Telomeres, stem cells, senescence, and cancer

Sharpless, Norman E.; DePinho, Ronald A.

doi:10.1172/jci20761

Cited by 417 publications

(200 citation statements)

References 119 publications

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“…In addition, we observed an increase in hepatic oxidative stress, with multiple harmful consequences, that may derive from an imbalance between pro‐ and anti‐oxidants, together with increased hepatic lipid content, a well‐known source of cellular oxidative stress. In an important way, oxidative stress could also contribute to potentiate the senescence pathways, and vice versa, thus creating a deleterious vicious cycle in the aged liver (Jin, Iakova, Jiang, Medrano, & Timchenko, 2011; Sharpless & De Pinho, 2004). …”

Section: Discussionmentioning

confidence: 99%

Effects of aging on liver microcirculatory function and sinusoidal phenotype

et al. 2018

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The socioeconomic and medical improvements of the last decades have led to a relevant increase in the median age of worldwide population. Although numerous studies described the impact of aging in different organs and the systemic vasculature, relatively little is known about liver function and hepatic microcirculatory status in the elderly. In this study, we aimed at characterizing the phenotype of the aged liver in a rat model of healthy aging, particularly focusing on the microcirculatory function and the molecular status of each hepatic cell type in the sinusoid. Moreover, major findings of the study were validated in young and aged human livers. Our results demonstrate that healthy aging is associated with hepatic and sinusoidal dysfunction, with elevated hepatic vascular resistance and increased portal pressure. Underlying mechanisms of such hemodynamic disturbances included typical molecular changes in the cells of the hepatic sinusoid and deterioration in hepatocyte function. In a specific manner, liver sinusoidal endothelial cells presented a dysfunctional phenotype with diminished vasodilators synthesis, hepatic macrophages exhibited a proinflammatory state, while hepatic stellate cells spontaneously displayed an activated profile. In an important way, major changes in sinusoidal markers were confirmed in livers from aged humans. In conclusion, our study demonstrates for the first time that aging is accompanied by significant liver sinusoidal deregulation suggesting enhanced sinusoidal vulnerability to chronic or acute injuries.

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Section: Discussionmentioning

confidence: 99%

Effects of aging on liver microcirculatory function and sinusoidal phenotype

et al. 2018

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“…Generally, cell cycle progression is well controlled by the cell cycle machinery, such as cyclins and cyclin-dependent kinases (CDKs) (Xu et al 2006). These cyclin/CDK complexes are further negatively regulated by two families of CDK inhibitors, including p21 and p57 (Morgan 1995, Sharpless & DePinho 2004, Gartel & Radhakrishnan 2005). p21 plays a crucial role in such negative regulation, and its activation consequently leads to restrained proliferation and maintenance of cellular quiescence (Sharpless & DePinho 2004).…”

Section: Discussionmentioning

confidence: 99%

“…These cyclin/CDK complexes are further negatively regulated by two families of CDK inhibitors, including p21 and p57 (Morgan 1995, Sharpless & DePinho 2004, Gartel & Radhakrishnan 2005). p21 plays a crucial role in such negative regulation, and its activation consequently leads to restrained proliferation and maintenance of cellular quiescence (Sharpless & DePinho 2004). Intriguingly, treatment with different classes of antidepressants inhibits the expression of p21, and knockout of p21 attenuates the therapeutic effects of antidepressants in mice (Pechnick et al 2008, Pechnick et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Effects of Antidepressants on DSP4/CPT-Induced DNA Damage Response in Neuroblastoma SH-SY5Y Cells

et al. 2015

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DNA damage is a form of cell stress and injury. Increased systemic DNA damage is related to the pathogenic development of neurodegenerative diseases. Depression occurs in a relatively high percentage of patients suffering from degenerative diseases, for whom antidepressants are often used to relieve depressive symptoms. However, few studies have attempted to elucidate why different groups of antidepressants have similar effects on relieving symptoms of depression. Previously, we demonstrated that neurotoxins N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4)- and camptothecin (CPT)-induced the DNA damage response in SH-SY5Y cells, and DSP4 caused cell cycle arrest which was predominately in the S-phase. The present study shows that CPT treatment also resulted in similar cell cycle arrest. Some classic antidepressants could reduce the DNA damage response induced by DSP4 or CPT in SH-SY5Y cells. Cell viability examination demonstrated that both DSP4 and CPT caused cell death, which was prevented by spontaneous administration of some tested antidepressants. Flow cytometric analysis demonstrated that a majority of the tested antidepressants protect cells from being arrested in S-phase. These results suggest that blocking the DNA damage response may be an important pharmacologic characteristic of antidepressants. Exploring the underlying mechanisms may allow for advances in the effort to improve therapeutic strategies for depression appearing in degenerative and psychiatric diseases.

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“…Moreover, activation of the SMAD3/β2SP/CTCF complex on the TERT promoter region may cooperate with MYC activation. MYC activation and telomerase dysfunction have been shown to play prominent roles in early HCC initiation 77. Therefore, the TGF‐β–mediated β2SP/SMAD3/CTCF complex regulates telomerase activity and is part of a pathway that suppresses the switch to tumorigenesis in BWS‐associated cancers.…”

Section: Tgf‐β In Liver Cancer Stem Cellsmentioning

confidence: 99%

Transforming growth factor‐β in liver cancer stem cells and regeneration

Rao

Zaidi

Banerjee

et al. 2017

Hepatology Communications

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Cancer stem cells have established mechanisms that contribute to tumor heterogeneity as well as resistance to therapy. Over 40% of hepatocellular carcinomas (HCCs) are considered to be clonal and arise from a stem‐like/cancer stem cell. Moreover, HCC is the second leading cause of cancer death worldwide, and an improved understanding of cancer stem cells and targeting these in this cancer are urgently needed. Multiple studies have revealed etiological patterns and multiple genes/pathways signifying initiation and progression of HCC; however, unlike the transforming growth factor β (TGF‐β) pathway, loss of p53 and/or activation of β‐catenin do not spontaneously drive HCC in animal models. Despite many advances in cancer genetics that include identifying the dominant role of TGF‐β signaling in gastrointestinal cancers, we have not reached an integrated view of genetic mutations, copy number changes, driver pathways, and animal models that support effective targeted therapies for these common and lethal cancers. Moreover, pathways involved in stem cell transformation into gastrointestinal cancers remain largely undefined. Identifying the key mechanisms and developing models that reflect the human disease can lead to effective new treatment strategies. In this review, we dissect the evidence obtained from mouse and human liver regeneration, and mouse genetics, to provide insight into the role of TGF‐β in regulating the cancer stem cell niche. (Hepatology Communications 2017;1:477–493)

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Telomeres, stem cells, senescence, and cancer

Cited by 417 publications

References 119 publications

Effects of aging on liver microcirculatory function and sinusoidal phenotype

Effects of aging on liver microcirculatory function and sinusoidal phenotype

Effects of Antidepressants on DSP4/CPT-Induced DNA Damage Response in Neuroblastoma SH-SY5Y Cells

Transforming growth factor‐β in liver cancer stem cells and regeneration

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