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.