Pateras I

Laiko Hospital, Athínai, Attica, Greece

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Publications (36)151.35 Total impact

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    ABSTRACT: Aging is the single biggest risk factor for malignant transformation. Among the most common age-associated malignancies are non-melanoma skin cancers, comprising the most common types of human cancer. Here we show that mutant H-Ras activation in mouse epidermis, a frequent event in cutaneous squamous cell carcinoma (SCC), elicits a differential outcome in aged versus young mice. Whereas H-Ras activation in the young skin results in hyperplasia that is mainly accompanied by rapid hair growth, H-Ras activation in the aged skin results in more dysplasia and gradual progression to in situ SCC. Progression is associated with increased inflammation, pronounced accumulation of immune cells including T cells, macrophages and mast cells as well as excessive cell senescence. We found not only an age-dependent increase in expression of several pro-inflammatory mediators, but also activation of a strong anti-inflammatory response involving enhanced IL4/IL10 expression and immune skewing toward a Th2 response. In addition, we observed an age-dependent increase in the expression of Pdl1, encoding an immune suppressive ligand that promotes cancer immune evasion. Moreover, upon switching off oncogenic H-Ras activity, young but not aged skin regenerates successfully, suggesting a failure of the aged epidermal stem cells to repair damaged tissue. Our findings support an age-dependent link between accumulation of senescent cells, immune infiltration and cancer progression, which may contribute to the increased cancer risk associated with old age.
    Cell Death and Differentiation 03/2015; DOI:10.1038/cdd.2015.21 · 8.39 Impact Factor
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    Tomer Cooks, Ioannis S Pateras, Vassilis G Gorgoulis
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    ABSTRACT: Mutant p53 functions as a key molecular element in the inflamed colon tissue joining forces with nuclear factor kappa-B (NF-κB) to prolong and intensify the inflammatory response, leading eventually to a higher risk for colitis associated colorectal cancer (CAC). This phenomenon coincides with the fact that mutations in p53 are an initiating factor of CAC unlike sporadic colorectal cancer (CRC) where they are considered a late event contributing to tumor progression. This research highlight attempts to illuminate the consequences of such a reshuffling in the molecular sequence of events from non-cancerous tissue to invasive carcinoma of the colon. Implications of this different role taken by mutant p53 when inflammation is involved might affect tumorigenesis, pathogenesis, and hierarchical morphogenesis and suggest the reevaluation of current animal models used to study CAC. We also discuss the possible role of mutant p53 in stromal and immune compartments, either in an autonomous or non-autonomous manner. Cancer Cell & Microenvironment 2014; 1:66-71. doi: 10.14800/ccm.135; © 2014 by Smart Science & Technology, LLC. The monolayered epithelia of the intestine have to maintain a constant delicate balance, taking into account radical changes at the luminal end. Throughout this continuous battle, which involves exposure to harsh mechanical, chemical and biological conditions, the intestinal epithelium is required to juggle between the absorption of nutrients and metabolites while restricting the penetration of unwelcome infectious agents [1, 2]
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    ABSTRACT: Colorectal cancer is frequently associated with chronic inflammation, with the intestinal epithelial barrier playing an important protective role against the infections and injuries that cause colitis. The p38α pathway regulates inflammatory responses but can also suppress tumor initiation in epithelial cells. We have found that p38α signaling has a dual function in colorectal tumorigenesis. On one side, p38α protects intestinal epithelial cells against colitis-associated colon cancer by regulating intestinal epithelial barrier function. Accordingly, p38α downregulation results in enhanced colitis-induced epithelial damage and inflammation, which potentiates colon tumor formation. Surprisingly, inhibition of p38α in transformed colon epithelial cells reduces tumor burden. Thus, p38α suppresses inflammation-associated epithelial damage and tumorigenesis but contributes to the proliferation and survival of tumor cells.
    Cancer cell 03/2014; DOI:10.1016/j.ccr.2014.02.019 · 23.89 Impact Factor
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    ABSTRACT: The DNA damage response (DDR) pathway and ARF function as barriers to cancer development. Although commonly regarded as operating independently of each other, some studies proposed that ARF is positively regulated by the DDR. Contrary to either scenario, we found that in human oncogene-transformed and cancer cells, ATM suppressed ARF protein levels and activity in a transcription-independent manner. Mechanistically, ATM activated protein phosphatase 1, which antagonized Nek2-dependent phosphorylation of nucleophosmin (NPM), thereby liberating ARF from NPM and rendering it susceptible to degradation by the ULF E3-ubiquitin ligase. In human clinical samples, loss of ATM expression correlated with increased ARF levels and in xenograft and tissue culture models, inhibition of ATM stimulated the tumour-suppressive effects of ARF. These results provide insights into the functional interplay between the DDR and ARF anti-cancer barriers, with implications for tumorigenesis and treatment of advanced tumours.
    Nature Cell Biology 07/2013; DOI:10.1038/ncb2795 · 20.06 Impact Factor
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    ABSTRACT: Oncogenic stimuli trigger the DNA damage response (DDR) and induction of the alternative reading frame (ARF) tumor suppressor, both of which can activate the p53 pathway and provide intrinsic barriers to tumor progression. However, the respective timeframes and signal thresholds for ARF induction and DDR activation during tumorigenesis remain elusive. Here, these issues were addressed by analyses of mouse models of urinary bladder, colon, pancreatic and skin premalignant and malignant lesions. Consistently, ARF expression occurred at a later stage of tumor progression than activation of the DDR or p16(INK4A), a tumor-suppressor gene overlapping with ARF. Analogous results were obtained in several human clinical settings, including early and progressive lesions of the urinary bladder, head and neck, skin and pancreas. Mechanistic analyses of epithelial and fibroblast cell models exposed to various oncogenes showed that the delayed upregulation of ARF reflected a requirement for a higher, transcriptionally based threshold of oncogenic stress, elicited by at least two oncogenic 'hits', compared with lower activation threshold for DDR. We propose that relative to DDR activation, ARF provides a complementary and delayed barrier to tumor development, responding to more robust stimuli of escalating oncogenic overload.Cell Death and Differentiation advance online publication, 12 July 2013; doi:10.1038/cdd.2013.76.
    Cell death and differentiation 07/2013; 20(11). DOI:10.1038/cdd.2013.76 · 8.39 Impact Factor
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    ABSTRACT: The tumor suppressor p53 is frequently mutated in human cancer. Common mutant p53 (mutp53) isoforms can actively promote cancer through gain-of-function (GOF) mechanisms. We report that mutp53 prolongs TNF-α-induced NF-κB activation in cultured cells and intestinal organoid cultures. Remarkably, when exposed to dextran sulfate sodium, mice harboring a germline p53 mutation develop severe chronic inflammation and persistent tissue damage, and are highly prone to inflammation-associated colon cancer. This mutp53 GOF is manifested by rapid onset of flat dysplastic lesions that progress to invasive carcinoma with mutp53 accumulation and augmented NF-κB activation, faithfully recapitulating features frequently observed in human colitis-associated colorectal cancer (CAC). These findings might explain the early appearance of p53 mutations in human CAC.
    Cancer cell 05/2013; 23(5):634-46. DOI:10.1016/j.ccr.2013.03.022 · 23.89 Impact Factor
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    ABSTRACT: Background: Ki67 is an immunohistochemical proliferation marker in many types of cancer and has been widely studied among breast cancer patients mostly through retrospective studies. Methods: The MEDLINE/PubMed database was searched for publications with the medical subject heading 'Ki 67' and the key words 'breast', 'cancer', and 'prognosis'. We restricted our search to articles published until 2012. Results: In this review, we included 78 articles and abstracts that were accessible and available in English. An effort to further explain the role of Ki67 in the prognosis of breast cancer has been made. Conclusions: The debate on the prognostic role of Ki67 in breast cancer is still open, although most of the studies have established a relation between Ki67 and overall and disease-free survival. Further research should be made in order to establish Ki67 as a standard prognostic marker in breast cancer.
    Oncology 01/2013; 84(4):219-225. DOI:10.1159/000346475 · 2.61 Impact Factor
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    ABSTRACT: Oncogene-induced DNA replication stress is thought to drive genomic instability in cancer. In particular, replication stress can explain the high prevalence of focal genomic deletions mapping within very large genes in human tumors. However, the origin of single-nucleotide substitutions (SNS) in nonfamilial cancers is strongly debated. Some argue that cancers have a mutator phenotype, whereas others argue that the normal DNA replication error rates are sufficient to explain the number of observed SNSs. Here, we sequenced the exomes of 24, mostly precancerous, colon polyps. Analysis of the sequences revealed mutations in the APC, CTNNB1, and BRAF genes as the presumptive cancer-initiating events and many passenger SNSs. We used the number of SNSs in the various lesions to calculate mutation rates for normal colon and adenomas and found that colon adenomas exhibit a mutator phenotype. Interestingly, the SNSs in the adenomas mapped more often than expected within very large genes, where focal deletions in response to DNA replication stress also map. We propose that single-stranded DNA generated in response to oncogene-induced replication stress compromises the repair of deaminated cytosines and other damaged bases, leading to the observed SNS mutator phenotype. Cancer Res; 72(23); 6279-89. ©2012 AACR.
    Cancer Research 12/2012; 72(23):6279-6289. DOI:10.1158/0008-5472.CAN-12-3869 · 9.28 Impact Factor
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    ABSTRACT: Inflammation is a double-edged sword presenting a dual effect on cancer development, from one hand promoting tumor initiation and progression and from the other hand protecting against cancer through immunosurveillance mechanisms. Cytokines are crucial components of inflammation, participating in the interaction between the cells of tumor microenvironment. A comprehensive study of the role of cytokines in the context of the inflammation-tumorigenesis interplay helps us to shed light in the pathogenesis of cancer. In this paper we focus on the role of cytokines in the development of genomic instability, an evolving hallmark of cancer.
    BioMed Research International 06/2012; 2012:536761. DOI:10.1155/2012/536761 · 2.71 Impact Factor
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    ABSTRACT: Intercellular adhesion molecule-1 (ICAM-1), a cell adhesion molecule with a key role in inflammation and immunosurveillance, has been implicated in carcinogenesis by facilitating instability of the tumor environment. The K469E single nucleotide polymorphism (SNP) (G>A) affects the ICAM-1 mRNA splicing pattern; the alternatively spliced isoform (ICAM-1-S) lacks transmembrane and intracellular domain, which affects the structural and signal transduction properties. Moreover, the expression of ICAM-1 is transcriptionally regulated by p53, and this SNP has been shown to be related with apoptosis. PCR-RFLP analysis was used to assess the K469E SNP status comparatively in 203 non-small cell lung cancer patients and 175 healthy sex-matched controls. This SNP was examined in relation to tumor kinetic parameters (Ki-67 immunohistochemical evaluation and Tdt-mediated dUTP nick end labeling assay), p53 immunohistochemistry status, and clinicopathological data in patients with operable stages. Both the genotype and allele frequency did not differ significantly between patients and controls. However, patients with the AG/AA genotypes had worse survival (39 vs 45 months, p = 0.036) and tended to be present in advanced stages (p = 0.057). Moreover, the AG/AA genotypes exerted a synergistic effect with aberrant p53 on tumor progression, while the GG genotype retained a better apoptotic index. The AG/AA genotypes correlated with worse survival and advanced stages probably due to defective immunosurveillance and apoptosis. These genetic backgrounds may confer a selective advantage for dissemination of tumor cells with high metastatic potential compared to GG genotype.
    Tumor Biology 05/2012; 33(5):1429-36. DOI:10.1007/s13277-012-0393-4 · 2.84 Impact Factor
  • 03/2012; DOI:10.4267/2042/46075
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    ABSTRACT: The etiology of sporadic cardiac myxomas remains elusive. The tendency for these lesions to recur following resection, their immunopathological characteristics, along with their histological and molecular profile, may implicate the presence of an infective agent in this type of tumor. In this study, we investigated the presence of herpes simplex virus (HSV) DNA in a cohort of cardiac myxomas in a tertiary referral centre. Twenty-nine formalin-fixed paraffin-embedded (FFPE) sporadic cardiac myxomas were obtained, 17 of which were shown to be informative. These were compared to 19 macroscopically and microscopically normal heart tissue specimens. The detection of HSV-1 and -2 genomic sequences was achieved with the use of a combined nested PCR-Restriction Fragment Length Polymorphism methodology. The presence of HSV-1 and/or -2 DNA was demonstrated in 6 of 17 (35%) informative sporadic cardiac myxomas, whereas no HSV DNA was detected in normal heart tissues (P < 0.01). The existence of HSV-1/2 DNA in sporadic cardiac myxomas, along with its absence from normal heart tissues, reinforces the possibility that HSV infection might be involved in the development of these lesions. Our findings raise the point of anti-HSV medication postsurgically with a potential benefit in reducing the rate of recurrences.
    BioMed Research International 02/2012; 2012:823949. DOI:10.1155/2012/823949 · 2.71 Impact Factor
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    ABSTRACT: Gastrocolic Fistula is, in the majority of cases the pathological communication between stomach and transverse colon, because cases involved with the small intestine, pancreas and skin have been also documented, even though are rare. It occurs mostly in adults, but they can be present to infants, as well, as a result of congenital abnormalities or iatrogenic procedures (i.e. migration of PEG tube that placed before). In the Western Countries, the most common cause is the adenocarcinoma of the colon, while in Japan, adenocarcinoma of the stomach is the most frequent cause. It seldom appears, as a complication of a benign peptic ulcer, in Crohn's disease and as a result of significant intake of steroids or NSAIDs. The typical symptoms of a gastrocolic fistula are abdominal pain, nausea-vomiting, diarrhea and weight loss. Radiology has been used for the detection of the fistulae all these years but the golden standard remained the barium enema. Barium meal and CT findings play a smaller role in the diagnosis. Although the management of gastrocolic fistulae has historically been surgical, medical treatment has recently been recommended as the first line when a malignancy can be excluded.
    International Journal of Surgery (London, England) 02/2012; 10(3):129-33. DOI:10.1016/j.ijsu.2012.02.011 · 1.65 Impact Factor
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    ABSTRACT: Aim-Background This review evaluates all the up-to-date published data of the literature concerning single incision laparoscopic hepatectomies (SILH) for malignant and benign conditions (colorectal liver metastasis, hepatocellular carcinoma, haemangiomas and liver adenomas). Methods The PubMed library database was used to gather data published until February 2011 concerning SILH, using the keywords: «single incision laparoscopic hepatectomy» and others related to the subject. Demographic data, taking into account patient’s age/sex, hepatectomy types, preoperative and postoperative care data, were evaluated. Operative data were calculated, including operative time, blood loss, conversion rate, haemostasis, etc. Single incision laparoscopy setup such as port type, instruments etc were all included in the data. Results This first ever review, to our knowledge, includes the 5 only case reports of SILH for malignant or benign diseases to be reported in the world bibliography, to date. All aforementioned demographic parameters were collectively reported as clearly as they were presented in their referral papers. Conclusion SIL wedge resections between liver segments I–III and left lateral sectionectomies are safe and applicable procedures, in a selected group of patients, without morbidity and mortality when performed by experienced laparoscopists. Main advantages include the parenchymal transection instruments that maintain haemostasis and oncologic margins. The liver transection line in front of the camera, towards segments I–IV, is an anatomic advantage in itself. Postoperative pain does not seem to surpass that of a simple cholecystectomy and hospital discharge is at 3 days median time.
    Hellēnikē cheirourgikē. Acta chirurgica Hellenica 02/2012; 84(1). DOI:10.1007/s13126-012-0005-1
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    ABSTRACT: Oxidative stress as a result of either exogenous stimuli or cellular metabolism affects several cellular processes such as proliferation, apoptosis, cell death and senescence. Consequently, it is implicated in the pathogenesis of various human diseases like cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases and aging. Oxidative stress is implicated in carcinogenesis either by directly provoking DNA damage or through the regulation of intracellular signaling cascades. In both cases the cellular response to oxidative stress is determined by the cellular context. ARF, the alternative protein product of the CDKN2A locus has been recently recognized as a novel sensor of oxidative stress, in a β-catenin and Hsp70-mediated manner. Since, improved understanding of cellular responses to oxidative stress may facilitate the design of novel antineoplastic regimens, we herein review the mechanisms by which oxidative stress promotes carcinogenesis, focusing on the role of ARF as a sensor of oxidative stress.
    Current Molecular Medicine 01/2012; 12(6):704-15. DOI:10.2174/156652412800792633 · 3.61 Impact Factor
  • 12η Πανελλήνια Επιστημονική Συνάντηση Ελληνικού Κολλεγίου Χειρουργών, Amalia Hotel, Καλαμπάκα; 01/2011
  • 12η Πανελλήνια Επιστημονική Συνάντηση Ελληνικού Κολλεγίου Χειρουργών, Amalia Hotel, Καλαμπάκα; 01/2011
  • 12η Πανελλήνια Επιστημονική Συνάντηση Ελληνικού Κολλεγίου Χειρουργών, Amalia Hotel, Καλαμπάκα; 01/2011
  • 12η Πανελλήνια Επιστημονική Συνάντηση Ελληνικού Κολλεγίου Χειρουργών, Amalia Hotel, Καλαμπάκα; 01/2011