Epithelial-mesenchymal transition triggers cancer stem cell generation in human thyroid cancer cells

Abstract

Abstract.Increasing evidence has shown that cancer stem cells or tumor initiating cells are the 'root cause' of malignant cancers. However, the exact origin of cancer stem cells still remains obscure in thyroid research. EMT has been implicated in the initiation and conversion of early-stage tumors into invasive malignancies and is associated with the stemness of cancer cells. Based on these facts, a new hypothesis was suggested that EMT induces cancer stem cell generation and tumor progression in human thyroid cancer cells in vitro. In the present study, FTC133 cells identified as EMT-negative cells were used for EMT induction by HIF-1α transfection. Overexpression of HIF-1α induced FTC133 cells to undergo EMT, downregulated the epithelial markers E-cadherin, upregulated the mesenchymal marker vimentin, and associated with highly invasive and metastatic properties. Most importantly, the induction of EMT promoted the stem-like side population cell proportion in the FTC133 cells. These results indicate that EMT induction promotes CSC traits and cell proportions in the thyroid cancer cells, which implies that EMT could induce cancer stem cell generation and tumor progression in thyroid cancers. Further understanding of the role of EMT and cancer stem cells in cancer progression may reveal new targets for the prevention or therapy of thyroid cancers. IntroductionAnaplastic thyroid carcinoma is an aggressive malignancy characterized by an extensive local invasion, early systemic dissemination and marked resistance to chemo-and radiotherapy, and always has a poor prognosis with a mean survival of only few months (1). Current systemic therapy fails to eradicate this cancer or even to stop tumor progress. It has been hypothesized that this may be explained by the failure of current drugs to effectively target cancer stem-like cells (CSCs) (2,3). To date, CSCs have been reported in various solid tumors and in cancer cell lines (4-9). However, until recently, there are only very few studies on adult thyroid stem/progenitor cells and thyroid CSCs (10-12). We and others have recently described and characterized thyroid cancer stem cells as a side population (13-17) that may play a critical role in the progression and recurrence of cancer and its subsequent metastasis (18).Epithelial to mesenchymal transition (EMT) is a vital process for morphogenesis during embryonic development, but it has also been implicated in the conversion of early stage tumors into invasive malignancies (19). More recent studies have further demonstrated that EMT plays a critical role not only in tumor metastasis but also in tumor recurrence that is believed to be tightly linked with the biology of cancer stem-like cells or cancer-initiating cells (20-23). The relationship between EMT and CSCs has been observed, with the evidence suggesting that EMT cells acquire stem cell-like traits and that CSCs exhibit a mesenchymal-like appearance in immortalized non-tumorigenic mammary epithelial cells and breast cancers (22). In thyroid cancer, it was found i...

Cancer stem-like cells and thyroid cancer

“…Overexpression of HIF1a which increased the stem-like side population in this cell line. These results suggest that EMT induction promotes CSCs in thyroid tumors (Lan et al 2013).…”

“…Recent studies have revealed that the epigenetic silencing of E-cadherin is orchestrated by a variety of histone-modifying enzymes that cooperate to repress the CDH1 promoter (Tam & Weinberg 2013). Further understanding of the role of EMT and CSCs in cancer progression may reveal new therapeutic targets thyroid cancers (Lan et al 2013). …”

Identification of CD90 as Putative Cancer Stem Cell Marker and Therapeutic Target in Insulinomas

“…However, no consensus has been obtained on the location of adult pancreatic stem cells that give rise to b-cells, as conflicting in vivo data suggest that they are either present in the ductal, acinar, or islet compartment of the pancreas [8]. The occurrence of epithelial-mesenchymal transition (EMT) fits with the second theory on the origin of CSCs, and has been implicated to induce CSC generation and epithelial tumor progression [9,10]. EMT has also been implicated as a critical step in tumorigenesis of pNETs [11].…”

Normal vs cancer thyroid stem cells: the road to transformation

“…Moreover, it was observed that cells with an over-expression of HIF1α shared stem-like cell features highlighting that EMT induction was directly associated with increased CSC populations. 84 Several lines of evidence also supported the cross-talk between Twist and ID proteins. Kebebew et al 93 observed over-expression of the DNA-binding protein inhibitor ID-1 in ATC tissues, reporting that the inhibition of ID1 mRNA expression results in decreased growth and reduction of Tg and NIS expression.…”

“…[81][82][83] This model is supported by the expression of EMT markers in CSCs and by the activation of SC markers in EMT-induced cells. 84,85 DTCs are considered the major cause of metastatic disease, chemo-resistance and recurrence, and are characterised by the capacity to migrate from primary tumours to secondary sites. Therefore, DTCs can exist for long time in a quiescent state called dormancy, corresponding to the latent period between primary tumour detection, treatment, recurrence and metastatic spread.…”