Abstract
The cancer stem cell (CSC) model depicts that tumors are hierarchically organized and maintained by CSCs lying at the apex. CSCs have been “identified” in a variety of tumors through the tumor-forming assay, in which tumor cells distinguished by a certain cell surface marker (known as a CSC marker) were separately transplanted into immunodeficient mice. In such assays, tumor cells positive but not negative for the CSC marker (hereby defined as CSC+ and CSC− cells, respectively) have the ability of tumor-forming and generating both progenies. However, here we show that CSC+ and CSC− cells exhibit similar proliferation in the native states. Using a cell tracing method, we demonstrate that CSC− cells exhibit similar tumorigenesis and proliferation as CSC+ cells when they were co-transplanted into immunodeficient mice. Through serial single-cell derived subline construction, we further demonstrated that CSC+ and CSC− cells from CSC marker expressing tumors could invariably generate both progenies, and their characteristics are maintained among different generations irrespective of the origins (CSC+-derived or CSC−-derived). These findings demonstrate that tumorigenic cells cannot be distinguished by common CSC markers alone and we propose that cautions should be taken when using these markers independently to identify cancer stem cells due to the phenotypic plasticity of tumor cells.
Highlights
A fundamental question in the field of tumor research is which cells can initiate tumors
Using a trypsin-free dissociation protocol, we detected the percentage of cancer stem cell (CSC) marker positive cells (e.g., CD34+CD382 for acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), and chronic myeloid leukemia (CML), CD44+CD242 for breast cancer, CD133+ for glioblastoma and colon cancer, and CD271+ for melanoma) in human primary tumors as well as tumor cell lines by flow cytometric analysis
We found that a considerable number of primary tumors or tumor cell lines do not express those CSC markers (Figure 1A), which is consistent with some other reports [38,39]
Summary
A fundamental question in the field of tumor research is which cells can initiate tumors. Two models have been put forward to explain the initiation of tumors [1,2]. The cancer stem cell (CSC) model ( known as the hierarchy model) argues that, like normal tissues, which are cellular hierarchies maintained by stem cells, tumors can be explained by hierarchical organizations, in which CSCs lying at the apex hold the capacity for tumor initiation, selfrenewal, and generation of phenotypically diverse cells with no or limited proliferative capacity. Advocates of the CSC model propose that CSCs may account for tumor behaviors such as metastasis [3,4] and resistance to chemotherapy or radiotherapy [5,6,7,8,9]. CSC-targeted therapy may be the future direction of tumor treatment [10,11,12,13]
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