Abstract
The cancer stem cell (CSC) model suggests that there are subsets of cells within a tumor with increased proliferation and self-renewal capacity, which play a key role in therapeutic resistance. The importance of cyclooxygenase-2 (COX-2) in carcinogenesis has been previously established and the use of COX-2 inhibitors as celecoxib has been shown to exert antitumor effects. The present study investigated whether treatment of esophageal adenocarcinoma (EAC) cells with 5-fluorouracil (5-FU) or the growth of tumor spheres increased the proportion of CSCs and also if treatment with celecoxib was able to reduce the putative CSC markers in this tumor. OE19 and OE33 EAC cells surviving 5-FU exposure exhibited an increase in CSC markers CD24 and ABCG2 and also an increased resistance to apoptosis. EAC cell lines had the capacity to form multiple spheres displaying typical CSC functionalities such as self-renewal and increased CD24 levels. In addition, after the induction of differentiation, cancer cells reached levels of CD24 similar to those observed in the parental cells. Treatment with celecoxib alone or in combination with 5-FU also resulted in a reduction of CD24 expression. Moreover, celecoxib inhibited the growth of tumor spheres. These findings showing a reduction in CSC markers induced by celecoxib suggest that the COX-2 inhibitor might be a candidate for combined chemotherapy in the treatment of EAC. However, additional clinical and experimental studies are needed.
Highlights
The incidence of esophageal adenocarcinoma (EAC) has increased dramatically in the last decade in western countries
To characterize whether cells that survived 5-FU exposure were related to the cancer stem phenotype, we compared gene expression of genes involved in cell survival (BAX and BCLL2) and drug resistance (ABCG2) among cells surviving 5FU exposure and control cells
Our first objective was to investigate the presence of cell-surface markers related to the stem phenotype implicated in chemoresistance on esophageal cancer cells. 5FU-treated OE19 cells showed elevated expression of ABCG2, and both tested cell lines exhibited increased resistance to apoptosis, properties consistent with stem cell phenotype
Summary
The incidence of EAC has increased dramatically in the last decade in western countries This tumor has a high index of radio- and chemo-resistance, and is frequently diagnosed at an advanced state; EAC has poor prognosis with a 5-year survival rate ranging from 15 to 39% despite the use of combined therapies (van Lanschot et al, 2002; DeMeester, 2006). The CSC model proposes that tumors are organized hierarchically, with a subpopulation of stem-like cells which is responsible for sustaining tumor growth. These CSCs. 5-FU-Induced CD24 Expression Esophageal Adenocarcinoma have the capacity to self-renew and differentiate to generate the cellular heterogeneity observed in tumors, and may play a pivotal role in local invasion, metastasis, resistance to therapy, and subsequent tumor recurrence. The identification of CSCs is important because it might provide new targets for cancer therapy and may be used to develop a new class of biomarkers
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