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

Our plain-English summary of The diagnostic utility of glycosaminoglycans (GAGs) in the early detection of cancer: a systematic review, by S. Douglah, R. Khalil, R. Kanaan, et al (PeerJ, 2024).

The study

• Authors: S. Douglah, R. Khalil, R. Kanaan, M. Almeqbaali, N. Abdelmonem, M. Abdelmessih, Y. Khairalla, N.H. Al-Rawi
• Journal: PeerJ
• Published: 2024;12:e18486
• Type of article: Systematic review
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© 2024 Douglah et al.

In plain English

This was a systematic review of published studies testing glycosaminoglycans (GAGs: sugar molecules including heparan sulfate, chondroitin sulfate and hyaluronic acid) as cancer markers. The authors searched four databases for English-language studies from 2008 to 2023 with at least 50 participants. Eleven studies were described individually, without pooled results. They covered kidney, ovarian, prostate, breast, upper gastrointestinal, colorectal, oral and lung cancers and pleural malignant mesothelioma. One study included 96 mesothelioma patients, 26 lung cancer patients and 42 patients with benign effusions. There, hyaluronic acid in pleural effusion fluid identified mesothelioma with an AUC (accuracy measure; 1.0 is perfect) of 0.89 (range labelled IQR, 0.82 to 0.94); serum hyaluronic acid was described as non-diagnostic. Using a 75 mg/L cutoff, high effusion hyaluronic acid was associated with longer median survival: 18.0 months (95% CI 13.7 to 22.4) versus 12.6 months (95% CI 8.4 to 16.8) with low levels (p = 0.004). Asbestos exposure was not discussed. The authors concluded that GAGs hold potential as early cancer detection biomarkers. They noted small samples, varied methods and limited geographic spread.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: systematic review with qualitative (non-pooled) synthesis of 11 observational studies (6 case-control, 5 cohort)
• Who was studied: 11 published human studies with at least 50 participants each, published 2008 to 2023 and found in PubMed, Scopus, EBSCO and Ovid. The studies were from Italy/Sweden, USA, Germany, Brazil, Sweden, Egypt, China, Iran and Australia. They included one Australian study of 96 malignant mesothelioma patients, 26 lung cancer patients and 42 patients with benign pleural effusions.
• Exposure: No asbestos exposure was studied. The tests reviewed were GAG levels (heparan sulfate, chondroitin sulfate, hyaluronic acid) measured in plasma, serum, urine, sputum, tissue or pleural effusion as possible cancer markers.
• Main results:
  • Study quality: on the Newcastle-Ottawa Scale, nine of the 11 included studies were rated good quality and two fair quality.
  • Pleural malignant mesothelioma (Creaney et al. 2013): effusion hyaluronic acid identified mesothelioma with an AUC of 0.89, with a range the review labels IQR 0.82 to 0.94. Effusion mesothelin alone had an AUC of 0.85.
  • Pleural malignant mesothelioma: a combined model with effusion hyaluronic acid, serum (as printed) and effusion mesothelin had an AUC of 0.92 (IQR 0.86 to 0.96). The review reported this as significantly higher than effusion mesothelin alone (AUC 0.85).
  • Pleural malignant mesothelioma: the review described serum hyaluronic acid as non-diagnostic, while effusion hyaluronic acid showed a biphasic distribution in mesothelioma patients.
  • Pleural malignant mesothelioma: using an effusion hyaluronic acid cutoff of 75 mg/L, patients with elevated levels had a median survival of 18.0 months (95% CI 13.7 to 22.4). Patients with low levels had a median survival of 12.6 months (95% CI 8.4 to 16.8), p = 0.004.
  • Renal cell carcinoma (Gatto et al. 2018): a plasma GAG score had 94.7% specificity and 100% sensitivity, with an AUC of 0.999 and a maximal accuracy of 98.9%.
  • Early-stage ovarian cancer (Biskup et al. 2021, n = 68): the chondroitin sulfate biomarker had 93% sensitivity and 100% specificity. The established CA-125 marker had 60% sensitivity and 83% specificity.
  • Prostate cancer (Silva et al. 2018, n = 58): urinary chondroitin sulfate levels did not differ significantly between patients and controls.
  • Breast cancer (El-Mezayen et al. 2013): hyaluronic acid distinguished metastatic from non-metastatic breast cancer with an AUC of 0.792. A multi-marker composite score had an AUC of 0.901.
  • Lung cancer (Rangel et al. 2015): sputum hyaluronic acid distinguished lung cancer patients from healthy controls with an AUC of 0.821, 66% sensitivity and 80% specificity.
• The authors' conclusion: The authors concluded that GAGs hold potential as early cancer detection biomarkers, and that validation in larger, more diverse populations is needed.
• Limitations the authors state:
  • GAG structures vary and there are no standardized analytical techniques, which hinders identifying and measuring cancer-specific GAG profiles.
  • The included studies had relatively small sample sizes and varying methods.
  • The included studies came mainly from certain areas of the world, so the results are not fully representative of the global population.

Topics

Medical terms in this study, explained in our Lexicon: Systematic Review, Angiogenesis, Metastasis, Hyaluronic Acid, Carcinoma, Ovarian Cancer, Lung Cancer, Colorectal Cancer.

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