Oxidative stress and cancer: have we moved forward?

2006 ◽  
Vol 401 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Barry Halliwell
Keyword(s):  
Oxidative Damage ◽  
Oxidation Products ◽  
Cancer Development ◽  
Malignant Tumours ◽  
Age Related ◽  
Dna Base ◽  
Increased Risk ◽  
Defence Enzymes ◽  
Risk Of Cancer

‘Reactive species’ (RS) of various types are formed in vivo and many are powerful oxidizing agents, capable of damaging DNA and other biomolecules. Increased formation of RS can promote the development of malignancy, and the ‘normal’ rates of RS generation may account for the increased risk of cancer development in the aged. Indeed, knockout of various antioxidant defence enzymes raises oxidative damage levels and promotes age-related cancer development in animals. In explaining this, most attention has been paid to direct oxidative damage to DNA by certain RS, such as hydroxyl radical (OH•). However, increased levels of DNA base oxidation products such as 8OHdg (8-hydroxy-2′-deoxyguanosine) do not always lead to malignancy, although malignant tumours often show increased levels of DNA base oxidation. Hence additional actions of RS must be important, possibly their effects on p53, cell proliferation, invasiveness and metastasis. Chronic inflammation predisposes to malignancy, but the role of RS in this is likely to be complex because RS can sometimes act as anti-inflammatory agents.

scholarly journals Quantifying Microsatellite Mutation Rates from Intestinal Stem Cell Dynamics in Msh2-Deficient Murine Epithelium

Genetics ◽  
2019 ◽  
Vol 212 (3) ◽  
pp. 655-665 ◽  
Author(s):  
Joseph Christopher ◽  
Ann-Sofie Thorsen ◽  
Sam Abujudeh ◽  
Filipe C. Lourenço ◽  
Richard Kemp ◽  
...  
Keyword(s):  
Stem Cell ◽  
Fold Increase ◽  
Mutation Rates ◽  
Wild Type ◽  
Cell Dynamics ◽  
Tissue Samples ◽  
Age Related ◽  
Increased Risk ◽  
Microsatellite Mutation ◽  
Risk Of Cancer

Microsatellite sequences have an enhanced susceptibility to mutation, and can act as sentinels indicating elevated mutation rates and increased risk of cancer. The probability of mutant fixation within the intestinal epithelium is dictated by a combination of stem cell dynamics and mutation rate. Here, we exploit this relationship to infer microsatellite mutation rates. First a sensitive, multiplexed, and quantitative method for detecting somatic changes in microsatellite length was developed that allowed the parallel detection of mutant [CA]n sequences from hundreds of low-input tissue samples at up to 14 loci. The method was applied to colonic crypts in Mus musculus, and enabled detection of mutant subclones down to 20% of the cellularity of the crypt (∼50 of 250 cells). By quantifying age-related increases in clone frequencies for multiple loci, microsatellite mutation rates in wild-type and Msh2-deficient epithelium were established. An average 388-fold increase in mutation per mitosis rate was observed in Msh2-deficient epithelium (2.4 × 10−2) compared to wild-type epithelium (6.2 × 10−5).

scholarly journals Obesity and cancer

2020 ◽  
Vol 48 (2-3) ◽  
pp. 89-102
Author(s):  
Franjo Cmrečak ◽  
◽  
Iva Andrašek ◽  
Višnja Gregov ◽  
Lidija Beketić-Orešković
Keyword(s):  
Intracellular Signaling ◽  
Cancer Recurrence ◽  
Epidemiological Data ◽  
Cancer Development ◽  
Malignant Diseases ◽  
Insulin Metabolism ◽  
Beneficial Effects ◽  
Increased Risk ◽  
After Cancer ◽  
Risk Of Cancer

For the past several decades, we have witnessed the emergence of the obesity pandemic worldwide and, simultaneously, the increase of incidence of malignant diseases. The effects of obesity and overweight on cancer incidence, morbidity, and mortality started to be meticulously researched only recently. According to the epidemiological data analysis, the connection between obesity and increased risk of numerous cancers has been established. Estimations are that a change in lifestyle and diet can prevent 30-50% of malignant diseases. After smoking, obesity is the second largest preventable cause of cancer. Obesity affects the quality of life and increases the risk of cancer recurrence and cancer-related mortality. By reducing body mass and avoiding gaining weight during adulthood, the risk of getting cancer is lowered. Numerous studies have shown the beneficial effects of physical activity during and after cancer treatment. Obesity influences cancer development; however, the mechanisms responsible for it are still unclear. It is considered that chronic inflammation, caused by the overabundance of nutrients, increases the levels of inflammatory cytokines and immune cells. It has been discovered that adipocytes have an important endocrine role; they synthesize numerous hormones and adipocytokines, such as leptin and adiponectin. High levels of leptons and low levels of adiponectin can activate intracellular signaling pathways involving malignant cells’ development. An important part of cancer development can be attributed to insulin metabolism, insulin-like growth factors, and sex hormones.

scholarly journals Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity

2018 ◽  
Author(s):  
Nelly Olova ◽  
Daniel J Simpson ◽  
Riccardo Marioni ◽  
Tamir Chandra
Keyword(s):  
Pluripotent Stem Cells ◽  
Tissue Replacement ◽  
Age Related ◽  
Epigenetic Age ◽  
Somatic Gene ◽  
Induced Pluripotent ◽  
Teratoma Formation ◽  
Human Ipsc ◽  
Risk Of Cancer

SummaryInduced pluripotent stem cells (IPSCs), with their unlimited regenerative capacity, carry the promise for tissue replacement to counter age-related decline. However, attempts to realise in vivo iPSC have invariably resulted in the formation of teratomas. Partial reprogramming in prematurely aged mice has shown promising results in alleviating age-related symptoms without teratoma formation. Does partial reprogramming lead to rejuvenation (i.e. “younger” cells), rather than dedifferentiation, which bears the risk of cancer? Here we analyse the dynamics of cellular age during human iPSC reprogramming and find that partial reprogramming leads to a reduction in the epigenetic age of cells. We also find that the loss of somatic gene expression and epigenetic age follow different kinetics, suggesting that they can be uncoupled and there could be a safe window where rejuvenation can be achieved with a minimised risk of cancer.

scholarly journals De Novo Cancer Incidence after Kidney Transplantation in South Korea from 2002 to 2017

2021 ◽  
Vol 10 (16) ◽  
pp. 3530
Author(s):  
Boyeon Kim ◽  
Minjin Kang ◽  
Yoonjung Kim ◽  
Hyung Soon Lee ◽  
Banseok Kim ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
South Korea ◽  
Cancer Incidence ◽  
Proportional Hazards ◽  
De Novo ◽  
Cancer Development ◽  
National Database ◽  
Monitoring Methods ◽  
Increased Risk ◽  
Risk Of Cancer

Advances in patient care and immunosuppressive drugs have improved graft survival, resulting in an increase in kidney transplantation (KT); however, persistent immunosuppression is thought to cause late occurrence of cancer. This population-based study consisted of a total of 14,842 patients whose data from the years 2002 to 2017 were collected from the National Health Information Database in South Korea. Malignancies occurred in 7.6% of the total KT patients. Prostate and thyroid cancers were the most common in males and females, respectively. From the age-adjusted incidence analysis, Kaposi’s sarcoma showed the highest standardized incidence ratio in both male and female patients. According to the linear regression model, cancer incidence in KT recipients under immunosuppressive conditions increased by approximately 0.1% each month. Patients’ age over 39 and the use of prednisolone as an initial steroid regimen were associated with increased risk of cancer development after KT. Our regression and proportional hazards models will help clinicians to predict the approximate cancer incidence risk when monitoring KT recipients. Based on the largest available national database, screening or monitoring methods for cancer detection and prevention can be established for KT patients by considering the factors involved in cancer development.

scholarly journals Cancer and mTOR inhibitors in kidney transplantation recipients

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5864
Author(s):  
Chih-Chin Kao ◽  
Jia-Sin Liu ◽  
Yu-Kang Chang ◽  
Ming-Huang Lin ◽  
Yen-Chung Lin ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
De Novo ◽  
Mtor Inhibitors ◽  
Cancer Development ◽  
Cumulative Exposure ◽  
National Database ◽  
Risk Of Death ◽  
Increased Risk ◽  
De Novo Cancer ◽  
Risk Of Cancer

Background Previous studies show that mTOR inhibitors decrease the risk of cancer development after kidney transplantation. However, the effect of cumulative doses of mTOR inhibitors on cancer after kidney transplantation is not well known. Methods In the current study, patients were registered into a national database in Taiwan. Between year 2000 and 2013, 4,563 patients received kidney transplantation. They were divided into two groups, according to mTOR inhibitors usage. The cumulative dose of mTOR inhibitors was recorded. Patients were followed-up until de novo cancer development, death, or the end of 2014. Results Patients were divided into two groups: mTOR inhibitors users (study group, n = 828) and mTOR inhibitors non-users (control group, n = 3,735). The median follow-up duration was 7.8 years. The risk of de novo cancer (hazards ratio (HR) 0.80, 95% CI [0.60–1.09], p = 0.16) and risk of death (HR 1.14, 95% CI [0.82–1.60], p = 0.43) was not different between mTOR inhibitor user and non-user groups. Neither high- nor low-dose exposure to mTOR inhibitors was associated with increased risk of cancer or mortality. Analysis of cancer subtypes showed no influence by mTOR inhibitors. In addition, the cause of mortality was not significantly different between the two groups. Discussion We could not find the association of mTOR inhibitors use and risk of de novo cancer development or mortality in patients with kidney transplantation in Chinese patients. Cumulative exposure to mTOR inhibitors did not change the results.

scholarly journals Oxidation Products of 5-Methylcytosine are Decreased in Senescent Cells and Tissues of Progeroid Mice

2018 ◽  
Vol 73 (8) ◽  
pp. 1003-1009 ◽  
Author(s):  
Ewelina Zarakowska ◽  
Jolanta Czerwinska ◽  
Agnieszka Tupalska ◽  
Matt J Yousefzadeh ◽  
Siobhán Q Gregg ◽  
...  
Keyword(s):  
Excision Repair ◽  
Oxidation Products ◽  
Proliferating Cells ◽  
Repair Capacity ◽  
Epigenetic Marks ◽  
Dna Repair Capacity ◽  
Dna Base ◽  
Primary Mouse ◽  
First Time

Abstract 5-Hydroxymethylcytosine and 5-formylcytosine are stable DNA base modifications generated from 5-methylcytosine by the ten-eleven translocation protein family that function as epigenetic markers. 5-Hydroxymethyluracil may also be generated from thymine by ten-eleven translocation enzymes. Here, we asked if these epigenetic changes accumulate in senescent cells, since they are thought to be inversely correlated with proliferation. Testing this in ERCC1-XPF-deficient cells and mice also enabled discovery if these DNA base changes are repaired by nucleotide excision repair. Epigenetic marks were measured in proliferating, quiescent and senescent wild-type (WT) and Ercc1−/− primary mouse embryonic fibroblasts. The pattern of epigenetic marks depended more on the proliferation status of the cells than their DNA repair capacity. The cytosine modifications were all decreased in senescent cells compared to quiescent or proliferating cells, whereas 5-(hydroxymethyl)-2′-deoxyuridine was increased. In vivo, both 5-(hydroxymethyl)-2′-deoxyuridine and 5-(hydroxymethyl)-2′-deoxycytidine were significantly increased in liver tissues of aged WT mice compared to young adult WT mice. Livers of Ercc1-deficient mice with premature senescence and aging had reduced level of 5-(hydroxymethyl)-2′-deoxycytidine and 5-formyl-2′-deoxycytidine compared to aged-matched WT controls. Taken together, we demonstrate for the first time, that 5-(hydroxymethyl)-2′-deoxycytidine is significantly reduced in senescent cells and tissue, potentially yielding a novel marker of senescence.

scholarly journals A truncating mutation in the autophagy gene UVRAG drives inflammation and tumorigenesis in mice

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Christine Quach ◽  
Ying Song ◽  
Hongrui Guo ◽  
Shun Li ◽  
Hadi Maazi ◽  
...  
Keyword(s):  
Risk Factor ◽  
Genetic Basis ◽  
Inflammatory Diseases ◽  
Cancer Development ◽  
Truncating Mutation ◽  
Autophagy Gene ◽  
Age Related ◽  
Underlying Mechanisms

AbstractAberrant autophagy is a major risk factor for inflammatory diseases and cancer. However, the genetic basis and underlying mechanisms are less established. UVRAG is a tumor suppressor candidate involved in autophagy, which is truncated in cancers by a frameshift (FS) mutation and expressed as a shortened UVRAGFS. To investigate the role of UVRAGFS in vivo, we generated mutant mice that inducibly express UVRAGFS (iUVRAGFS). These mice are normal in basal autophagy but deficient in starvation- and LPS-induced autophagy by disruption of the UVRAG-autophagy complex. iUVRAGFS mice display increased inflammatory response in sepsis, intestinal colitis, and colitis-associated cancer development through NLRP3-inflammasome hyperactivation. Moreover, iUVRAGFS mice show enhanced spontaneous tumorigenesis related to age-related autophagy suppression, resultant β-catenin stabilization, and centrosome amplification. Thus, UVRAG is a crucial autophagy regulator in vivo, and autophagy promotion may help prevent/treat inflammatory disease and cancer in susceptible individuals.

scholarly journals p16INK4a deficiency promotes IL-4–induced polarization and inhibits proinflammatory signaling in macrophages

Blood ◽  
2011 ◽  
Vol 118 (9) ◽  
pp. 2556-2566 ◽  
Author(s):  
Céline Cudejko ◽  
Kristiaan Wouters ◽  
Lucía Fuentes ◽  
Sarah Anissa Hannou ◽  
Charlotte Paquet ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Macrophage Polarization ◽  
Suppressor Gene ◽  
In Vivo Model ◽  
Macrophage Phenotype ◽  
Age Related ◽  
Increased Risk ◽  
Increased Sensitivity

Abstract The CDKN2A locus, which contains the tumor suppressor gene p16INK4a, is associated with an increased risk of age-related inflammatory diseases, such as cardiovascular disease and type 2 diabetes, in which macrophages play a crucial role. Monocytes can polarize toward classically (CAMφ) or alternatively (AAMφ) activated macrophages. However, the molecular mechanisms underlying the acquisition of these phenotypes are not well defined. Here, we show that p16INK4a deficiency (p16−/−) modulates the macrophage phenotype. Transcriptome analysis revealed that p16−/− BM-derived macrophages (BMDMs) exhibit a phenotype resembling IL-4–induced macrophage polarization. In line with this observation, p16−/− BMDMs displayed a decreased response to classically polarizing IFNγ and LPS and an increased sensitivity to alternative polarization by IL-4. Furthermore, mice transplanted with p16−/− BM displayed higher hepatic AAMφ marker expression levels on Schistosoma mansoni infection, an in vivo model of AAMφ phenotype skewing. Surprisingly, p16−/− BMDMs did not display increased IL-4–induced STAT6 signaling, but decreased IFNγ-induced STAT1 and lipopolysaccharide (LPS)–induced IKKα,β phosphorylation. This decrease correlated with decreased JAK2 phosphorylation and with higher levels of inhibitory acetylation of STAT1 and IKKα,β. These findings identify p16INK4a as a modulator of macrophage activation and polarization via the JAK2-STAT1 pathway with possible roles in inflammatory diseases.

scholarly journals Role of Nitrative and Oxidative DNA Damage in Inflammation-Related Carcinogenesis

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Mariko Murata ◽  
Raynoo Thanan ◽  
Ning Ma ◽  
Shosuke Kawanishi
Keyword(s):  
Oxidative Dna Damage ◽  
Promoter Hypermethylation ◽  
Physical Factors ◽  
Barr Virus ◽  
Dna Base ◽  
Increased Risk ◽  
Epstein Barr ◽  
Cancer Tissues ◽  
Risk Of Cancer

Chronic inflammation induced by biological, chemical, and physical factors has been found to be associated with the increased risk of cancer in various organs. We revealed that infectious agents including liver fluke,Helicobacter pylori, and human papilloma virus and noninfectious agents such as asbestos fiber induced iNOS-dependent formation of 8-nitroguanine and 8-oxo-7, 8-dihydro-2′-deoxyguanosine (8-oxodG) in cancer tissues and precancerous regions. Our results with the colocalization of phosphorylated ATM andγ-H2AX with 8-oxodG and 8-nitroguanine in inflammation-related cancer tissues suggest that DNA base damage leads to double-stranded breaks. It is interesting from the aspect of genetic instability. We also demonstrated IL-6-modulated iNOS expression via STAT3 and EGFR in Epstein-Barr-virus-associated nasopharyngeal carcinoma and found promoter hypermethylation in several tumor suppressor genes. Such epigenetic alteration may occur by controlling the DNA methylation through IL-6-mediated JAK/STAT3 pathways. Collectively, 8-nitroguanine would be a useful biomarker for predicting the risk of inflammation-related cancers.

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