Time filter

Source Type

Bedhomme S.,Institute Biologia Molecular Y Celular Of Plantas | Bedhomme S.,Catalan Institute of Oncology ICO | Lafforgue G.,Institute Biologia Molecular Y Celular Of Plantas | Elena S.F.,Institute Biologia Molecular Y Celular Of Plantas | Elena S.F.,Santa Fe Institute
BMC Evolutionary Biology | Year: 2013

Background: The importance of historical contingency in determining the potential of viral populations to evolve has been largely unappreciated. Identifying the constraints imposed by past adaptations is, however, of importance for understanding many questions in evolutionary biology, such as the evolution of host usage dynamics by multi-host viruses or the emergence of escape mutants that persist in the absence of antiviral treatments. To address this issue, we undertook an experimental approach in which sixty lineages of Tobacco etch potyvirus that differ in their past evolutionary history and degree of adaptation to Nicotiana tabacum were allowed to adapt to this host for 15 rounds of within host multiplication and transfer. We thereafter evaluated the degree of adaptation to the new host as well as to the original ones and characterized the consensus sequence of each lineage. Results: We found that past evolutionary history did not determine the phenotypic outcome of this common host evolution phase, and that the signal of local adaptation to past hosts had largely disappeared. By contrast, evolutionary history left footprints at the genotypic level, since the majority of host-specific mutations present at the beginning of this experiment were retained in the end-point populations and may have affected which new mutations were consequently fixed. This resulted in further divergence between the sequences despite a shared selective environment. Conclusions: The present experiment reinforces the idea that the answer to the question "How important is historical contingency in evolution?" strongly depends on the level of integration of the traits studied. A strong historical contingency was found for TEV genotype, whereas a weak effect of on phenotypic evolution was revealed. In an applied context, our results imply that viruses are not easily trapped into suboptimal phenotypes and that (re)emergence is not evolutionarily constrained. © 2013 Bedhomme et al; licensee BioMed Central Ltd.


Gonzalez C.A.,Catalan Institute of Oncology ICO | Sanz-Anquela J.M.,University of Alcalá | Gisbert J.P.,Hospital Universitario Of La Princesa | Correa P.,Vanderbilt University
International Journal of Cancer | Year: 2013

The identification and surveillance of patients with preneoplastic lesions at high risk of progressing to gastric cancer (GC) represents the most effective way of reducing the burden of GC. The incomplete type of intestinal metaplasia (IM) could be considered as the best candidate for surveillance. However, the usefulness of subtyping of IM has been considered by some authors as limited and inconsistent. A search was carried out to identify all cross-sectional (n=14) and follow-up (n=10) studies that assessed the risk of GC among subjects with different types of IM. Out of the 14 cross-sectional studies, 13 reported that the prevalence of incomplete IM was statistically significantly higher in GC than in other gastric lesions. Out of the ten follow-up studies, six found a statistically significant association between incomplete IM and subsequent GC risk. The relative risks of GC were from 4- to 11-fold higher for the presence of incomplete type in comparison to complete type or in comparison to the absence of incomplete type, among the studies that reported the magnitude of the risk. According to this comprehensive review, most of the scientific evidence supports the utility of subtyping IM as a predictor of GC risk. Recognizing its usefulness by gastroenterologists should encourage pathologists to subtype IM. Copyright © 2012 UICC.


Munk C.,Heinrich Heine University Düsseldorf | Willemsen A.,Center for Public Health Research | Bravo I.G.,Center for Public Health Research | Bravo I.G.,Catalan Institute of Oncology ICO | Bravo I.G.,Lhospitalet Of Llobregat
BMC Evolutionary Biology | Year: 2012

Background: The APOBEC3 (A3) genes play a key role in innate antiviral defense in mammals by introducing directed mutations in the DNA. The human genome encodes for seven A3 genes, with multiple splice alternatives. Different A3 proteins display different substrate specificity, but the very basic question on how discerning self from non-self still remains unresolved. Further, the expression of A3 activity/ies shapes the way both viral and host genomes evolve. Results: We present here a detailed temporal analysis of the origin and expansion of the A3 repertoire in mammals. Our data support an evolutionary scenario where the genome of the mammalian ancestor encoded for at least one ancestral A3 gene, and where the genome of the ancestor of placental mammals (and possibly of the ancestor of all mammals) already encoded for an A3Z1-A3Z2-A3Z3 arrangement. Duplication events of the A3 genes have occurred independently in different lineages: humans, cats and horses. In all of them, gene duplication has resulted in changes in enzyme activity and/or substrate specificity, in a paradigmatic example of convergent adaptive evolution at the genomic level. Finally, our results show that evolutionary rates for the three A3Z1, A3Z2 and A3Z3 motifs have significantly decreased in the last 100 Mya. The analysis constitutes a textbook example of the evolution of a gene locus by duplication and sub/neofunctionalization in the context of virus-host arms race. Conclusions: Our results provide a time framework for identifying ancestral and derived genomic arrangements in the APOBEC loci, and to date the expansion of this gene family for different lineages through time, as a response to changes in viral/retroviral/retrotransposon pressure. © 2012 Münk et al.; licensee BioMed Central Ltd.


Gonzalez C.A.,Catalan Institute of Oncology ICO | Figueiredo C.,University of Porto | Lic C.B.,Catalan Institute of Oncology ICO | Ferreira R.M.,University of Porto | And 7 more authors.
American Journal of Gastroenterology | Year: 2011

Objectives: There are no established predictive markers of progression of gastric preneoplastic lesions. The aim of this study was to analyze the relationship between Helicobacter pylori cagA and vacA genotypes and progression of gastric preneoplastic lesions. Methods: This was a follow-up study that carried out in a province of Spain with a high risk of gastric cancer. A total of 312 patients who underwent upper endoscopy with gastric biopsy in 1988-1994 with diagnoses of normal mucosa, non-atrophic gastritis (NAG), non-metaplastic multifocal atrophic gastritis (MAG), and complete or incomplete intestinal metaplasia (IM), and who accepted to undergo a new biopsy during 2005-2007 or had an end point during follow-up, were included in this study. Detection and characterization of H. pylori cagA and vacA genotypes was performed directly in baseline paraffin-embedded gastric biopsy specimens by PCR followed by reverse hybridization onto a line probe assay. Inter- and intra-observer variability of histological diagnosis was assessed. Analysis was done using unconditional logistic regression. Results: The mean age of patients was 48.5 years (45% males) and the mean of follow-up was 12.8 years. H. pylori strains harboring cagA, vacA s1, and vacA m1 genotypes were more frequently found in patients with more advanced gastric preneoplastic lesions. Infection with cagA-positive, vacA s1, and vacA m1 strains was associated with progression of gastric preneoplastic lesions (multivariate odds ratio (OR)2.28, 95% confidence interval (CI) 1.13-4.58; OR2.90, 95% CI 1.38-6.13; and OR3.38, 95% CI 1.34-8.53, respectively). Infection with strains that are simultaneously cagA positive and vacA s1/m1 was associated with progression of gastric precancerous lesions with an OR of 4.80 (95% CI 1.71-13.5) in relation to those infected with cagA-negative/vacA s2/m2 strains. Conclusions: H. pylori genotyping may be useful for the identification of patients at high risk of progression of gastric preneoplastic lesions and who need more intensive surveillance. © 2011 by the American College of Gastroenterology.


Cufi S.,Catalan Institute of Oncology ICO | Cufi S.,Girona Biomedical Research Institute IdIBGi | Vazquez-Martin A.,Catalan Institute of Oncology ICO | Vazquez-Martin A.,Girona Biomedical Research Institute IdIBGi | And 7 more authors.
Cell Cycle | Year: 2010

Transforming Growth Factorβ (TGFβ) is a major driving force of the Epithelial-to-Mesenchymal (EMT) genetic program, which becomes overactive in the pathophysiology of many age-related human diseases. TGFβ-driven EMT is sufficient to generate migrating cancer stem cells by directly linking the acquisition of cellular motility with the maintenance of tumor-initiating (stemness) capacity. Chronic diseases exhibiting excessive fibrosis can be caused by repeated and sustained infliction of TGFβ-driven EMT, which increases collagen and extracellular matrix synthesis. Pharmacological prevention and/ or reversal of TGFβ-induced EMT may therefore have important clinical applications in the management of cancer metastasis as well as in the prevention and/or treatment of end-state organ failures. Earlier studies from our group have revealed that clinically-relevant concentrations of the biguanide derivative metformin, the most widely used oral agent to lower blood glucose concentration in patients with type 2 diabetes and metabolic syndrome, notably decreased both the self-renewal and the proliferation of trastuzumab-refractory breast cancer stem cell populations. Given that: (a) tumor-initiating cancer stem cells display a significant enrichment in the expression of basal/mesenchymal or myoepithelial markers, including an increased secretion of TGFβ; (b) metformin treatment impedes the ontogeny of generating the stem cell phenotype by transcriptionally repressing key drivers of the EMT genetic program (e.g., ZEB1, TWIST1, SNAIL2 [Slug], TGFβs), we recently hypothesized that prevention of TGFβ-induced EMT might represent a common molecular mechanism underlying the anti-cancer stem cells and anti-fibrotic actions of metformin. Remarkably, metformin exposure not only impedes TGFβ-promoted loss of the epithelial marker E-cadherin in MCF-7 breast cancer cells but it prevents further TGF-induced cell scattering and accumulation of the mesenchymal marker vimentin in Madin-Darby canine kidney (MDCK) cells. We now propose that metformin, by weakening the ability of TGFβ signaling to fully induce mesenchymal cell states in a variety of pathological processes including fibrosis (e.g., chronic renal disease, non-alcoholic steatohepatitis, heart failure or sclerosis) and malignant progression (and likely by reducing TGFβ-regulated inflammation and immune responses - inflammaging-), molecularly behaves as a bona fide anti-aging modality. © 2010 Landes Bioscience.


Iliou M.S.,Hospital Duran i Reynals | Da Silva-Diz V.,Hospital Duran i Reynals | Carmona F.J.,Hospital Duran i Reynals | Ramalho-Carvalho J.,Hospital Duran i Reynals | And 6 more authors.
Oncogene | Year: 2014

Disruption of microRNA (miRNA) expression patterns is now being recognized as a hallmark of human cancer. The causes of these altered profiles are diverse, and, among them, we found the existence of defects in the miRNA processing machinery. However, little is known about how these alterations affect the biology of the underlying tumors. Herein, we show that colorectal cancer cells with an impairment in DICER1, a major miRNA biogenesis gene, undergo enrichment of tumor stemness features and an epithelial-to-mesenchymal transition. These phenotypes are associated with the downregulation of miRNAs, such as miR-34a, miR-126 and those of the miR-200 family, that target critical coding genes in these pathways. Most importantly, DICER1 impairment also induces the acquisition of a greater capacity for tumor initiation and metastasis, two properties associated with cancer stem cells. © 2014 Macmillan Publishers Limited.


Vazquez-Martin A.,Catalan Institute of Oncology ICO | Vazquez-Martin A.,Girona Biomedical Research Institute IdIBGi | Oliveras-Ferraros C.,Catalan Institute of Oncology ICO | Oliveras-Ferraros C.,Girona Biomedical Research Institute IdIBGi | And 8 more authors.
Cell Cycle | Year: 2010

The sole overexpression of pivotal regulators of the embryonic Epithelial-Mesenchymal Transition (EMT) genetic program ("EMT status") may be sufficient to efficiently drive the ontogeny of the breast cancer stem cell molecular signature independently of changes in EMT functioning ("EMT phenotype"). Using basal-like breast cancer models naturally enriched in either CD44 posCD24 low/neg or CD44 posCD24 pos tumor-initiating cell populations we herein illustrate that non-cytotoxic concentrations of the anti-diabetic drug metformin efficiently impedes the ontogeny of generating the stem cell phenotype by transcriptionally repressing the stem cell property EMT. Metformin treatment dynamically regulated the CD44 posCD24 neg/low breast cancer stem cell immunophenotype, transcriptionally reprogrammed cells through decreased expression of key drivers of the EMT machinery including the transcription factors ZEB1, TWIST1 and SNAI2 (Slug) and the pleiotrophic cytokines TGFβs, and lastly impeded the propensity of breast cancer stem cells to form multicellular "microtumors" in non-adherent and non-differentiating conditions (i.e., "mammospheres"). These findings, altogether, provide strong motivation for the continued molecular understanding and clinical development of metformin as a non-toxic therapeutic aimed to interdict the breast cancer stem cell phenotype by targeting EMT, a molecular process that is central to the ontogenesis of the breast cancer stem cell molecular signature. © 2010 Landes Bioscience.


Garcia-Perez R.,Catalan Institute of Oncology ICO
Genome biology and evolution | Year: 2014

Papillomaviruses (PVs) are widespread pathogens. However, the extent of PV infections in bats remains largely unknown. This work represents the first comprehensive study of PVs in Iberian bats. We identified four novel PVs in the mucosa of free-ranging Eptesicus serotinus (EserPV1, EserPV2, and EserPV3) and Rhinolophus ferrumequinum (RferPV1) individuals and analyzed their phylogenetic relationships within the viral family. We further assessed their prevalence in different populations of E. serotinus and its close relative E. isabellinus. Although it is frequent to read that PVs co-evolve with their host, that PVs are highly species-specific, and that PVs do not usually recombine, our results suggest otherwise. First, strict virus-host co-evolution is rejected by the existence of five, distantly related bat PV lineages and by the lack of congruence between bats and bat PVs phylogenies. Second, the ability of EserPV2 and EserPV3 to infect two different bat species (E. serotinus and E. isabellinus) argues against strict host specificity. Finally, the description of a second noncoding region in the RferPV1 genome reinforces the view of an increased susceptibility to recombination in the E2-L2 genomic region. These findings prompt the question of whether the prevailing paradigms regarding PVs evolution should be reconsidered.


Martin-Castillo B.,Catalan Institute of Oncology ICO | Vazquez-Martin A.,Catalan Institute of Oncology ICO | Oliveras-Ferraros C.,Catalan Institute of Oncology ICO | Menendez J.A.,Catalan Institute of Oncology ICO
Cell Cycle | Year: 2010

In the early 1970s, Professor Vladimir Dilman originally developed the idea that antidiabetic biguanides may be promising as geroprotectors and anticancer drugs ("metabolic rehabilitation"). In the early 2000s, Anisimov's experiments revealed that chronic treatment of female transgenic HER2-/neu mice with metformin significantly reduced the incidence and size of mammary adenocarcinomas and increased the mean latency of the tumors. Epidemiological studies have confirmed that metformin, but not other anti-diabetic drugs, significantly reduces cancer incidence and improves cancer patients' survival in type 2 diabetics. At present, pioneer work by Dilman & Anisimov at the Petrov Institute of Oncology (St. Petersburg, Russia) is rapidly evolving due to ever-growing preclinical studies using human tumor-derived cultured cancer cells and animal models. We herein critically review how the antidiabetic drug metformin is getting reset to metabolically fight cancer. Our current perception is that metformin may constitute a novel "hybrid anti-cancer pill" physically combining both the long-lasting effects of antibodies - by persistently lowering levels of blood insulin and glucose-and the immediate potency of a cancer cell - targeting molecular agent-by suppressing the pivotal AMPK/mTOR/S6K1 axis and several protein kinases at once, including tyrosine kinase receptors such as HER1 and HER2-. In this scenario, we discuss the relevance of metformin doses in pre-clinical models regarding metformin's mechanisms of action in clinical settings. We examine recent landmark studies demonstrating metformin's ability to specifically target the cancer-initiating stem cells from which tumor cells develop, thereby preventing cancer relapse when used in combination with cytotoxic chemotherapy (dandelion hypothesis). We present the notion that, by acting as an efficient caloric restriction mimetic, metformin enhanced intrinsic capacity of mitotically competent cells to self-maintenance and repair (hormesis) might trigger counterintuitive detrimental effects. Ongoing chemopreventive, neoadjuvant and adjuvant trials should definitely establish whether metformin's ability to kill the "dandelion root" beneath the "cancer soil" likely exceeds metformin-related dangers of hormesis. © 2010 Landes Bioscience.


Salazar R.,Catalan Institute of Oncology ICO | Tabernero J.,Autonomous University of Barcelona
Clinical Cancer Research | Year: 2014

A six-gene prognostic colorectal cancer hypoxia score was generated from expression data from in vitro experiments and microarray datasets and was validated in two distinct patient cohorts. The approach followed by the authors is original and biologically sound but could be limited by potential biases and other methodologic limitations. © 2014 AACR.

Loading Catalan Institute of Oncology ICO collaborators
Loading Catalan Institute of Oncology ICO collaborators