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Author

Michalis Liontos

Other affiliations: Alexandra Hospital
Bio: Michalis Liontos is an academic researcher from National and Kapodistrian University of Athens. The author has contributed to research in topics: Medicine & Ovarian cancer. The author has an hindex of 22, co-authored 80 publications receiving 4052 citations. Previous affiliations of Michalis Liontos include Alexandra Hospital.


Papers
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Journal ArticleDOI
30 Nov 2006-Nature
TL;DR: It is shown that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks, and, together with apoptosis, provides a barrier to malignant progression.
Abstract: Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.

1,829 citations

Journal ArticleDOI
TL;DR: It is shown that in human fibroblasts resistant to premature p16INK4a induction, SAHF are preferentially formed following oncogene activation but are not detected during replicative cellular senescence or on exposure to a variety ofsenescence-inducing stimuli.
Abstract: Two major mechanisms have been causally implicated in the establishment of cellular senescence: the activation of the DNA damage response (DDR) pathway and the formation of senescence-associated heterochromatic foci (SAHF). Here we show that in human fibroblasts resistant to premature p16(INK4a) induction, SAHF are preferentially formed following oncogene activation but are not detected during replicative cellular senescence or on exposure to a variety of senescence-inducing stimuli. Oncogene-induced SAHF formation depends on DNA replication and ATR (ataxia telangiectasia and Rad3-related). Inactivation of ATM (ataxia telangiectasia mutated) or p53 allows the proliferation of oncogene-expressing cells that retain increased heterochromatin induction. In human cancers, levels of heterochromatin markers are higher than in normal tissues, and are independent of the proliferative index or stage of the tumours. Pharmacological and genetic perturbation of heterochromatin in oncogene-expressing cells increase DDR signalling and lead to apoptosis. In vivo, a histone deacetylase inhibitor (HDACi) causes heterochromatin relaxation, increased DDR, apoptosis and tumour regression. These results indicate that heterochromatin induced by oncogenic stress restrains DDR and suggest that the use of chromatin-modifying drugs in cancer therapies may benefit from the study of chromatin and DDR status of tumours.

311 citations

01 Jan 2006
TL;DR: In this paper, the authors show that senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with opoptosis, provides a barrier to malignant progression.
Abstract: . The relationshipbetween these two barriers, if any, has not been elucidated. Herewe show that oncogene-induced senescence is associated withsignsofDNAreplicationstress,includingprematurelyterminatedDNAreplicationforksandDNAdouble-strand breaks.Inhibitingthe DNA double-strand break response kinase ataxia telangiecta-siamutated(ATM)suppressedtheinductionofsenescenceandina mouse model led to increased tumour size and invasiveness.Analysis of human precancerous lesions further indicated thatDNA damage and senescence markers cosegregate closely. Thus,senescence in human preneoplastic lesions is a manifestation ofoncogene-induced DNA replication stress and, together withapoptosis, provides a barrier to malignant progression.There are several forms of senescence. Replicative senescence, theform induced by eroded telomeres, depends on activation of theDNA double-strand break (DSB) checkpoint kinases ATM andcheckpointkinase2(Chk2)

279 citations

Journal ArticleDOI
TL;DR: It is shown that ROS are indeed mitogenic signaling molecules that fuel oncogene-driven aberrant cell proliferation, however, by their very same ability to mediate cell hyperproliferation, ROS eventually cause DDR activation.
Abstract: Oncogene-induced reactive oxygen species (ROS) have been proposed to be signaling molecules that mediate proliferative cues. However, ROS may also cause DNA damage and proliferative arrest. How these apparently opposite roles can be reconciled, especially in the context of oncogene-induced cellular senescence, which is associated both with aberrant mitogenic signaling and DNA damage response (DDR)-mediated arrest, is unclear. Here, we show that ROS are indeed mitogenic signaling molecules that fuel oncogene-driven aberrant cell proliferation. However, by their very same ability to mediate cell hyperproliferation, ROS eventually cause DDR activation. We also show that oncogenic Ras-induced ROS are produced in a Rac1 and NADPH oxidase (Nox4)-dependent manner. In addition, we show that Ras-induced ROS can be detected and modulated in a living transparent animal: the zebrafish. Finally, in cancer we show that Nox4 is increased in both human tumors and a mouse model of pancreatic cancer and specific Nox4 small-molecule inhibitors act synergistically with existing chemotherapic agents.

248 citations

Journal ArticleDOI
TL;DR: Repeated audit, continuous education and alertness of doctors, on the basis of assessment of factors contributing to laboratory overutilisation, result in restraining the redundant ordering of tests in the hospital setting.
Abstract: Aims: To identify factors contributing to laboratory overutilisation in an academic medical department, and to assess the effect of an educational feedback strategy on inappropriate test-ordering behaviour. Methods: The records of 426 patients admitted during a 6-month period were reviewed. The usefulness of 25 investigations (haematology, basic biochemistry and arterial blood gases) was assessed according to implicit criteria. Trainees’ acquaintance with investigation costs was assessed via a multiple-choice questionnaire. The medical staff was informed about their test-ordering behaviour, cost awareness and the factors associated with overuse of diagnostic tests. The test-ordering behaviour of the same doctors was reassessed on 214 patients managed during 6 months after the intervention. Results: Overall, 24 482 laboratory tests were ordered before the intervention (mean 2.96 tests/patient/day). Among those, 67.9% were not considered to have contributed towards management of patients (mean avoidable 2.01 tests/patient/day). Patient age ⩾65 years, hospitalisation beyond 7 days and increased case difficulty (death or inability to establish a diagnosis) were factors independently associated with overuse of laboratory tests. Senior trainees ordered more laboratory examinations, but the percentage of avoidable tests requested by junior trainees was higher. A moderate and disparate level of trainees’ awareness about the cost of common laboratory examinations was disclosed. The avoidable tests/patient/day were significantly decreased after the intervention (mean 1.58, p = 0.002), but containment of unnecessary ordering of tests gradually waned during the semester after the intervention. Conclusion: Repeated audit, continuous education and alertness of doctors, on the basis of assessment of factors contributing to laboratory overutilisation, result in restraining the redundant ordering of tests in the hospital setting.

233 citations


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Journal ArticleDOI
TL;DR: Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.
Abstract: Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an additional response by adopting a state of permanent cell-cycle arrest that is termed cellular senescence. Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.

3,677 citations

Journal ArticleDOI
TL;DR: Genetic evidence suggests that tumour cells may also require specific interphase CDKs for proliferation, and selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.
Abstract: Tumour-associated cell cycle defects are often mediated by alterations in cyclin-dependent kinase (CDK) activity. Misregulated CDKs induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, mammalian CDKs are essential for driving each cell cycle phase, so therapeutic strategies that block CDK activity are unlikely to selectively target tumour cells. However, recent genetic evidence has revealed that, whereas CDK1 is required for the cell cycle, interphase CDKs are only essential for proliferation of specialized cells. Emerging evidence suggests that tumour cells may also require specific interphase CDKs for proliferation. Thus, selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.

3,146 citations

Journal Article
TL;DR: In this paper, the coding exons of the family of 518 protein kinases were sequenced in 210 cancers of diverse histological types to explore the nature of the information that will be derived from cancer genome sequencing.
Abstract: AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore PL02-05 All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

2,737 citations

20 Sep 2013
TL;DR: Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.
Abstract: Purpose The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). Patients and Methods In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). Results A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. Conclusion Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

2,380 citations

Journal ArticleDOI
TL;DR: The idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence is discussed.
Abstract: For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.

2,074 citations