Principles and characteristics of lasting cell-cycle arrest conditions
| Long-term arrest condition . | Senescence . | Quiescence . | Dormancya . | 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 p16INK4a, 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 p21CIP1 and p27KIP1, 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 . | Dormancya . | 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 p16INK4a, 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 p21CIP1 and p27KIP1, 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)