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Molecular pathology underlying the robustness of cancer stem cells - PubMed

  • ️Fri Jan 01 2021

Review

Molecular pathology underlying the robustness of cancer stem cells

Go J Yoshida et al. Regen Ther. 2021.

Abstract

Intratumoral heterogeneity is tightly associated with the failure of anticancer treatment modalities including conventional chemotherapy, radiation therapy, and molecularly targeted therapy. Such heterogeneity is generated in an evolutionary manner not only as a result of genetic alterations but also by the presence of cancer stem cells (CSCs). CSCs are proposed to exist at the top of a tumor cell hierarchy and are undifferentiated tumor cells that manifest enhanced tumorigenic and metastatic potential, self-renewal capacity, and therapeutic resistance. Properties that contribute to the robustness of CSCs include the abilities to withstand redox stress, to rapidly repair damaged DNA, to adapt to a hyperinflammatory or hyponutritious tumor microenvironment, and to expel anticancer drugs by the action of ATP-binding cassette transporters as well as plasticity with regard to the transition between dormant CSC and transit-amplifying progenitor cell phenotypes. In addition, CSCs manifest the phenomenon of metabolic reprogramming, which is essential for maintenance of their self-renewal potential and their ability to adapt to changes in the tumor microenvironment. Elucidation of the molecular underpinnings of these biological features of CSCs is key to the development of novel anticancer therapies. In this review, we highlight the pathological relevance of CSCs in terms of their hallmarks and identification, the properties of their niche-both in primary tumors and at potential sites of metastasis-and their resistance to oxidative stress dependent on system xc (-).

Keywords: ABC, ATP-binding cassette; ALDH, Aldehyde dehydrogenase; BMP, Bone morphogenetic protein; CAF, Cancer-associated fibroblast; CD44 variant; CD44v, CD44 variant; CSC, Cancer stem cell; CTC, Circulating tumor cell; CagA, Cytotoxin-associated gene A; Cancer stem cell; DTC, Disseminated tumor cell; E/M, Epithelial/mesenchymal; ECM, Extracellular matrix; EGF, Epidermal growth factor; EMT, Epithelial-to-mesenchymal transition; EpCAM, Epithelial cell adhesion moleculeE; Epithelial-to-mesenchymal transition (EMT); GSC, Glioma stem cell; GSH, reduced glutathione; HGF, Hepatocyte growth factor; HNSCC, Head and neck squamous cell cancer; IL, Interleukin; Intratumoral heterogeneity; MAPK, mitogen-activated protein kinase; MET, mesenchymal-to-epithelial transition; NSCLC, non–small cell lung cancer; Niche; Nrf2, nuclear factor erythroid 2–related factor 2; OXPHOS, Oxidative phosphorylation; Plasticity; Prrx1, Paired-related homeodomain transcription factor 1; ROS, Reactive oxygen species; SRP1, Epithelial splicing regulatory protein 1; TGF-β, Transforming growth factor–β.

© 2021 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1

The hierarchical and dynamic stemness models. In the hierarchical model, cancer stem cells (CSCs) give rise to differentiated non-CSCs and thereby contribute to the maintenance and growth of tumor tissue. The coexistence of both CSCs and non-CSC tumor cells is responsible for intratumoral heterogeneity. In contrast, the dynamic stemness model emphasizes the plasticity between CSCs and non-CSCs. According to this model, the transition between undifferentiated CSCs and differentiated non-CSCs is reversible.

Fig. 2
Fig. 2

Tumor self-seeding by circulating tumor cells (CTCs). CTCs tend to reinfiltrate an established tumor, enriching it with aggressive cells that have withstood a period of dissemination. This process, known as “tumor self-seeding,” may have consequences for tumor growth and the generation of metastatic cell progeny.

Fig. 3
Fig. 3

Regulation of redox stress by the ESRP1-CD44v-xCT-GSH axis. (a) Epithelial splicing regulatory protein 1 (ESRP1) contributes to alternative splicing of CD44 pre-mRNA that generates CD44v8-10 (CD44v). CD44v stabilizes the xCT (SLC7A11) subunit of system xc (−) at the plasma membrane and thereby promotes the intracellular uptake of cystine. Given that cysteine is an essential and rate-limiting factor for synthesis of the reduced form of glutathione (GSH), the interaction between CD44v and xCT protects cells from oxidative stress and the induction of ferroptosis. (b) CD44v-positive cancer stem cells (CSCs) with high levels of GSH are predominantly responsible for colonization of the premetastatic niche for breast cancer cells in the lungs. In contrast to CD44v-negative differentiated tumor cells, CD44v-positive cancer cells are sensitive to sulfasalazine (SSZ).

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