Epigenetics and Cancer Stem Cells: Unleashing, Hijacking, and Restricting Cellular Plasticity

Abstract

Epigenetic mechanisms have emerged as key players in cancer development which affect cellular states at multiple stages of the disease. During carcinogenesis, alterations in chromatin and DNA methylation resulting from genetic lesions unleash cellular plasticity and favor oncogenic cellular reprogramming. At later stages, during cancer growth and progression, additional epigenetic changes triggered by interaction with the microenvironment modulate cancer cell phenotypes and properties, and shape tumor architecture. We review here recent advances highlighting the interplay between epigenetics, genetics, and cell-to-cell signaling in cancer, with particular emphasis on mechanisms relevant for cancer stem cell formation (CSC) and function.

Keywords: cancer; cancer stem cells; chromatin; epigenetics; intratumoral heterogeneity; plasticity.

Figure 1

Oncogenic Reprogramming Induced by Mutated Epigenetic Regulators. Genetic alterations in chromatin-related proteins and factors involved in the establishment and maintenance of DNA methylation lead to disruption of epigenetic regulation in either adult stem cells or committed cells, and promote neoplastic transformation. The normal function of epigenetic mechanisms (left, in blue) and the consequences of epigenetic alterations induced by mutations (right, in red) are indicated. Normal or altered chromatin in the cell nucleus is depicted in color or in grey, respectively. Empty and black circles represent unmethylated and methylated CpGs, respectively. Chromatin image adapted from the webpage of the laboratory of S. Tang (www.personal.psu.edu/sxt30/projects_chromatinenzymes.html). Abbreviation: CSC, cancer stem cell.

Figure 2

Epigenetic Mechanisms Integrate Cell-Intrinsic and Cell-Extrinsic Changes Affecting Cancer Cells and Generate Functional Intratumoral Heterogeneity. Schematic depiction of the distinct layers of alterations that affect cells during cancer development via epigenetic mechanisms. Initiating mutations (pink dash inside the nuclei) affect the cell epigenome (cylinders inside the cell nuclei) either directly, when mutations hit epigenetic regulators, or indirectly, when mutations in other drivers trigger gene expression changes mediated by chromatin remodeling and DNA methylation . In either case, epigenetic reprogramming translates mutations into malignant phenotypes and promotes the acquisition of uncontrolled self-renewal. Secondary mutations occurring during tumor growth (red and black dashes) and signals from tumor microenvironment (pink, red, and black dots outside cells) induce further changes in the epigenome of the cells, either enhancing (red) or inhibiting (black) cancer cell self-renewal in a subclone- and context-dependent manner. The phenotype of each cell within a tumor is the result of all these alterations, which collectively shape the epigenome of the cell and determine which cells drive cancer growth. In the combined layers, the cell with a pink nucleus and a thin arrow represents a cell that has maintained the self-renewal ability conferred by the initiating events. Cells with red nuclei and thick arrows represent cells with enhanced self-renewal ability due to either favorable secondary mutations (cell on the right) or signaling (cell on the left). Cells with grey nuclei represent cells that have lost self-renewal ability due to either deleterious secondary mutations or signaling.

Figure 3

Key Figure: The Complex Role of Epigenetic Mechanisms in Cancer The diagram summarizes mechanisms that affect cellular plasticity in cancer through changes in chromatin and DNA methylation. Mechanisms operating during carcinogenesis unleash cellular plasticity. During tumor growth, cellular plasticity is exploited by cancer cells (hijacking) and is further modulated either positively, to favor adaptation of cells and cancer growth (enhancing), or negatively (restricting). Blue, red/purple, and grey cells represent normal cells, self-renewing, and differentiated cancer cells, respectively. Double arrows indicate reversible transitions between cell states. Mechanisms involving indirect reprogramming of the epigenome by oncogenic hits or environmental cues are not discussed in this review because they have been described elsewhere , . Abbreviation: CSC, cancer stem cell.