Vassilis G Gorgoulis

The University of Manchester, Manchester, England, United Kingdom

Are you Vassilis G Gorgoulis?

Claim your profile

Publications (229)1282.08 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: IL-15 regulates the development, survival, and proliferation of multiple innate and adaptive immune cells and plays a dual role, inducing both tumor cell growth and anti-tumor immunity. However, the role of IL-15 in inflammation-induced cancer remains unclear. To explore this, we have compared the colon carcinoma burden of Il15−/- and Il15rα−/- mice with wild type (WT) mice after induction of colitis-associated colon carcinogenesis utilizing the AOM/DSS model. Compared to WT mice, Il15−/- but not Il15rα−/- mice showed reduced survival, along with higher tumor incidence, colon weight and tumor size. This suggests that low affinity IL-15 signaling via the shared IL-2Rβ/γc decreases the risk for developing colitis-associated cancer. CD11c-Il15 mice, in which IL-15 expression is reconstituted in Il15−/- mice under the control of the CD11c-promoter, showed that selective reconstitution of IL-15 in antigen-presenting cells restored the CD8+ T and NK cell compartments, serum levels of IFN-γ, G-CSF, IL-10 and CXCL1 and reduced tumor burden. After demonstrating IL-15 expression in human colorectal cancer cells in situ, we investigated the role of this cytokine in the modulation of key colonic oncogenic pathways in the tumor. Whilst these pathways were found to be unaltered in the absence of IL-15, tumor transcriptome analysis showed that loss of IL-15 up-regulates key inflammatory mediators associated with colon cancer progression, such as IL-1β, IL-22, IL-23, Cxcl5 and Spp1. These findings provide evidence that IL-15 suppresses colitis-associated colon carcinogenesis through regulation of anti-tumor cytotoxicity, and modulation of the inflammatory tumor micromilieu.
    OncoImmunology 05/2015; DOI:10.1080/2162402X.2014.1002721 · 6.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Colorectal cancer is a major health problem and the second cause of cancer related death in western countries. Signaling pathways that control tissue homeostasis are often deregulated during tumorigenesis and contribute to tumor development. Studies in mouse models have shown that the p38 MAPK pathway regulates homeostasis in colon epithelial cells but also plays an important role in colon tumor maintenance. In this study, we have investigated the role of p38 MAPK signaling in patient-derived xenografts (PDXs) from three different human colon tumors representing clinical heterogeneity and that recapitulate the human tumor conditions both at histological and molecular levels. We have found that PH797804, a chemical inhibitor of p38 MAPK, reduces tumor growth of the three PDXs, which correlates with impaired colon tumor cell proliferation and survival. The inhibition of p38 MAPK in PDXs results in downregulation of the IL-6/STAT3 signaling pathway, which is a key regulator of colon tumorigenesis. Our results show the importance of p38 MAPK in human colon tumor growth using a preclinical model, and support that inhibition of p38 MAPK signaling may have therapeutic interest for colon cancer treatment.
    Oncotarget 04/2015; · 6.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cells experience damage from exogenous and endogenous sources that endanger genome stability. Several cellular pathways have evolved to detect DNA damage and mediate its repair. Although many proteins have been implicated in these processes, only recent studies have revealed how they operate in the context of high-ordered chromatin structure. Here, we identify the nuclear oncogene SET (I2PP2A) as a modulator of DNA damage response (DDR) and repair in chromatin surrounding double-strand breaks (DSBs). We demonstrate that depletion of SET increases DDR and survival in the presence of radiomimetic drugs, while overexpression of SET impairs DDR and homologous recombination (HR)-mediated DNA repair. SET interacts with the Kruppel-associated box (KRAB)-associated co-repressor KAP1, and its overexpression results in the sustained retention of KAP1 and Heterochromatin protein 1 (HP1) on chromatin. Our results are consistent with a model in which SET-mediated chromatin compaction triggers an inhibition of DNA end resection and HR. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; DOI:10.1016/j.celrep.2015.03.005 · 7.21 Impact Factor
  • [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Common fragile sites (CFSs) are regions of the genome with a predisposition to DNA double-strand breaks in response to intrinsic (oncogenic) or extrinsic replication stress. CFS breakage is a common feature in carcinogenesis from its earliest stages. Given that a number of oncogenes and tumor suppressors are located within CFSs, a question that emerges is whether fragility in these regions is only a structural "passive" incident or an event with a profound biological effect. Furthermore, there is sparse evidence that other elements, like non-coding RNAs, are positioned with them. By analyzing data from various libraries, like miRbase and ENCODE, we show a prevalence of various cancer-related genes, miRNAs, and regulatory binding sites, such as CTCF within CFSs. We propose that CFSs are not only susceptible structural domains, but highly organized "functional" entities that when targeted, severe repercussion for cell homeostasis occurs.
    Cellular and Molecular Life Sciences CMLS 09/2014; 71(23). DOI:10.1007/s00018-014-1717-x · 5.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in expression of NPM1(NPM)-ALK oncogenic kinase. The latter is capable of activating ERK kinase, which upregulates JUNB expression through ETS1. JUNB, in turn, interacts with the TNFRSF8 (CD30) gene promoter and induces CD30 (TNFRSF8) overexpression. However, the role of CD30 overexpression in ALK+ ALCL oncogenesis remains unknown. Here we show that the JUNB gene is frequently amplified in ALK+ ALCL, suggesting gene amplification as an additional underlying mechanism for JUNB overexpression. Silencing of JUNB resulted in reduced cell growth and colony formation associated with decreased activator protein-1 activity and G1/S and G2/M cell cycle arrest. These effects were linked to decreased CD30 levels, downregulation of CCNA2 (Cyclin A), CCND2 (Cyclin D2) and CCND3 (Cyclin D3) and upregulation of cyclin-dependent kinase inhibitors CDKN2A (p14) and CDKN1A (p21), but not CDKN1B (p27). Similar cell cycle changes were observed following the knock-down of TNFRSF8 gene or blockade of its function using anti-CD30 antibodies, which were associated with upregulation of CDKN2A and CDKN1A, but not CDKN1B. These findings indicate that JUNB may partly operate through CD30 signalling. Silencing of JUNB also sensitized NPM1-ALCL+ cells to standard chemotherapeutic agents. Our findings uncover the oncogenic role of the JUNB/CD30 axis and its potential as therapeutic target in ALK+ ALCL.
    British Journal of Haematology 08/2014; 167(4). DOI:10.1111/bjh.13079 · 4.96 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alternative reading frame (ARF) is a tumor suppressor protein that senses oncogenic and other stressogenic signals. It can trigger p53-dependent and -independent responses with cell cycle arrest and apoptosis induction being the most prominent ones. Other ARF activities, particularly p53-independent ones, that could help in understanding cancer development and provide potential therapeutic exploitation are underrated. Although ARF is generally not expressed in normal tissues, it is essential for ocular and male germ cells development. The underlying mechanism(s) in these processes, while not clearly defined, point toward a functional link between ARF, DNA damage and angiogenesis. Based on a recent study from our group demonstrating a functional interplay between ataxia-telangiectasia mutated (ATM) and ARF during carcinogenesis, we discuss the role of ARF at the crossroads of cancer and developmental processes.
    Frontiers in Genetics 07/2014; 5:236. DOI:10.3389/fgene.2014.00236
  • Source
    Tomer Cooks, Ioannis S Pateras, Vassilis G Gorgoulis
    [Show abstract] [Hide abstract]
    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]
  • Source
    [Show abstract] [Hide abstract]
    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. <>
    Cell Death and Differentiation 06/2014; 24(6):998-1012. DOI:10.1038/cdd.2014.16 · 8.39 Impact Factor
  • European Journal of Neurology 05/2014; 21:677. · 3.85 Impact Factor
  • Neurology 04/2014; 82(10):209. · 8.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sensing, integrating, and processing of stressogenic signals must be followed by accurate differential response(s) for a cell to survive and avoid malignant transformation. The DNA damage response (DDR) pathway is vital in this process, as it deals with genotoxic/oncogenic insults, having p53 as a nodal effector that performs most of the above tasks. Accumulating data reveal that other pathways are also involved in the same or similar processes, conveying also to p53. Emerging questions are if, how, and when these additional pathways communicate with the DDR axis. Two such stress response pathways, involving the MKK7 stress-activated protein kinase (SAPK) and ARF, have been shown to be interlocked with the ATM/ATR-regulated DDR axis in a highly ordered manner. This creates a new landscape in the DDR orchestrated response to genotoxic/oncogenic insults that is currently discussed.
    Cell cycle (Georgetown, Tex.) 03/2014; 13(8). DOI:10.4161/cc.28654 · 5.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ionizing radiation (IR) has been described as a double-edged sword, since it is used for diagnostic and therapeutic medical applications, and at the same time it is a well known human mutagen and carcinogen, causing wide-ranging chromosomal aberrations. It is nowadays accepted that the detrimental effects of IR are not restricted only in the irradiated cells, but also to non-irradiated bystander or even distant cells manifesting various biological effects. This review presents the role of oxidative stress in the induction of bystander effects referring to the types of the implicated oxidative DNA lesions, the contributing intercellular and intracellular stress mediators, the way they are transmitted from irradiated to bystander cells and finally, the complex role of the bystander effect in the therapeutic efficacy of radiation treatment of cancer.
    Cancer letters 02/2014; 356(1). DOI:10.1016/j.canlet.2014.01.023 · 5.02 Impact Factor
  • Molecular Cancer Therapeutics 01/2014; 12(11_Supplement):B73-B73. DOI:10.1158/1535-7163.TARG-13-B73 · 6.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cardiovascular disease (CVD) is a major cause of death in smokers, particularly in those with chronic obstructive pulmonary disease (COPD). Circulating endothelial progenitor cells (EPC) are required for endothelial homeostasis, and their dysfunction contributes to CVD. To investigate EPC dysfunction in smokers, we isolated and expanded blood outgrowth endothelial cells (BOEC) from peripheral blood samples from healthy nonsmokers, healthy smokers, and COPD patients. BOEC from smokers and COPD patients showed increased DNA double-strand breaks and senescence compared to nonsmokers. Senescence negatively correlated with the expression and activity of sirtuin-1 (SIRT1), a protein deacetylase that protects against DNA damage and cellular senescence. Inhibition of DNA damage response by silencing of ataxia telangiectasia mutated (ATM) kinase resulted in upregulation of SIRT1 expression and decreased senescence. Treatment of BOEC from COPD patients with the SIRT1 activator resveratrol or an ATM inhibitor (KU-55933) also rescued the senescent phenotype. Using an in vivo mouse model of angiogenesis, we demonstrated that senescent BOEC from COPD patients are dysfunctional, displaying impaired angiogenic ability and increased apoptosis compared to cells from healthy nonsmokers. Therefore, this study identifies epigenetic regulation of DNA damage and senescence as pathogenetic mechanisms linked to endothelial progenitors' dysfunction in smokers and COPD patients. These defects may contribute to vascular disease and cardiovascular events in smokers and could therefore constitute therapeutic targets for intervention. Stem Cells 2013;31:2813–2826
    Stem Cells 12/2013; 31(12). DOI:10.1002/stem.1488 · 7.70 Impact Factor
  • Thorax 11/2013; 68(Suppl 3):A2-A3. DOI:10.1136/thoraxjnl-2013-204457.5 · 8.56 Impact Factor
  • Free Radical Biology and Medicine 09/2013; 65:S52-S53. DOI:10.1016/j.freeradbiomed.2013.08.089 · 5.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    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

Publication Stats

7k Citations
1,282.08 Total Impact Points


  • 2014–2015
    • The University of Manchester
      Manchester, England, United Kingdom
  • 2006–2015
    • National and Kapodistrian University of Athens
      • • Division of Histology - Embryology
      • • Department of Cell Biology and Biophysics
      Athínai, Attica, Greece
    • Danish Cancer Society
      København, Capital Region, Denmark
  • 2011–2014
    • Academy of Athens
      Athínai, Attica, Greece
  • 2002–2013
    • Harokopion University of Athens
      Athínai, Attica, Greece
    • Harvard University
      • Department of Oral Health Policy and Epidemiology
      Cambridge, Massachusetts, United States
  • 2012
    • Hospital Universitario Madrid Sanchinarro
      Madrid, Madrid, Spain
  • 2009
    • Palacký University of Olomouc
      • Laboratory of Genome Integrity
      Olmütz, Olomoucký, Czech Republic
  • 2002–2007
    • University of Patras
      • • Department of General Biology
      • • School of Medicine
      Rhion, West Greece, Greece
  • 2005–2006
    • Agricultural University of Athens
      • Department of Anatomy and Physiology of Farm Animals
      Athínai, Attica, Greece
    • William Penn University
      Filadelfia, Pennsylvania, United States
    • Onassis Cardiac Surgery Center
      Kallithea, Attica, Greece
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1998–2004
    • Wistar Institute
      Filadelfia, Pennsylvania, United States
  • 1995–2004
    • Laiko Hospital
      • First Department of Surgery
      Athínai, Attica, Greece
  • 1993–1995
    • Red Cross Hospital, Athens
      Athínai, Attica, Greece
    • University Hospital of Heraklion
      Irákleio, Attica, Greece