Abstract
BackgroundTumor cell death generates products that can be measured in the circulation of cancer patients. CK18-Asp396 (M30 antigen) is a caspase-degraded product of cytokeratin 18 (CK18), produced by apoptotic epithelial cells, and is elevated in breast and lung cancer patients.MethodsWe determined the CK18-Asp396 and total CK18 levels in plasma of 49 colorectal cancer patients, before and after surgical resection of the tumor, by ELISA. Correlations with patient and tumor characteristics were determined by Kruskal-Wallis H and Mann-Whitney U tests. Disease-free survival was determined using Kaplan-Meier methodology with Log Rank tests, and univariate and multivariate Cox proportional hazard analysis.ResultsPlasma CK18-Asp396 and total CK18 levels in colorectal cancer patients were related to disease stage and tumor diameter, and were predictive of disease-free survival, independent of disease-stage, with hazard ratios (HR) of patients with high levels (> median) compared to those with low levels (≤ median) of 3.58 (95% CI: 1.17–11.02) and 3.58 (95% CI: 0.97–7.71), respectively. The CK18-Asp396/CK18 ratio, which decreased with tumor progression, was also predictive of disease-free survival, with a low ratio (≤ median) associated with worse disease-free survival: HR 2.78 (95% CI: 1.06–7.19). Remarkably, the plasma CK18-Asp396 and total CK18 levels after surgical removal of the tumor were also predictive of disease-free survival, with patients with high levels having a HR of 3.78 (95% CI: 0.77–18.50) and 4.12 (95% CI: 0.84–20.34), respectively, indicating that these parameters can be used also to monitor patients after surgery.ConclusionCK18-Asp396 and total CK18 levels in the circulation of colorectal cancer patients are predictive of tumor progression and prognosis and might be helpful for treatment selection and monitoring of these patients.
Highlights
Tumor cell death generates products that can be measured in the circulation of cancer patients
Male and female colorectal cancer patients had similar plasma cytokeratin 18 (CK18)-Asp396 and total CK18 levels, and these were not correlated with patients' age
Both CK18Asp396 and total CK18 levels were significantly higher in the eight patients with a Dukes' D tumor in which the tumor was not resected
Summary
Tumor cell death generates products that can be measured in the circulation of cancer patients. CK18-Asp396 (M30 antigen) is a caspase-degraded product of cytokeratin 18 (CK18), produced by apoptotic epithelial cells, and is elevated in breast and lung cancer patients. Caspase activity itself or the presence of specific degradation products can be used for the detection of tumor cell apoptosis. The M30 antibody detects a caspase-degraded product, CK18-Asp396, of the important cytoskeletal protein cytokeratin 18 (CK18) of epithelial cells, which is expressed by most carcinomas, including those of breast, prostate, lung and colon [3]. The levels of CK18Asp396 can be determined in the circulation by a specific ELISA, allowing the detection of tumor cell apoptosis in the serum/plasma of cancer patients [6,7]. CK18-Asp396 detection in the plasma is not tumor specific, healthy controls have background levels, due to apoptosis of normal epithelial cells. Circulating CK18Asp396 levels increased shortly after chemotherapy in hormone-refractory prostate cancer and lung cancer, implying that this was a result of chemotherapy-induced tumor cell apoptosis [9,10,11]
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