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.