Cancer Stem Cell Plasticity - A Deadly Deal

Abstract

Intratumoral heterogeneity is a major ongoing challenge in the effective therapeutic targeting of cancer. Accumulating evidence suggests that a fraction of cells within a tumor termed Cancer Stem Cells (CSCs) are primarily responsible for this diversity resulting in therapeutic resistance and metastasis. Adding to this complexity, recent studies have shown that there can be different subpopulations of CSCs with varying biochemical and biophysical traits resulting in varied dissemination and drug-resistance potential. Moreover, cancer cells can exhibit a high level of plasticity or the ability to dynamically switch between CSC and non-CSC states or among different subsets of CSCs. In addition, CSCs also display extensive metabolic plasticity. The molecular mechanisms underlying these different interconnected axes of plasticity has been under extensive investigation and the trans-differentiation process of Epithelial to Mesenchymal transition (EMT) has been identified as a major contributing factor. Besides genetic and epigenetic factors, CSC plasticity is also shaped by non-cell-autonomous effects such as the tumor microenvironment (TME). In this review, we discuss the latest developments in decoding mechanisms and implications of CSC plasticity in tumor progression at biochemical and biophysical levels, and the latest in silico approaches being taken for characterizing cancer cell plasticity. These efforts can help improve existing therapeutic approaches by taking into consideration the contribution of cellular plasticity/heterogeneity in enabling drug resistance.

Keywords: cancer stem cells; epithelial-mesenchymal transition; metabolic plasticity; metastasis; microenvironment; plasticity.

FIGURE 1

Cancer stem cells (CSCs) constitute a minor sub-population of tumor mass. Phenotypic plasticity can enable CSCs and non-CSCs to interconvert among one another, depending on cell-intrinsic (e.g., epigenetic) and cell-extrinsic (e.g., tumor microenvironment) features.

FIGURE 2

Cancer stem cell plasticity is the ability to dynamically switch between CSC and non-CSC states. It is a complex process regulated by both cell intrinsic and extrinsic factors. Plasticity plays an important role in the evolution of therapeutic resistance, tumor relapse and metastasis.

FIGURE 3

Methods to characterize CSCs and their subsets at a glance. Biochemical and biophysical characteristics of the CSCs can be strikingly different and this diversity can be understood by using multiple assays. Analyzing the properties of CSCs at Single-cell resolution enables to better comprehend the CSC plasticity. Different computational and mathematical models are also being used which helps to gain insights regarding the CSC diversity and plasticity.