期刊
STEM CELLS
卷 34, 期 8, 页码 2040-2051出版社
OXFORD UNIV PRESS
DOI: 10.1002/stem.2395
关键词
Intra-tumoral heterogeneity; Cancer stemness; Oxidative stress; c-MYC; Esophageal squamous cell carcinoma
资金
- Canadian Institutes of Health Research (CIHR)
- Natural Science Foundation of China-GuangDong [U1301227]
- National Science Foundation of China [81472613]
- Li Ka Shing scholarship
- China Scholarship Council
The importance of intratumoral heterogeneity has been highlighted by the identification and characterization of cancer stem cells (CSCs). Based on the differential responsiveness to a Sox2 reporter, SRR2, we had found a novel dichotomy in esophageal squamous cell carcinoma (ESCC) cells, with reporter-responsive (RR) cells showing more CSC-like features than reporter-unresponsive (RU) cells. Specifically, RR cells exhibited significantly higher tumorsphere formation capacity, proportions of CD44(High) cells, chemoresistance to cisplatin, and tumorigenic potential in vivo. H2O2, a potent inducer of oxidative stress and reactive oxygen species, was found to induce a conversion from RU to RR cells; importantly, converted RR cells acquired CSC-like features. The PI3K/AKT/c-MYC signalling axis is important in this context, since pharmacologic blockade of PI3K-AKT or siRNA knockdown of c-MYC effectively inhibited the RR phenotype and its associated CSC-like features, as well as the H2O2-induced RU/RR conversion. In a cohort of 188 ESCC patient samples, we found a significant correlation between strong c-MYC expression and a short overall survival (p = .009). In conclusion, we have described a novel intratumoral heterogeneity in ESCC. The identification of the PI3K/AKT/c-MYC axis as a driver of CSC-like features carries therapeutic implications.
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