Cell plasticity, senescence, and quiescence in cancer stem cells: Biological and therapeutic implications

Abstract

Cancer stem cells (CSCs) are a distinct population of cells within tumors with capabilities of self-renewal and tumorigenicity. CSCs play a pivotal role in cancer progression, metastasis, and relapse and tumor resistance to cytotoxic therapy. Emerging scientific evidence indicates that CSCs adopt several mechanisms, driven by cellular plasticity, senescence and quiescence, to maintain their self-renewal capability and to resist tumor microenvironmental stress and treatments. These pose major hindrances for CSC-targeting anti-cancer therapies: cell plasticity maintains stemness in CSCs and renders tumor cells to acquire stem-like phenotypes, contributing to tumor heterogeneity and CSC generation; cellular senescence induces genetic reprogramming and stemness activation, leading to CSC-mediated tumor progression and metastasis; cell quienscence facilitates CSC to overcome their intrinsic vulnerabilities and therapeutic stress, inducing tumor relapse and therapy resistance. These mechanisms are subjected to spatiotemporal regulation by hypoxia, CSC niche, and extracellular matrix in the tumor microenvironment. Here we integrate the recent advances and current knowledge to elucidate the mechanisms involved in the regulation of plasticity, senescence and quiescence of CSCs and the potential therapeutic implications for the future.

Keywords: Cancer stem cells; Plasticity; Quiescence; Senescence; Therapy resistance; Tumor microenvironment.

Figure 1.. Plasticity in cancer stem cells –

Tumors are heterogenous population of cells, composed of cells belonging to different hierarchies in the epigenetic landscape (adapted from Corad Waddington’s diagram). The cells at the top of the hierarchy are the cancer stem cells (CSCs) with the potential to give rise to all other cells in the tumor. The cells at the bottom of the landscape are the non-stem cells which usually have a limited tumorigenic potential, and stay within their respective state. Upregulation of stem cell pathways in these cells, can make them transition into a cell state higher up in the hierarchy, which is reffered as plasticity. The pathways inducing the push toward stemness are mediated through eptithelial-mesenchymal transition (EMT) transcriptiom factors such as SNAIL and ZEB1, stem cell transcription factors such as SOX2, Hippo/YAP/TAZ, NOTCH/CSL, and epigenetic modulator MLL5.

Figure 2.. Senescence and quiescence in cancer stem cells –

Senescence is a halt mainly in cell cycle G1, induced by persistent DNA damage, reactive oxygen species (ROS), and oncogenic stress. Senescence-associated secretory phenotype, a feature of senescence, induces secretion of cytokines such as IL-6 and IL-8 to promote tumorigenesis via paracrine effects. Senescent cells also undergo reprogramming and activation of stem cell transcriptional factors including WNT/LEF1, OCT4 and NANOG to induce plasticity and stemness activation. The paracrine effect and the genetic reprograming may lead to reversal of cell senescence. Quiescence is a cell state of resting a G₀ phase to overcome vulnerabilities and maintain stemness, which is induced by therapeutic stress, ROS, or microenvironmental cues. Quiescence is a reversible state where cells switch into a diving state upon favorable conditions through KDM6, NOTCH/CSL, SOX, AKT1.

Figure 3.. Cancer stem cell niche regulating plasticity, senescence and quiescence –

The niche of CSCs is defined by the support provided by their peripheral environment, namely, the vasculature, fibroblasts, and extracellular matrix (ECM), which is characterized by hypoxia. Hypoxia downregulates p21 to inhibit senescence, modulates Akt and CBP activity to induce cell quiescence, and activaes EMT and stem-cell pathways Notch/CSL, OCT4, and c-MYC to regulate plasticity and stemness. The CSCs and vasculature support each other by secreting various growth factors including VEGF and bFGF. ECM proteins, including periostin, collagen, hyaluronan, and tenacin-C, mainly derived from fibroblasts, activate stemness-activating pathways mediated through WNT/β-catenin, FAK, EMT, and NOTCH/CSL. Tumor-associated macrophages foster CSC phenotypes through ephrin-A ligands, pleiotrophin, IL-6, and TGF-β, and CSCs reciprocally induce macrophage recruitment and polarization through CCL2, CCL5, CSF1, periostin, and WISP1.