Markers and Reporters to Reveal the Hierarchy in Heterogeneous Cancer Stem Cells

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.

Sterculic Acid Alters Adhesion Molecules Expression and Extracellular Matrix Compounds to Regulate Migration of Lung Cancer Cells

“…CD44 is the main cell surface receptor of hyaluronan (HA), which is associated with the rapid remodeling of the matrix [48]. CD44 is a classic cancer stem cell marker [78] and it is closed related to TGF-β-induced EMT in the A549 cell line [79]. We detected a strong inhibition of CD44 expression in the A549 cell line after 72 h of SA treatment, while H1299 kept constant levels of the gene.…”

Connexin46 Expression Enhances Cancer Stem Cell and Epithelial-to-Mesenchymal Transition Characteristics of Human Breast Cancer MCF-7 Cells

“…It is well known that CSC stemness has been related to poor patient prognosis in several types of cancers [22][23][24] whose properties are driven by transcription factors, the most important being OCT4, Sox2, and Nanog [25]. In our breast cancer cell model, the expression of Cx46GFP increased mRNA levels of OCT4 and Sox2; however, the Nanog mRNA levels were unchanged (Figure 2A).…”

Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment

“…In PC sections, 46% (± 15%) of cancer cells were CD44-positive ( Figure 1B and Supplementary Figure 1B ), indicating that nearly half of all PC tumor cells expressed this stem cell marker. Next, we analyzed CD133, which is also a transmembrane glycoprotein that is overexpressed in several cancers ( 39 ). In human PC sections, 5% (± 9%) of tumor cells were CD133-positive ( Figure 1B and Supplementary Figure 1B ).…”

“…These senescence escapers exhibit stem cell characteristics and express increased levels of the stem cell marker CD133 ( 53 ). CD133 upregulates the WNT signaling pathway via PI3K/AKT pathway, increasing stem cell properties ( 39 ). A recent study by the group of Clemens Schmitt showed that the chemotherapeutic Adriamycin (Doxorubicin) induced senescence in mouse lymphoma cells and that these senescent lymphoma cells expressed stem cell markers such as CD133 or CD44.…”