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, 17 (2), 161-169
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Screening and Surveillance of Multiple Solid Tumours Using Plasma Placental-Like Chondroitin Sulfate A (pl-CSA)

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Screening and Surveillance of Multiple Solid Tumours Using Plasma Placental-Like Chondroitin Sulfate A (pl-CSA)

Juzuo Zhang et al. Int J Med Sci.

Abstract

Rationale: Placental-like chondroitin sulfate A (pl-CSA) is known to be exclusively synthesized in multiple cancer tissues and associated with disease severity. Here, we aimed to assess whether pl-CSA is released into bio-fluids and can serve as a cancer biomarker. Methods: A novel ELISA was developed to analyse pl-CSA content in bio-fluids using pl-CSA binding protein and an anti-pl-CSA antibody. Immunohistochemical staining of tissue chips was used as the gold standard control. Results: The developed ELISA method was specific and sensitive (1.22 μg/ml). The pl-CSA content was significantly higher in lysates and supernatants of cancer cell lines than in those of normal cell lines, in plasma from mouse cancer models than in that from control mice, and in plasma from patients with oesophageal, cervical, ovarian, or lung cancer than in that from healthy controls. Similar to the tissue chip analysis, which showed a significant difference in pl-CSA positivity between cancer tissues and normal adjacent tissues, the plasma pl-CSA analysis had 100% sensitivity and specificity for differentiating oesophageal and lung cancer patients from healthy controls. Importantly, in oesophageal and lung cancer patients, the pl-CSA content was significantly higher in late-stage disease than in early-stage disease, and it dramatically decreased after surgical resection of the tumour. Conclusion: These data indicate a direct link between plasma pl-CSA content and tumour presence, indicating that plasma pl-CSA may be a non-invasive biomarker with clinical applicability for the screening and surveillance of patients with multiple types of solid tumours.

Keywords: biomarker; cancer screening; circulating pl-CSA.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Specificity and repeatability of the double-antibody sandwich ELISA. (A) Assay sensitivity: the pl-CSA concentrations were 0.31 μg/ml, 0.61 μg/ml, 1.22 μg/ml, 2.44 μg/ml, 4.88 μg/ml, 9.77 μg/ml, 19.53 μg/ml, 39.06 μg/ml, 78.13 μg/ml, 156.25 μg/ml, 312.50 μg/ml, 625.00 μg/ml, 1250.00 μg/ml, 2500.00 μg/ml, and 5000.00 μg/ml. The lowest detectable concentration was 0.31 μg/ml. (B) Assay repeatability: The pl-CSA concentrations were 3.91 μg/ml, 7.81 μg/ml, 15.63 μg/ml, 31.25 μg/ml, 62.50 μg/ml, 125.00 μg/ml, 250.00 μg/ml, and 500.00 μg/ml. The content in each sample was measured 5 times.
Figure 2
Figure 2
Pl-CSA content was increased in the supernatants and lysates of cancer cells and in the plasma from mouse cancer models. (A) The cell lysates and cell culture supernatants from fifteen cell lines were collected and analysed using the double-antibody sandwich ELISA. The evaluated cell lines included six human cancer cell lines and four mouse cancer cell lines, as well as two normal human cell lines and two normal mouse cell lines as negative controls and the HTR8 cell line as a positive control. (B) The plasma concentration of pl-CSA was significantly higher in mouse cancer models than in control mice.
Figure 3
Figure 3
Plasma Pl-CSA content was higher in cancer patients than in healthy controls. (A) The plasma pl-CSA content was significantly higher in patients with oesophageal cancer, ovarian cancer, cervical cancer or lung cancer than in healthy controls. (B) ROC curve analysis of plasma pl-CSA for differentiating oesophageal cancer patients from healthy controls. (C) Sensitivity and specificity of plasma pl-CSA content for distinguishing lung cancer patients from healthy controls.
Figure 4
Figure 4
Plasma pl-CSA context was higher in late-stage patients and was significantly decreased after surgical tumour removal in patients with oesophageal or lung cancer. (A) The plasma concentration of pl-CSA was significantly higher in late-stage patients with oesophageal cancer than in early-stage patients. (B) The plasma content of pl-CSA in oesophageal cancer patients was lower after surgery than before surgery. (C) The plasma concentration of pl-CSA in late-stage patients with lung cancer was significantly higher than that in early-stage patients. (D) The plasma content of pl-CSA in patients with lung cancer was lower after surgery than before surgery.
Figure 5
Figure 5
Plasma pl-CSA content was significantly increased after chemotherapy in patients with oesophageal cancer. The plasma concentration of pl-CSA in pre-chemotherapy patients with oesophageal cancer was significantly lower than that in post-chemotherapy patients.
Figure 6
Figure 6
Pl-CSA was synthesized in cancer tissue and cancer cell lines and released in bio-fluids. (A) Pl-CSA was detectable by immunohistochemistry in oesophageal and lung cancer tissue but not in normal adjacent tissue (scale bar: 50 μm). (B) The analysis of pl-CSA-positive cases indicated 72% and 100% positivity in oesophageal and lung cancer tissues, respectively, compared with normal adjacent tissue. (C) A small amount of pl-CSA was released into the supernatant by the lung cancer cell lines, and the pl-CSA content was significantly higher in the lysates than in the supernatants. (D) A small amount of pl-CSA was released into the supernatant by the oesophageal cancer cell lines, and the pl-CSA content in the lysates was significantly higher than that in the supernatants.

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