Cancer Stemness, Immune Cells, and Epithelial–Mesenchymal Transition Cooperatively Predict Prognosis in Colorectal Carcinoma

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Abstract

Micro-Abstract:

In an assessment of the clinical significance of combining cancer stem cells, immune cells, and epithelial–mesenchymal transition (EMT) traits in colorectal cancer (CRC), an immunohistochemical method was applied in 419 CRC samples. Stem cell markers, EMT markers, and immune cells were detected; cancer stemness, immune state, and EMT were found to be associated with each other. A novel CRC classification comprising the 3 types of markers showed independent significance for 5-year survival, which may provide prognostic information complementary to existing pathologic assessments.

Background:

Tumor tissues consist of heterogeneous cancer cells and stroma cells, including cancer stem cells and immune cells. Epithelial–mesenchymal transition (EMT) programs closely associate with acquisition of stemness. We investigated for the first time the clinical significance of combining cancer stem cells, immune cells, and EMT traits.

Materials and Methods:

In 419 colorectal carcinomas, stem-cell markers (Nanog, Lgr5, CD44v6, ALDH1A1), EMT markers (E-cadherin, Snail), and immune-cell markers (CD3+, CD4+ or CD8+ T lymphocytes, CD20+ B lymphocytes, CD68+ macrophages) were detected in tumor center (TC) and tumor invasive front by an immunohistochemical method. Unsupervised hierarchical clustering analysis was performed to group the data according to correlation analyses. Survival analysis and chi-square test were performed to explore the significance of this clustering.

Results:

There were correlations among the expression of Nanog, Lgr5, CD44v6, and immune cell counts (P < .05). Nanog, Lgr5, CD44v6, and ALDH1A1 positively related to E-cadherin or Snail (P < .05). A cluster (termed cluster SIE) based on cancer stemness markers (Nanog, Lgr5, CD44v6, ALDH1A1 in TC), EMT markers (E-cadherin, Snail in TC), and immune-cell markers (CD4+ and CD8+ T-lymphocyte counts in TC, and CD68+ macrophages in tumor invasive front) could significantly predict 5-year survival (P = .040). Multivariate Cox proportional hazard model showed that only tumor, node, metastasis classification system stage and cluster SIE were independent prognostic predictors (hazard ratio = 1.920; 95% confidence interval, 1.082–3.407; P = .026).

Conclusion:

Cancer stemness, immune state, and EMT programs should be considered as a whole. Cluster SIE was an independent predictor for 5-year survival of patients with colorectal cancer.

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