Endometrial Cells Get Side-Tracked

Abstract

Like stem cells, a subpopulation of cancer cells is characterized by the property of self-renewal, unlimited and high proliferative potential, expression of multidrug-resistance proteins, active DNA repair capacity, apoptosis resistance, and an enormous developmental plasticity. 1Based on these observations, the concept of cancer stem cells has been developed, which proposes that tumor-initiating cancer cells may either originate from normal stem cells, or that cancer cells may undergo progressive de-differentiation, ultimately leading to a stem-cell like state. The stem cell-like properties of tumorinitiating cells are thought to be a major underlying cause of therapeutic resistance and tumor relapse; therefore, a specific targeting of cancer stem cells within a mixed tumor cell population may represent a particularly efficient form of anticancer therapy.In this issue of The American Journal of Pathology, Kato et al 2 have exploited a common property of stem cells and tumor-initiating cells, the side-population phenotype, to isolate and functionally characterize a cancer stem cell-like subpopulation of endometrial carcinoma. Side population (SP) cells can be identified by flow cytometry based on their property of effluxing the fluorescent dye Hoechst 33342 via ATP-binding cassette transporter proteins such as ABCG/Brcp1.3 Stem cells express high levels of this protein, and are therefore highly enriched in the SP of a given tissue. High expression of ABCG/Brcp1 by cancer stem cells is thought to be an underlying cause of resistance to chemotherapy, as this protein allows for a rapid clearance of therapeutic drugs from the cells cytoplasm. 1,3When Kato et al 2 used flow cytometry on primary endometrial cancer cells and the established endometrial cancer cell line Hec1, they were able to identify a small percentage (Ͻ1%) of SP cells. Isolation and further cultivation of Hec1-derived SP and non-SP cells demonstrated that the SP cells were capable of asymmetric cell division, generating both SP and non-SP cells, which is one hallmark of stem cells. In contrast, the non-SP cells could only generate non-SP cells, but no SP cells, in accordance with a limited differentiation potential. Further analysis revealed that the SP cells expressed lower levels of the differentiation markers CD9 and CD13 compared with non-SP cells. Of note, SP cells showed a high proliferative capacity, and they were capable of dividing for at least 2 months, whereas non-SP cells stopped growing after 2 weeks of culture in mesenchymal stem cell maintenance medium. Similar results were obtained when SP and non-SP cells from an activated ( 12 Val) K-Ras-transformed rat endometrial cell line were analyzed. Plating of Hec1 SP and non-SP cell lines at a low, clonal density resulted in colony formation in the case of SP cells only. These cells also showed self-renewal properties as they could be serially cloned with similar cloning efficiencies, 2 which is an additional hallmark of stem cell function.

Syndecan-1 (CD138) Modulates Triple-Negative Breast Cancer Stem Cell Properties via Regulation of LRP-6 and IL-6-Mediated STAT3 Signaling

“…Successful silencing of Syndecan-1 in Syndecan-1 siRNA vs control siRNA-transfected MDA-MB-231 cells was confirmed by flow cytometry ( Figure 1A ). We next investigated the SP phenotype, a surrogate marker for putative stem cell activity based on the ability of effluxing the fluorescent dye Hoechst 33342 via ABC transporters [ 20 , 21 ], in the Syndecan-1-depleted cells. Hoechst 33342 dye exclusion assays revealed that Syndecan-1 siRNA transfected cells contained on average 0.62% (±0.36%) SP cells, whereas control cells contained 1.55% (±0.65%) SP cells ( Figure 1B ), corresponding to a significant >60% relative decrease of the SP upon Syndecan-1 depletion (p<0.01, n=3) ( Figure 1E ).…”

“…Side population (SP) analysis has been shown to enrich breast CSCs [ 19 ]. The SP can be identified by flow cytometry based on their property of effluxing the fluorescent dye Hoechst 33342 via ATP-binding cassette transporter proteins such as ABCG/Brcp1 [ 3 , 20 , 21 ]. Furthermore, breast CSCs can be isolated based on expression of CD44(+)/CD24(-/low), and aldehyde dehydrogenase activity (ALDH1+) [ 22 , 23 ].…”

MicroRNA-34a inhibits cells proliferation and invasion by downregulating Notch1 in endometrial cancer

“…To date, although the exact mechanism of progression and metastasis in endometrial cancer remains largely unknown, it is worth noting that ECSCs have been identified in endometrial cancer tissues [ 30 - 34 ] and considered to be an engine of tumor evolution [ 35 - 38 ]. In this study, we performed enriched ECSCs by serum-free suspension cultivation.…”

Syndecan-1 is a novel molecular marker for triple negative inflammatory breast cancer and modulates the cancer stem cell phenotype via the IL-6/STAT3, Notch and EGFR signaling pathways

“…Several lines of evidence indicate that the aggressive phenotype of IBC is due to enrichment for chemo- and radioresistant cancer stem cells (CSCs) [ 13 ]. These cells are characterized by self-renewal, unlimited and high proliferative potential, expression of multidrug-resistance proteins, efficient DNA repair capacity and apoptosis resistance [ 14 , 15 ]. Using flow cytometry, CSCs can be distinguished from the bulk of the tumor by their expression of cell surface makers CD44 and CD24 (as a CD44 (+) CD24 (-/low) subpopulation) and based on the activity of ALDH1 [ 16 ].…”

“…Using flow cytometry, CSCs can be distinguished from the bulk of the tumor by their expression of cell surface makers CD44 and CD24 (as a CD44 (+) CD24 (-/low) subpopulation) and based on the activity of ALDH1 [ 16 ]. Due to their functional link to therapeutic resistance, CSCs represent an attractive therapeutic target to dampen tumor recurrence [ 15 , 16 ].…”