Ovarian cancer stem-like cells with induced translineage-differentiation capacity and are suppressed by alkaline phosphatase inhibitor

Abstract

Spheroid formation is one property of stem cells—such as embryo-derived or neural stem cells—that has been used for the enrichment of cancer stem-like cells (CSLCs). However, it is unclear whether CSLC-derived spheroids are heterogeneous or whether they share common embryonic stemness properties. Understanding these features might lead to novel therapeutic approaches. Ovarian carcinoma is a deadly disease of women. We identified two types of spheroids (SR1 and SR2) from ovarian cancer cell lines and patients' specimens according to their morphology. Both types expressed stemness markers and could self-renew and initiate tumors when a low number of cells were used. Only SR1 could differentiate into multiple-lineage cell types under specific induction conditions. SR1 spheroids could differentiate to SR2 spheroids through epithelial–mesenchymal transition. Alkaline phosphatase (ALP) was highly expressed in SR1 spheroids, decreased in SR2 spheroids, and was absent in differentiated progenies in accordance with the loss of stemness properties. We verified that ALP can be a marker for ovarian CSLCs, and patients with greater ALP expression is related to advanced clinical stages and have a higher risk of recurrence and lower survival rate. The ALP inhibitor, levamisole, disrupted the self-renewal of ovarian CSLCs in vitro and tumor growth in vivo. In summary, this research provides a plastic ovarian cancer stem cell model and a new understanding of the cross-link between stem cells and cancers. This results show that ovarian CSLCs can be suppressed by levamisole. Our findings demonstrated that some ovarian CSLCs may restore ALP activity, and this suggests that inhibition of ALP activity may present a new opportunity for treatment of ovarian cancer.

TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target

“…We then assessed TET1 expression in OCSCs, and their differentiated progenies, in our previously established OCSC model . Our data showed that TET1 expression levels were increased in OCSCs but decreased in OCSC progeny cells (Figure E,F).…”

GATA3 as a master regulator and therapeutic target in ovarian high‐grade serous carcinoma stem cells

“…15 After quantile normalization, log 2transformed values were used to select for most significantly differentially expressed genes, based on genes with their RefSeq categories (with NM_ accession prefix). 15 After quantile normalization, log 2transformed values were used to select for most significantly differentially expressed genes, based on genes with their RefSeq categories (with NM_ accession prefix).…”

“…15 Elucidating the difference between stem (SR-I) and progenitor (SR-II) ovarian HGSC cells may further our understanding of CSCs biology and lead to novel therapies. Targeting CSCs with translineage capability suggests that targeting their territory at a higher hierarchy, may provide opportunities to overcome the bottleneck.…”

“…By contrast, type II spheroids (SR-II) have a morula-like surface, express N-cadherin and less alkaline phosphatase, and exhibit only limited translineage differentiation capability. 15 Elucidating the difference between stem (SR-I) and progenitor (SR-II) ovarian HGSC cells may further our understanding of CSCs biology and lead to novel therapies.…”

Enrichment for Chemoresistant Ovarian Cancer Stem Cells from Human Cell Lines

“…Comparison of stem cell markers, response to therapy, and best system for in vivo analysis needs to be conducted between different methods for generating/selection of CSCs. It has been suggested that there are different types of CSCs with different expression patterns of stem cell markers and different prognosis for patients [10][11][12] , thus further definition of what type of CSCs are generated by this protocol may help determine how they relate to human malignancy. Finally, in order to rigorously demonstrate that the CSCs isolated from this protocol are definitive CSCs, cells need to be injected into immunocompromised mice in a limiting dilution assay.…”