Cell state plasticity, stem cells, EMT, and the generation of intra-tumoral heterogeneity

Abstract

Cellular heterogeneity in cancer represents a significant challenge. In order to develop effective and lasting therapies, it is essential to understand the source of this heterogeneity, and its role in tumor progression and therapy resistance. Here, we consider not only genetic and epigenetic mechanisms, but also inflammation and cell state reprogramming in creating tumor heterogeneity. We discuss similarities between normal mammary epithelial developmental states and various breast cancer molecular sub-types, and the cells that are thought to propagate them. We emphasize that while stem cell phenotypes and mesenchymal character have often been conflated, existing data suggest that the combination of intrinsic genetic and epigenetic changes, and microenvironmental influences generate multiple types of tumor propagating cells distinguishable by their positions along a continuum of epithelial to mesenchymal, stem to differentiated and embryonic to mature cell states. Consequently, in addition to the prospect of stem cell-directed tumor therapies, there is a need to understand interrelationships between stem cell, epithelial–mesenchymal, and tumor-associated reprogramming events to develop new therapies that mitigate cell state plasticity and minimize the evolution of tumor heterogeneity.

Breast Cancer: Multiple Subtypes within a Tumor?

“…The heterogeneity of the observed CSC populations could be a representation of the diversity in normal mammary stem/progenitor cells that are spatially and temporally regulated [20–31]. This is in line with the view that there can be “mesenchymal-oriented breast CSCs” and “epithelial-like breast CSCs” which are more similar to adult mammary stem cells (aMaSCs) and fetal MaSCs (fMaSCs), respectively [22, 31]. Although a common view in the CSC paradigm is that cells with the least differentiated state (at the apex of the hierarchy) would exhibit the most malignant traits (e.g.…”

“…The epithelial-to-mesenchymal transition (EMT) process has been shown to enable the acquisition of stem-like properties in normal and malignant mammary cells, indicating that the EMT process could be key in cell state plasticity [12, 22]. Protein Kinase C alpha (PKCα) has been shown to be a central signaling node that regulates EMT and could potentially be targeted to curb plasticity, alongside other EMT inducing pathways such as TGF-beta, WNT and STAT3 [44, 45].…”

Is an Entropy-Based Approach Suitable for an Understanding of the Metabolic Pathways of Fermentation and Respiration?

“…Indeed, according to various studies neoplastic tissue is, like other tissues, supported by CSC and has transit-amplifying cells and differentiated cells. Although there has been a confirmation by several models of this behaviour [20,21], it is not yet clear whether the CSC originate from adult stem cells (ASC) or from a process similar to the induction of pluripotency stem cells (iPSC), namely from the reprogramming of somatic cells. However, there are experimental evidences [22,23] suggesting that the CSC could originate from ASC and from phenomena correlated to their asymmetric division [22][23][24].…”

New Opportunities and Challenges to Defeat Cancer Stem Cells

“…Finally, stemness regulators such as SOX2 and EZH2 work in the absence of p53 and RB1 to confer lineage plasticity, allowing CSCs to survive anti-tumor therapies [58, 59]. Thus, the intrinsic heterogeneity, plasticity and adaptive resistance of CSCs to stress contribute to the protection of CSCs, allow them to foster the tumor mass and establish secondary tumors, and provide resistance to anti-tumor therapies [127, 133]. Whether the current CSC identification and targeting strategies are sufficient and effective enough to overcome a wide array of mechanisms CSCs possess that enable them to resist anti-tumor therapies is an open question.…”