up examination. Mean follow-up time for the entire patient population was 41 ± 33 months, and 71 ± 27 months for patients classified as disease-free. Results: Preoperative positivity was 16% for CEA, 35% for CA 19-9, and 20% for CA 72-4. Recurrence of disease was found in 75 patients (56%). Marker sensitivity in recurrent cases was 44% for CEA, 56% for CA 19-9, and 51% for CA 72-4; the combined use of the three markers increased sensitivity to 87%, which reached 100% in patients with positive preoperative levels. Marker specificity, evaluated in 58 disease-free patients, was 79% for CEA, 74% for CA 19-9, and 97% for CA 72-4. Conclusions: The combined assay of CEA, CA 19-9, and CA 72-4 may be useful for early diagnosis of recurrence of gastric cancer; however, only CA 72-4 positivity should be considered a specific predictor of tumor recurrence.

Clinical utility of CEA, CA 19-9, and CA 72-4 in the follow-up of patients with resectable gastric cancer

Background and Objectives

Preoperative positivity of serum tumor markers has been reported to be a prognostic factor in several neoplasms. The aim of this longitudinal study was to evaluate the correlation between CEA, CA 19-9, and CA 72-4 preoperative serum levels and the site of recurrence after curative surgery for gastric cancer.



Methods

One hundred sixty-seven patients resected for primary gastric cancer between January 1988 and June 1996 were considered. All patients were followed-up according to the same protocol, with a mean follow-up time of 45 ± 39 months (range: 2–130). The correlation between marker positivity and the incidence of recurrence was studied by means of univariate and multivariate analyses.



Results

A tumor recurrence was found in 92 patients (55.1%). For each of the three markers, preoperative positivity was related to a higher incidence of hematogenous recurrences with respect to negative cases; univariate analysis also revealed a higher incidence of locoregional recurrences in CA 72-4-positive cases. At multivariate analysis, preoperative positivity for one or more tumor markers proved to be an independent predictor of hematogenous recurrences (P < 0.005, relative risk [RR] 4.82), in addition to lymph node involvement (P < 0.05, RR 3.82); no correlation between marker positivity and the onset of locoregional or peritoneal recurrences was found.



Conclusions

Preoperative positivity for CEA, CA 19-9 or CA 72-4 is an independent risk factor for hematogenous recurrences of gastric carcinoma; this aspect should be considered in the option of using adjuvant chemotherapy after surgery for gastric cancer. J. Surg. Oncol. 2001;78:253–258. © 2001 Wiley-Liss, Inc.

Maurizio Farnetani

Papers

Prognostic significance of CEA, CA 19-9 and CA 72-4 preoperative serum levels in gastric carcinoma.

Clinical utility of CEA, CA 19-9, and CA 72-4 in the follow-up of patients with resectable gastric cancer

Preoperative positivity of serum tumor markers is a strong predictor of hematogenous recurrence of gastric cancer