Abstract
Cancer stem cells (CSC) exhibit high tumorigenic capacity in several tumor models. We have now determined an extended phenotype for cervical cancer stem cells. Our results showed increased CK-17, p63+, AII+, CD49f+ expression in these cells, together with higher Aldehyde dehydrogenase (ALDHbright)activity in Cervical CSC (CCSC) enriched in cervospheres. An increase in stem cell markers, represented by OCT-4, Nanog, and β-catenin proteins, was also observed, indicating that under our culture conditions, CCSC are enriched in cervospheres, as compared to monolayer cultures. In addition, we were able to show that an increased ALDHbright activity correlated with higher tumorigenic activity. Flow cytometry and immunflorescence assays demonstrated that CCSC in cervosphere cultures contain a sub-population of cells that contain Annexin II, a Human papillomavirus (HPV) co-receptor. Taken together, under our conditions there is an increase in the number of CCSC in cervosphere cultures which exhibit the following phenotype: CK-17, p63+, AII+, CD49f+ and high ALDH activity, which in turn correlates with higher tumorigenicity. The presence of Annexin II and CD49f in CCSC opens the possibility that normal cervical stem cells could be the initial target of infection by high risk HPV.
Highlights
Cervical cancer (CC) continues to be an important human public health problem in developing countries [1, 2]
Since we studied cells with stemness and putative stem cell markers in cervical cancer cell lines growing in monolayer tissue culture conditions, it is necessary to claim for them the name stemloids, a term used to describe proliferating cells with self-renewal capacity [9]
We must be careful to use the term cervical cancer stem cells (CCSC), since our spheres are cultured without fetal bovine serum and we using a commercial medium for enriching stem cells with EGF and bFGF, we suggest that our spheres are enriched for cervical tumorigenic cells and they could named cervical cancer stem cell-like cells, characterized by stemness and cervical stem markers
Summary
Cervical cancer (CC) continues to be an important human public health problem in developing countries [1, 2]. For high-risk premalignant lesions and carcinomas, aggressive protocols are the therapeutic options for patients, including chemoand radiotherapies (reviewed in [3]). Disease relapse could be a consequence of resistant cancer cell clonal selection, including stem and/or nonstem cells, in which the accumulation of mutations in these cells can be associated with the ability to develop anti-cancer therapy resistance resulting in tumor progression [5]. These CSC can bypass drug cytotoxicity due to the presence of an efflux pump belonging to the www.impactjournals.com/oncotarget
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