Table 1. Principles and characteristics... | Rockefeller University Press

Table 1.

Principles and characteristics of lasting cell-cycle arrest conditions

Long-term arrest condition	Senescence	Quiescence	Dormancy^{^a}	Diapause-like
Features
Lead biological property	Terminal cell-cycle arrest and secretion (SASP) (Herranz and Gil, 2018; Schmitt et al., 2023)	Stand-by arrest under insufficient growth-supportive conditions (Marescal and Cheeseman, 2020)	Protective, hibernation-like economized survival strategy, likely overlapping with quiescence—possibly as the “quiescence of stem-like cells” (Triana-Martínez et al., 2020)	A state of suspended development as a reproductive survival strategy under unfavorable environmental conditions, especially insufficient nutrient supply (originally leading to delayed blastocyst implantation but adopted by other cells as a diapause-like adaptation) (Hu et al., 2020)
Biomedical implications	Embryonic development, wound healing, natural aging versus age-related pathologies, cancer development and therapy, auto-immunity, cardiovascular disorders, metabolic diseases, neurodegeneration, and virus infection (Baker et al., 2011, 2016; Bodnar et al., 1998; Budamagunta et al., 2021; Bussian et al., 2018; Demaria et al., 2014; Gorgoulis et al., 2019; Hayflick and Moorhead, 1961; Lee and Schmitt, 2019; Lee et al., 2021; McHugh and Gil, 2018; Muñoz-Espín et al., 2013; Schmitt et al., 2023; Song et al., 2020; Storer et al., 2013; Yu et al., 1990)	Reduced mitochondrial activity to protect from oxidative damage (Marescal and Cheeseman, 2020)	Protective low-level metabolic state in less supportive environment, reversible upon changes of external conditions—hence, an adaptive survival mechanism, deleterious as a cancer cell persister state (difficult to target and a risk as a source of late recurrence or metastasis), latent pluripotency program (Endo and Inoue, 2019; Phan and Croucher, 2020; Triana-Martínez et al., 2020)	As a “diapause-like” state usurpation of an embryonic program to lower both nutritive needs and cellular vulnerabilities under ongoing stresses (such as anticancer therapy) (Dhimolea et al., 2021; Hu et al., 2020)
Impact on tumor fate	Tumor-suppressive (acute) and tumor-promoting (via SASP and long-term persisters), the potential similarity between long-term persistent senescent cells and dormant cells, epithelial–mesenchymal transition (EMT) (Ansieau et al., 2008; Schmitt et al., 2023; Triana-Martínez et al., 2020)	As a mere quiescent state presumably tumor-suppressive, but less treatment-sensitive, see also dormancy or senescence	Tumor-suppressive (even of oncogenic signaling), but a potential source of late relapses, especially metastasis (arising from early disseminated cancer cells), partial EMT features (Harper et al., 2016; Riethmüller and Klein, 2001; Triana-Martínez et al., 2020)	Similar to a drug-tolerant persister state, diapause-like high signature-positive colorectal cancer patients experience inferior outcome (Takata et al., 1998)
Mechanisms of arrest control	Eroded telomeres, mitogenic oncogenes, anticancer therapeutics, virus infection and pro-senescent cytokines as triggers, PTEN loss, CDK inhibition, cooperation of upstream damage signaling (replication stress, DNA damage), elevated cell-cycle inhibitor expression and heterochromatinization of growth-promoting gene loci; SASP-mediated paracrine senescence as a reinforcing mechanism (Acosta et al., 2013; Alimonti et al., 2010; Bartkova et al., 2006; Braumüller et al., 2013; Coppé et al., 2008; Di Micco et al., 2006; Narita et al., 2003; Perez et al., 2015; Reimann et al., 2010)	Insufficient supply of external growth signals, niche signals, and/or nutrients, progression to a firmer senescent arrest might be prevented by the transcriptional repressor HES1 (Sang et al., 2008)	Induced by less supportive microenvironmental cues (e.g., hypoxic regions), “seed & soil” imbalance-driven, deprivation of growth factors or secretion of pro-dormant T-cell-originated cytokines, lack of outside-in β1 integrin signaling, triggered by anticancer therapy, especially tyrosine kinase inhibitors (TKI) (Endo and Inoue, 2019; Paget, 1889; Wang et al., 2019; White et al., 2004)	Myc suppression, mTOR suppression, and upregulated polycomb complex members (such as CBX7), leading to H3K27me3-marked gene repression, chemotherapy but not CDKi may evoke a diapause-like transcriptional expression profile (Dhimolea et al., 2021; Hu et al., 2020; Scognamiglio et al., 2016)
(In)sensitivity to external growth stimuli	Insensitive	Sensitive	Potentially sensitive	Sensitive
Cell death sensitivity	Reduced due to elevated anti-apoptotic pathways (Bcl2 family members, pro-survival kinase networks) (Zhu et al., 2017)	Variable	Insensitive (Bcl2 family members upregulated) (Minassian et al., 2019)	Low apoptotic priming (Dhimolea et al., 2021)
Metabolic characteristics and autophagic state	Hypermetabolic, active autophagy (also termed “geroconversion”) (Blagosklonny, 2014; Dörr et al., 2013; Kaplon et al., 2013; Young et al., 2009)	Decreased metabolic activity, enhanced autophagy and mitophagy (Marescal and Cheeseman, 2020)	Very low metabolic activity, minimized energetic (ATP) needs, active autophagy (Endo and Inoue, 2019)	Low metabolic activity, closely linked to activated autophagy (Dhimolea et al., 2021)
Transcriptional and translational activity	Enhanced, based on complex (de)regulation (Dörr et al., 2013)	Reduced biosynthesis	Reduced biosynthesis, “hypotranscription”	Profoundly reduced biosynthesis (Dhimolea et al., 2021; Scognamiglio et al., 2016)
Epigenomic reorganization and cellular plasticity	Extensive (Chandra et al., 2015; De Cecco et al., 2013; Martínez-Zamudio et al., 2020, 2023; Narita et al., 2006; Shah et al., 2013; Tasdemir et al., 2016; Zhang et al., 2005)	Remains to be investigated in greater detail, potential overlap with analyses from senescent and dormant cells	Remains to be investigated in greater detail, potential overlap with analyses from senescent and dormant cells	Remains to be investigated in greater detail
Cell morphology	Enlarged, flattened, vacuole/granule-rich, vanishing cell borders, SAHF, multi-nucleation (Dimri et al., 1995; Hayflick and Moorhead, 1961; Narita et al., 2003; Serrano et al., 1997)	Reduced cell size, potentially invasive and migrating (Triana-Martínez et al., 2020)	High migration capacity (Wnt-, RANK-dependent) (Triana-Martínez et al., 2020)	Not consistently reported yet
Environmental remodeling and immune crosstalk	SASP, exocytosis, cytoplasmic cell–cell bridges, immune recognition by innate and adaptive immune cells, upregulation of MHC I/II and immune checkpoint ligands (Chen et al., 2023a; Chuprin et al., 2013; Coppé et al., 2008; Eggert et al., 2016; Kang et al., 2011; Marin et al., 2023; Reimann et al., 2021; Sagiv et al., 2013; Xue et al., 2007)	No consistent reports	MHC II upregulated, but adaptive immune resistance (“immune cloaking”) via upregulation of immune checkpoint ligands, potentially SASP-like secretome (Phan and Croucher, 2020; Triana-Martínez et al., 2020)	No consistent reports
(Ir)reversibility and underlying mechanisms	Escape mostly via endogenous (epi)genetic defects, H3K9 demethylation, CDK inhibitor loss, Rb or p53 inactivation (Beauséjour et al., 2003; Lee and Schmitt, 2019; Martínez-Zamudio et al., 2023; Milanovic et al., 2018; Rane et al., 2002; Sage et al., 2003; Saleh et al., 2019; Schleich et al., 2020; Yu et al., 2018)	Reversible via extrinsic growth-promoting signals, e.g., through Coco, Noggin, Taz, FAK-ERK-Yap (Triana-Martínez et al., 2020)	Reversible via blockade of p38MAPK activity, but typically through extrinsic growth-promoting signals (Aguirre-Ghiso et al., 2003)	Reversible, potentially via Myc reelevation
Functional fate upon arrest cessation	Self-renewal, cancer stemness, reprogramming, plasticity/transdifferentiation, promotion of metastasis (Demaria et al., 2017; Laberge et al., 2012; Lapasset et al., 2011; Milanovic et al., 2018; Mosteiro et al., 2016; Ritschka et al., 2017; Webster et al., 2015)	Regrowth	Some similarity of dormancy and tissue stem cells, “awakening” into proliferation/self-renewal by growth factors and changes in niche conditions (Phan and Croucher, 2020)	Exit from diapause reinstates pluripotency, rather reestablishment of previous growth capacity when exiting from diapause-like conditions (Dhimolea et al., 2021; Scognamiglio et al., 2016)
Therapeutic targeting	Rather drug-resistant, but susceptible to senomorphics (to blunt the SASP) or senolytics (to selectively eliminate) (Birch and Gil, 2020; Chaib et al., 2022)	Rather drug-resistant, but susceptible to some targeted therapies or senolytics upon conversion to senescence (geroconversion) as a “lock-in” strategy, alternatively growth factor-enforced “lock-out” strategy followed by conventional anticancer agents (Marescal and Cheeseman, 2020; Triana-Martínez et al., 2020)	Rather drug-resistant, but susceptible to targeting of niche factors (e.g., CXCR4 antagonist, hypomethylating agents such as 5-azacytidine, proteasome blockade, G-CSF), Axl inhibition, YAP/TEAD targeting, potentially susceptible to senolytics with or without preceding (gero-)conversion to senescence (Kurppa et al., 2020; Phan and Croucher, 2020)	Rather drug-resistant, reminiscent of a TKI-preexposed “drug-tolerant persister” state, sensitive to CDK9 inhibition (Dhimolea et al., 2021; Hata et al., 2016; Rehman et al., 2021)
Best discriminating markers	SA-β-gal, high-level p16^INK4a, H3K9me3, and—less discriminative—DDR signature, PML bodies, NF-κB and C/EBPβ activity, SASP, elevated urokinase-plasminogen activator receptor (uPAR) expression (Amor et al., 2020; Bartkova et al., 2006; Braig et al., 2005; Coppé et al., 2008; de Stanchina et al., 2004; Dimri et al., 1995; Kuilman et al., 2008; Serrano et al., 1997)	Not very distinctive, elevated CDKi such as p21^CIP1 and p27^KIP1, enhanced TGF-β, HIFα1 and Gas6 signaling (Triana-Martínez et al., 2020)	Low ERK/p38MAPK ratio, low Myc levels, low pAKT and mTORC1 signaling, increased NR2F1, SPARC, low uPAR expression, and—less discriminative—elevated TGF-β2 signaling, increased stemness (Wnt, Rank, Nanog, Sox9), enhanced endoplasmic reticulum stress (Aguirre Ghiso et al., 1999; Endo and Inoue, 2019; Phan and Croucher, 2020)	Low Myc levels, and—less discriminative—decreased mTOR signaling, activated ERK1/2 signaling

Long-term arrest condition	Senescence	Quiescence	Dormancy^a	Diapause-like
Features
Lead biological property	Terminal cell-cycle arrest and secretion (SASP) (Herranz and Gil, 2018; Schmitt et al., 2023)	Stand-by arrest under insufficient growth-supportive conditions (Marescal and Cheeseman, 2020)	Protective, hibernation-like economized survival strategy, likely overlapping with quiescence—possibly as the “quiescence of stem-like cells” (Triana-Martínez et al., 2020)	A state of suspended development as a reproductive survival strategy under unfavorable environmental conditions, especially insufficient nutrient supply (originally leading to delayed blastocyst implantation but adopted by other cells as a diapause-like adaptation) (Hu et al., 2020)
Biomedical implications	Embryonic development, wound healing, natural aging versus age-related pathologies, cancer development and therapy, auto-immunity, cardiovascular disorders, metabolic diseases, neurodegeneration, and virus infection (Baker et al., 2011, 2016; Bodnar et al., 1998; Budamagunta et al., 2021; Bussian et al., 2018; Demaria et al., 2014; Gorgoulis et al., 2019; Hayflick and Moorhead, 1961; Lee and Schmitt, 2019; Lee et al., 2021; McHugh and Gil, 2018; Muñoz-Espín et al., 2013; Schmitt et al., 2023; Song et al., 2020; Storer et al., 2013; Yu et al., 1990)	Reduced mitochondrial activity to protect from oxidative damage (Marescal and Cheeseman, 2020)	Protective low-level metabolic state in less supportive environment, reversible upon changes of external conditions—hence, an adaptive survival mechanism, deleterious as a cancer cell persister state (difficult to target and a risk as a source of late recurrence or metastasis), latent pluripotency program (Endo and Inoue, 2019; Phan and Croucher, 2020; Triana-Martínez et al., 2020)	As a “diapause-like” state usurpation of an embryonic program to lower both nutritive needs and cellular vulnerabilities under ongoing stresses (such as anticancer therapy) (Dhimolea et al., 2021; Hu et al., 2020)
Impact on tumor fate	Tumor-suppressive (acute) and tumor-promoting (via SASP and long-term persisters), the potential similarity between long-term persistent senescent cells and dormant cells, epithelial–mesenchymal transition (EMT) (Ansieau et al., 2008; Schmitt et al., 2023; Triana-Martínez et al., 2020)	As a mere quiescent state presumably tumor-suppressive, but less treatment-sensitive, see also dormancy or senescence	Tumor-suppressive (even of oncogenic signaling), but a potential source of late relapses, especially metastasis (arising from early disseminated cancer cells), partial EMT features (Harper et al., 2016; Riethmüller and Klein, 2001; Triana-Martínez et al., 2020)	Similar to a drug-tolerant persister state, diapause-like high signature-positive colorectal cancer patients experience inferior outcome (Takata et al., 1998)
Mechanisms of arrest control	Eroded telomeres, mitogenic oncogenes, anticancer therapeutics, virus infection and pro-senescent cytokines as triggers, PTEN loss, CDK inhibition, cooperation of upstream damage signaling (replication stress, DNA damage), elevated cell-cycle inhibitor expression and heterochromatinization of growth-promoting gene loci; SASP-mediated paracrine senescence as a reinforcing mechanism (Acosta et al., 2013; Alimonti et al., 2010; Bartkova et al., 2006; Braumüller et al., 2013; Coppé et al., 2008; Di Micco et al., 2006; Narita et al., 2003; Perez et al., 2015; Reimann et al., 2010)	Insufficient supply of external growth signals, niche signals, and/or nutrients, progression to a firmer senescent arrest might be prevented by the transcriptional repressor HES1 (Sang et al., 2008)	Induced by less supportive microenvironmental cues (e.g., hypoxic regions), “seed & soil” imbalance-driven, deprivation of growth factors or secretion of pro-dormant T-cell-originated cytokines, lack of outside-in β1 integrin signaling, triggered by anticancer therapy, especially tyrosine kinase inhibitors (TKI) (Endo and Inoue, 2019; Paget, 1889; Wang et al., 2019; White et al., 2004)	Myc suppression, mTOR suppression, and upregulated polycomb complex members (such as CBX7), leading to H3K27me3-marked gene repression, chemotherapy but not CDKi may evoke a diapause-like transcriptional expression profile (Dhimolea et al., 2021; Hu et al., 2020; Scognamiglio et al., 2016)
(In)sensitivity to external growth stimuli	Insensitive	Sensitive	Potentially sensitive	Sensitive
Cell death sensitivity	Reduced due to elevated anti-apoptotic pathways (Bcl2 family members, pro-survival kinase networks) (Zhu et al., 2017)	Variable	Insensitive (Bcl2 family members upregulated) (Minassian et al., 2019)	Low apoptotic priming (Dhimolea et al., 2021)
Metabolic characteristics and autophagic state	Hypermetabolic, active autophagy (also termed “geroconversion”) (Blagosklonny, 2014; Dörr et al., 2013; Kaplon et al., 2013; Young et al., 2009)	Decreased metabolic activity, enhanced autophagy and mitophagy (Marescal and Cheeseman, 2020)	Very low metabolic activity, minimized energetic (ATP) needs, active autophagy (Endo and Inoue, 2019)	Low metabolic activity, closely linked to activated autophagy (Dhimolea et al., 2021)
Transcriptional and translational activity	Enhanced, based on complex (de)regulation (Dörr et al., 2013)	Reduced biosynthesis	Reduced biosynthesis, “hypotranscription”	Profoundly reduced biosynthesis (Dhimolea et al., 2021; Scognamiglio et al., 2016)
Epigenomic reorganization and cellular plasticity	Extensive (Chandra et al., 2015; De Cecco et al., 2013; Martínez-Zamudio et al., 2020, 2023; Narita et al., 2006; Shah et al., 2013; Tasdemir et al., 2016; Zhang et al., 2005)	Remains to be investigated in greater detail, potential overlap with analyses from senescent and dormant cells	Remains to be investigated in greater detail, potential overlap with analyses from senescent and dormant cells	Remains to be investigated in greater detail
Cell morphology	Enlarged, flattened, vacuole/granule-rich, vanishing cell borders, SAHF, multi-nucleation (Dimri et al., 1995; Hayflick and Moorhead, 1961; Narita et al., 2003; Serrano et al., 1997)	Reduced cell size, potentially invasive and migrating (Triana-Martínez et al., 2020)	High migration capacity (Wnt-, RANK-dependent) (Triana-Martínez et al., 2020)	Not consistently reported yet
Environmental remodeling and immune crosstalk	SASP, exocytosis, cytoplasmic cell–cell bridges, immune recognition by innate and adaptive immune cells, upregulation of MHC I/II and immune checkpoint ligands (Chen et al., 2023a; Chuprin et al., 2013; Coppé et al., 2008; Eggert et al., 2016; Kang et al., 2011; Marin et al., 2023; Reimann et al., 2021; Sagiv et al., 2013; Xue et al., 2007)	No consistent reports	MHC II upregulated, but adaptive immune resistance (“immune cloaking”) via upregulation of immune checkpoint ligands, potentially SASP-like secretome (Phan and Croucher, 2020; Triana-Martínez et al., 2020)	No consistent reports
(Ir)reversibility and underlying mechanisms	Escape mostly via endogenous (epi)genetic defects, H3K9 demethylation, CDK inhibitor loss, Rb or p53 inactivation (Beauséjour et al., 2003; Lee and Schmitt, 2019; Martínez-Zamudio et al., 2023; Milanovic et al., 2018; Rane et al., 2002; Sage et al., 2003; Saleh et al., 2019; Schleich et al., 2020; Yu et al., 2018)	Reversible via extrinsic growth-promoting signals, e.g., through Coco, Noggin, Taz, FAK-ERK-Yap (Triana-Martínez et al., 2020)	Reversible via blockade of p38MAPK activity, but typically through extrinsic growth-promoting signals (Aguirre-Ghiso et al., 2003)	Reversible, potentially via Myc reelevation
Functional fate upon arrest cessation	Self-renewal, cancer stemness, reprogramming, plasticity/transdifferentiation, promotion of metastasis (Demaria et al., 2017; Laberge et al., 2012; Lapasset et al., 2011; Milanovic et al., 2018; Mosteiro et al., 2016; Ritschka et al., 2017; Webster et al., 2015)	Regrowth	Some similarity of dormancy and tissue stem cells, “awakening” into proliferation/self-renewal by growth factors and changes in niche conditions (Phan and Croucher, 2020)	Exit from diapause reinstates pluripotency, rather reestablishment of previous growth capacity when exiting from diapause-like conditions (Dhimolea et al., 2021; Scognamiglio et al., 2016)
Therapeutic targeting	Rather drug-resistant, but susceptible to senomorphics (to blunt the SASP) or senolytics (to selectively eliminate) (Birch and Gil, 2020; Chaib et al., 2022)	Rather drug-resistant, but susceptible to some targeted therapies or senolytics upon conversion to senescence (geroconversion) as a “lock-in” strategy, alternatively growth factor-enforced “lock-out” strategy followed by conventional anticancer agents (Marescal and Cheeseman, 2020; Triana-Martínez et al., 2020)	Rather drug-resistant, but susceptible to targeting of niche factors (e.g., CXCR4 antagonist, hypomethylating agents such as 5-azacytidine, proteasome blockade, G-CSF), Axl inhibition, YAP/TEAD targeting, potentially susceptible to senolytics with or without preceding (gero-)conversion to senescence (Kurppa et al., 2020; Phan and Croucher, 2020)	Rather drug-resistant, reminiscent of a TKI-preexposed “drug-tolerant persister” state, sensitive to CDK9 inhibition (Dhimolea et al., 2021; Hata et al., 2016; Rehman et al., 2021)
Best discriminating markers	SA-β-gal, high-level p16^INK4a, H3K9me3, and—less discriminative—DDR signature, PML bodies, NF-κB and C/EBPβ activity, SASP, elevated urokinase-plasminogen activator receptor (uPAR) expression (Amor et al., 2020; Bartkova et al., 2006; Braig et al., 2005; Coppé et al., 2008; de Stanchina et al., 2004; Dimri et al., 1995; Kuilman et al., 2008; Serrano et al., 1997)	Not very distinctive, elevated CDKi such as p21^CIP1 and p27^KIP1, enhanced TGF-β, HIFα1 and Gas6 signaling (Triana-Martínez et al., 2020)	Low ERK/p38MAPK ratio, low Myc levels, low pAKT and mTORC1 signaling, increased NR2F1, SPARC, low uPAR expression, and—less discriminative—elevated TGF-β2 signaling, increased stemness (Wnt, Rank, Nanog, Sox9), enhanced endoplasmic reticulum stress (Aguirre Ghiso et al., 1999; Endo and Inoue, 2019; Phan and Croucher, 2020)	Low Myc levels, and—less discriminative—decreased mTOR signaling, activated ERK1/2 signaling

Of note, there is no clear genetics- or marker-based evidence that these conditions are biologically truly distinct principles; it remains conceivable that they present with largely overlapping but tissue- or context-dependent variations and may even reflect dynamically interchangeable presentations of the same cell over time.

Including less clearly characterized states such as cellular hibernation or topor (Bouma et al., 2012; Dias et al., 2021; Oedekoven et al., 2021)

[ViewLarge]

Gift article access

Gift article access

Gift article access

Gift article access

Sharing Unavailable