Clinical relevance of a candidate stem cell marker, p75 neurotrophin receptor (p75NTR) expression in circulating tumor cells

Despite advances in its diagnosis and multimodal therapies, the prognosis of esophageal squamous cell carcinoma (ESCC) patients remains poor, because of high incidences of metastasis. Recent reports suggested that circulating tumor stem cells (CTSCs), rather than circulating tumor cells (CTCs), were more accurate diagnostic marker for metastasis, because tumor stem cells or cancer stem cells (CSCs) are more responsible for metastasis through processes such as epithelial mesenchymal transition (EMT) and tumor initiation. A neurotrophin receptor p75 (p75NTR) is expressed in a candidate CSCs in ESCC, which possess enhanced tumorigenicity along with strong expression of EMT-related genes. Our recent report using two-color flow cytometry demonstrated that CTC counts based on a combined expression of epithelial cell adhesion molecule (EpCAM) and p75NTR was significantly higher in peripheral blood samples of ESCC patients than healthy controls. In addition, EpCAM + p75NTR+, but not EpCAM + p75NTR- CTC counts, correlated with clinically diagnosed distant metastasis and pathological venous invasion in surgically resected primary ESCC tumors. Malignant cytology of the isolated EpCAM + p75NTR+ cells was microscopically confirmed as well. These results demonstrated that EpCAM + p75NTR+ CTC count was a more accurate diagnostic marker than EpCAM+ CTC count, suggesting the highly metastatic potential of CTCs with p75NTR expression. Investigation using the isolated EpCAM + p75NTR+ CTCs to assess their stem cell properties may shed light on their roles in tumor metastasis in ESCC. Further investigations based on large-scale prospective studies with long term follow up may provide us with evidences for its clinical use.