Abstract
A subpopulation within cancer, known as cancer stem cells (CSCs), regulates tumor initiation, chemoresistance, and metastasis. At a closer look, CSCs show functional heterogeneity and hierarchical organization. The present review is an attempt to assign marker profiles to define the functional heterogeneity and hierarchical organization of CSCs, based on a series of single-cell analyses. The evidences show that analogous to stem cell hierarchy, self-renewing Quiescent CSCs give rise to the Progenitor CSCs with limited proliferative capacity, and later to a Progenitor-like CSCs, which differentiates to Proliferating non-CSCs. Functionally, the CSCs can be tumor-initiating cells (TICs), drug-resistant CSCs, or metastasis initiating cells (MICs). Although there are certain marker profiles used to identify CSCs of different cancers, molecules like CD44, CD133, ALDH1A1, ABCG2, and pluripotency markers [Octamer binding transcriptional factor 4 (OCT4), SOX2, and NANOG] are used to mark CSCs of a wide range of cancers, ranging from hematological malignancies to solid tumors. Our analysis of the recent reports showed that a combination of these markers can demarcate the heterogeneous CSCs in solid tumors. Reporter constructs are widely used for easy identification and quantification of marker molecules. In this review, we discuss the suitability of reporters for the widely used CSC markers that can define the heterogeneous CSCs. Since the CSC-specific functions of CD44 and CD133 are regulated at the post-translational level, we do not recommend the reporters for these molecules for the detection of CSCs. A promoter-based reporter for ABCG2 may also be not relevant in CSCs, as the expression of the molecule in cancer is mainly regulated by promoter demethylation. In this context, a dual reporter consisting of one of the pluripotency markers and ALDH1A1 will be useful in marking the heterogeneous CSCs. This system can be easily adapted to high-throughput platforms to screen drugs for eliminating CSCs.
Highlights
Tumor heterogeneity had been considered as a hallmark of tumors from the very beginning, since the origin of the clonal evolution of cancer
These cells can migrate to new sites and reside as dormant cells, which might have been the dormant population observed in label-retaining cells with low expression of all the genes, including the pluripotency markers
If we use a single pluripotency marker to screen drugs targeting cancer stem cells (CSCs), we identify the Quiescent and Progenitor population, but do not take the Progenitor-like population into account, which are really important with respect to drug response and metastasis
Summary
Tumor heterogeneity had been considered as a hallmark of tumors from the very beginning, since the origin of the clonal evolution of cancer. With the tremendous technological advancement over these years, when cells at a single-cell level can be analyzed, it is evident that malignant cells exhibit heterogeneity at the genetic level as well as phenotypic level. Another important feature is the plasticity of these heterogeneous populations, which can be defined as the ability to dynamically switch between these phenotypes. All the widely-used markers identify CSCs enriched for tumor initiation potential, drug resistance, and metastasis initiating efficiency (Table 1) In other words, these markers identify a group of CSCs exhibiting different characteristics and levels of differentiation. A detailed analysis revealing the phenotype of each CSC-subpopulation can reveal a marker profile that can demarcate the subpopulations of CSCs
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