Abstract
Cancer stem cells (CSCs) have been shown to mediate tumorigenicity, chemo-resistance, radio-resistance and metastasis, which suggest they be considered therapeutic targets. Because their differentiated daughter cells are no longer tumorigenic, to induce the differentiation of CSCs can be one of strategies which can eradicate CSCs. Here we show that ATOH1 can induce the differentiation of gastric cancer stem cells (GCSCs). Real time PCR and western blot analysis showed that ATOH1 was induced during the differentiation of GCSCs. Furthermore, the lentivirus-induced overexpression of ATOH1 in GCSCs and in gastric cancer cell lines significantly induced differentiation, reduced proliferation and sphere formation, and reduced in vivo tumor formation in the subcutaneous injection and liver metastasis xenograft models. These results suggest ATOH1 be considered for the development of a differentiation therapy for gastric cancer.
Highlights
After cancer stem cells (CSCs) were initially isolated from leukemia patients, they had been isolated from many cancer types, including gastric cancer [1,2,3,4,5,6]
We found as gastric cancer stem cells (GCSCs) approached terminal stages of differentiation, the expression of ATOH1 increased (Fig 1)
We show that ATOH1, a HLH transcription factor, can induce the differentiation of GCSCs, and this leads to a loss of tumorigenicity
Summary
After cancer stem cells (CSCs) were initially isolated from leukemia patients, they had been isolated from many cancer types, including gastric cancer [1,2,3,4,5,6]. The poor prognosis of patients with greater CSC population, encourages the development of therapeutics that target CSCs [10]. One of characteristics of CSCs is that they can differentiate into daughter cells which are no longer tumorigenic, for example, CSCs from colon and stomach cancers have been induced to differentiate by serum [5,6]. This means the CSC hypothesis differs fundamentally from the traditional clonal expansion hypothesis. The hierarchical relationship between CSCs and their daughter cells can be explained by epigenetic mechanisms that can be applied
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