A matter of life and death: stem cell survival in tissue regeneration and tumour formation


In recent years, great strides have been made in our understanding of how stem cells (SCs) govern tissue homeostasis and regeneration. The inherent longevity of SCs raises the possibility that the unique protective mechanisms in these cells might also be involved in tumorigenesis. In this Opinion article, we discuss how SCs are protected throughout their lifespan, focusing on quiescent behaviour, DNA damage response and programmed cell death. We briefly examine the roles of adult SCs and progenitors in tissue repair and tumorigenesis and explore how signals released from dying or dormant cells influence the function of healthy or aberrant SCs. Important insight into the mechanisms that regulate SC death and survival, as well as the 'legacy' imparted by departing cells, may unlock novel avenues for regenerative medicine and cancer therapy.

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Figure 1: Adult stem cell niches.
Figure 2: A stem cell perspective of wound healing versus tumour formation.
Figure 3: The DNA damage response.
Figure 4: The extrinsic and intrinsic apoptotic pathways.
Figure 5: Signals emanating from dying and dormant cells in model organisms.


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The authors apologize to colleagues whose contributions could not be adequately cited because of space constraints. The authors thank E. Koren, I. Maniv, Y. Yosefzon and A. Pérez-Garijo for discussion, advice and assistance. D.S. is supported by the Aly-Kaufman and Coleman-Cohen fellowship. Y.F. is the Deloro Career Advancement Chair and is supported by the German-Israeli Foundation for Scientific Research and Development (GIF; I-2381-412.13/2015) and Israel Cancer Research Fund (ICRF; 15-771-RCDA) grants.

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Both authors researched data for the article; made substantial contributions to discussing the content; and wrote, reviewed and edited the manuscript.

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Correspondence to Yaron Fuchs.

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Adult stem cells

(SCs). Stem cells found in different tissues in the adult organism that divide to replenish tissues and organs.


Loss of hair from parts of the head or body.

BH3 mimetics

A class of small-molecule compounds that mimic the action of proapoptotic BH3-only proteins by binding the prosurvival BCL-2 family members and consequently activating apoptosis in cells that express these proteins.

BH3 profiling

A tool used to predict the cellular response to different synthetic BH3 peptides that mimic BH3-only proteins. It provides information on which BCL-2 family protein is required for survival of specific cell types (healthy or malignant).


A transient structure formed during regeneration that consists of a proliferating mass of a morphologically homogeneous population of undifferentiated cells.

Cancer stem cell

(CSC). An immortal cell that resides within the tumour and is equipped with the capacity to self-renew and differentiate into different cell types that make up the tumour.


A family of cysteine proteases that cleave various substrates in the cell to implement apoptosis.

Homologous recombination

(HR). A DNA double strand break repair mechanism in which the genomic sequence of the broken DNA ends is restored by using sister chromatids as a template for the repair.

Interfollicular epidermis

(IFE). A stratified squamous epithelium consisting of a basal layer of proliferative cells that differentiate while they migrate upwards to form the outermost layers of the skin.

Keratin pearls

A keratinized structure formed by concentric layers of malignant squamous cells that reside in the centre of most squamous cell carcinomas.

Lineage tracing

The process of identifying all progeny of a single cell.

Nonhomologous end joining

(NHEJ). A DNA double strand break repair mechanism in which damaged DNA is repaired by bringing together the two broken ends and rejoining them by DNA ligation, resulting in small loss of nucleotides.

Progenitor cells

Dividing cells with the capacity to differentiate into a restricted lineage.


A reversible state of cell cycle arrest where cells cease to proliferate but retain their ability to re-enter the cell cycle upon specific signals.


The process by which stem cells generate additional stem cells to maintain the stem cell pool.


An irreversible state of cell cycle arrest characterized by sustained metabolic activity, changes in morphology and unresponsiveness to growth factors.

Stem cell niches

The microenvironments where stem cells reside, which maintain and regulate their fate.

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Soteriou, D., Fuchs, Y. A matter of life and death: stem cell survival in tissue regeneration and tumour formation. Nat Rev Cancer 18, 187–201 (2018). https://doi.org/10.1038/nrc.2017.122

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