The evolving concept of cancer stem-like cells in thyroid cancer and other solid tumors

Abstract

The cancer stem-like cell (CSC) hypothesis postulates that a small population of cells in a cancer has self-renewal and clonal tumor initiation properties. These cells are responsible for tumor initiation, growth, recurrence and for resistance to chemotherapy and radiation therapy. CSCs can be characterized using markers such as SSEA-1, SSEA-4, CD44, CD24, ALDEFLUOR and others. CSCs form spheres when they are cultured in serum-free condition in low attachment plates and can generate tumors when injected into immune-deficient mice. During epithelial to mesenchymal transition (EMT), cells lose cellular adhesion and polarity and acquire an invasive phenotype. Recent studies have established a relationship between EMT and increased numbers of CSCs in some solid malignancies. Non-coding RNAs such as microRNAs and long non-coding RNAs (lncRNAs) have been shown to have important roles during EMT and some of these molecules also have regulatory roles in the proliferation of CSCs. Specific lncRNAs enhanced cell migration and invasion in breast carcinomas, which was associated with the generation of stem cell properties. The tumor microenvironment of CSCs also has an important role in tumor progression. Recent studies have shown that the interaction between tumor cells and the local microenvironment at the metastatic site leads to the development of premetastatic niche(s) and allows for the proliferation of the metastatic cells during colonization. The role of exosomes in the microenvironment during the EMT program is currently a major area of research. This review examines CSCs and the relationship between EMT and CSCs in solid tumors with emphasis on thyroid CSCs. The role of non-coding RNAs and of the microenvironment in EMT and in tumor progression are also examined. This review also highlights the growing number of studies that show the close association of EMT and CSCs and the role of exosomes and other elements of the tissue microenvironment in CSC metastasis. A better understanding of these mechanisms will lead to more effective targeting of primary and metastatic malignancies.

Junctional adhesion molecule‐A is down‐regulated in anaplastic thyroid carcinomas and reduces cancer cell aggressiveness by modulating p53 and GSK3 α/β pathways

“…24,25 It is well recognized that EMT represents a major mechanism of tumor progression and, in particular, in thyroid carcinogenesis. [26][27][28] Here, through an EMT profiler array, we found that JAM-A was one of the most downregulated genes in ATC and this was confirmed at the protein level. In addition, we showed that JAM-A impaired several hallmarks of thyroid malignant transformation by regulating p53 and GSK3 α/β pathways.…”

“…EMT is a very complex process during carcinogenesis, in which polarized epithelial cells lose epithelial properties and acquire mesenchymal phenotype, thereby promoting tumor invasion and metastasis . In thyroid tumors, EMT plays an important role in the progression of NTs into PTC and ATC . More important, a strict molecular network of genes involved in cell‐cell adhesion and in tight junction formation, driving EMT, are deregulated in ATC .…”

“…36,37 In thyroid tumors, EMT plays an important role in the progression of NTs into PTC and ATC. 27,38 More important, a strict molecular network of genes involved in cell-cell adhesion and in tight junction formation, driving EMT, are deregulated in ATC. 26,28 Consequently, the molecular players of the EMT process could represent potential novel molecular targets for more effective treatment of ATC.…”

“…It is well recognized that EMT represents a major mechanism of tumor progression and, in particular, in thyroid carcinogenesis …”

Targeting autophagy in thyroid cancers

“…Epithelial-to-mesenchymal transition (EMT) is associated with the development and invasion of thyroid cancers, especially PTC and ATC (Hardy et al 2007, Hardin et al 2017. EMT and autophagy are two distinct events but a cross-talk exists between these two events in a controversial way (Marcucci et al 2017).…”