[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.
[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.
[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; · 8.24 Impact Factor
[Show abstract][Hide abstract] 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. · 25.29 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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. · 1.44 Impact Factor
[Show abstract][Hide abstract] 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. · 4.20 Impact Factor
[Show abstract][Hide abstract] 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 01/2012; 2012:823949. · 2.71 Impact Factor
[Show abstract][Hide abstract] 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 01/2012; 2012:536761. · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: DNA lesions trigger the DNA damage response (DDR) machinery, which protects genomic integrity and sustains cellular survival. Increasing data underline the significance of the integrity of the DDR pathway in chemotherapy response. According to a recent work, persistent exposure of A549 lung carcinoma cells to doxorubicin induces an initial DDR-dependent checkpoint response, followed by a later DDR-independent, but p27Kip1-dependent one. Prompted by the above report and to better understand the involvement of the DDR signaling after chemotherapeutic stress, we examined the potential role of the canonical DDR pathway in A549 cells treated with doxorubicin. Exposure of A549 cells, prior to doxorubicin treatment, to ATM, ATR and DNA-PKcs inhibitors either alone or in various combinations, revealed that the earlier documented two-step response was DDR-dependent in both steps. Notably, inhibition of both ATM and ATR or selective inhibition of ATM or DNA-PKcs resulted in cell-cycle re-entry despite the increased levels of p27Kip1 at all time points analyzed. We further investigated the regulation of p27Kip1 protein levels in the particular setting. Our results showed that the protein status of p27Kip1 is mainly determined by p38-MAPK, whereas the role of SKP2 is less significant in the doxoroubicin-treated A549 cells. Cumulatively, we provide evidence that the DNA damage signaling is responsible for the prolonged cell cycle arrest observed after persistent chemotherapy-induced genotoxic stress. In conclusion, precise identification of the molecular mechanisms that are activated during the chemotherapeutic cycles could potentially increase the sensitization to the therapy applied.
Journal of Cellular and Molecular Medicine 08/2010; · 4.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Unstable atherosclerotic plaques of the carotid arteries are at great risk for the development of ischemic cerebrovascular events. The degradation of the extracellular matrix by matrix metalloproteinases (MMPs) and NO-induced apoptosis of vascular smooth muscle cells (VSMCs) contribute to the vulnerability of the atherosclerotic plaques. Basic fibroblast growth factor (bFGF) through its mitogenic and angiogenic properties has already been implicated in the pathogenesis of atherosclerosis. However, its role in plaque stability remains elusive. To address this issue, a panel of human carotid atherosclerotic plaques was analyzed for bFGF, FGF-receptors-1 and -2 (FGFR-1/-2), inducible nitric oxide synthase (iNOS) and MMP-9 expression. Our data revealed increased expression of bFGF and FGFR-1 in VSMCs of unstable plaques, implying the existence of an autocrine loop, which significantly correlated with high iNOS and MMP-9 levels. These results were recapitulated in vitro by treatment of VSMCs with bFGF. bFGF administration led to up-regulation of both iNOS and MMP-9 that was specifically mediated by nuclear factor-kappaB (NF-kappaB) activation. Collectively, our data demonstrate a novel NF-kappaB-mediated pathway linking bFGF with iNOS and MMP-9 expression that is associated with carotid plaque vulnerability.
Journal of Cellular and Molecular Medicine 05/2010; · 4.75 Impact Factor