The diagnostic utility of glycosaminoglycans (GAGs) in the early detection of cancer: a systematic review

Background: Glycosaminoglycans (GAGs) are a family of polysaccharides found abundantly in the extracellular matrix (ECM) of tissues. Research has indicated that the dysregulation of ECM, including changes and disruptions in GAGs, contributes to various cancer hallmarks such as metabolic reprogramming, persistent growth signals, immunosuppression, angiogenesis, tumor invasion, and metastasis.

Objective: This systematic review aims to evaluate the diagnostic accuracy of GAGs, including heparan sulfate (HS), chondroitin sulfate (CS), and hyaluronic acid (HA), in early detection of cancer.

Method: Four databases (PubMed, Scopus, EBSCO, and Ovid) were searched for studies in English within the last 15 years, involving at least 50 human participants. Using a two-stage process: identification and screening, 11 articles were selected and critically appraised using Critical Appraisal Skills Programme (CASP) checklists and Newcastle-Ottawa Scale (NOS) appropriate for each study design.

Result: Eleven studies met the inclusion criteria, encompassing various cancers like renal cell carcinoma (RCC), upper GI cancer (UGI), ovarian cancer, prostate cancer, breast cancer, lung cancer, colorectal cancer and oral cancer. Methodological quality was assessed using two established tools, with no studies exhibiting a high risk of bias. Heparan sulfate levels showed diagnostic potential in renal cancer with a maximum accuracy of 98.9%, achieving 94.7% specificity and 100% sensitivity. Chondroitin sulfate disaccharides emerged as a promising diagnostic marker in ovarian cancer and showed potential as diagnostic markers in renal cancer. However, there were no statistically significant differences in urinary chondroitin sulfate levels between patients and controls in prostate cancer. In breast cancer, hyaluronic acid showed moderate accuracy (AUC = 0.792) in distinguishing metastatic from non-metastatic disease, and a composite score incorporating multiple markers, including HA, showed even higher accuracy (AUC = 0.901) in detecting metastatic breast cancer. HA demonstrated moderate diagnostic accuracy for UGI cancers. Serum HA levels were significantly elevated in patients with oral cancer and pleural malignant mesothelioma and associated with tumor progression in patients with lung cancer. Elevated low molecular weight form of hyaluronan (~6 k Da HA) levels were found in colorectal cancer tissues.

Conclusion: GAGs hold potential as early cancer detection biomarkers. Further validation with larger, diverse populations is needed to validate their diagnostic accuracy and clinical utility.