Discusion
Recently, a small population of cancer cells referred to as CSCs has been implicated in tumor initiation, relapse, and resistance to chemotherapy or RT; as a result, eradication of CSCs is considered essential in cancer therapy (15,16). The CSC hypothesis has also been coined for HNSCC in the head and neck; some cell surface markers have been reported as CSC markers in HNSCC cancers, such as CD44, CD133, ALDH1 and ABCG2 (17-19), and high expression of these markers is usually considered an indicator of poor prognosis. Among them, CD44 is the most reported CSC marker in HNSCC (20-22). Chen et al. reported that ALDH1-positive cells are phenotypic and functional precursors of CSCs. These cells develop from ALDH1 cell lines and have more proliferative activity (24). In the same study, it was shown that ALDH1-positive cells had similar genetic structure to mesenchymal stem cells. Guided by these studies, ALDH1 expression is thought to be a good biomarker for CSCs in head and neck cancers (24,25).
A study by Chen et al. showed that colony formation was stimulated with 0–10 Gy radiation in isolated ALDH1-positive cells. The study also compared CD44-positive, CD24-negative cells that were positive and negative for ALDH1. A total of 226 HNSCC patients who were positive for ALDH1 were evaluated, and ALDH1 levels were found to be associated with advanced-stage disease and undifferentiated tumors. In addition, it was determined that patients who were positive for ALDH1 had poorer survival with oncological treatment (26). In an experimental study, authors reported that a small portion of the population of CD 44 possitive cancer cells, which typically comprise < 10 % of the cells in a head and neck squamous cell carcinoma tumor, but not the CD44 negative cancer cells, gave rise to new tumor in vivo. Immunohistochemistry showed that the CD44 possitive cancer cells have a primitive cellular structure and costain with the basal cell marker Cytokeratin 5/14, whereas the CD44 negative cancer cells resemble differentiated squamous epithelium and express the differentiation marker Involucrin. The tumors that arose from purified CD44 possitive cells reproduced the original tumor heterogeneity and could be serially passaged, thus demonstrating the two defining properties of stem cells: ability to self-renew and to differentiate (27).
In our study, the prevalence of ALDH1 positivity was significantly higher among patients with tumor recurrence due to RT failure. Al-Assar et al. reported that several biomarkers such as CD44, CD24, CD133, and epithelial-specific antigen may be related to radiosensitivity. In this study, it was found that CSCs, except those that were CD24-negative, did not have a radioresistant phenotype (28). In a meta-analysis, ALDH1 expression was reported to be associated with low overall and disease-related survival (29). In contrast, Lopez-Gonzales reported that patients with stage 1-2 lung cancer and ALDH1 nuclear expression showed good survival (30). This seems completely opposite of our study, in which ALDH1 positivity was significantly more common among patients with failed RT while CD44 positivity was not significantly different between the two groups. ALDH1 positivity was found to be an independent risk factor for DFS and significantly associated with poor prognosis.
This study has limitations such as the small sample size, and not specifying the smoking status and comorbidities of the patients. Because patients with anterior commissure involvement excluded from the study, sample size is small.