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Menendez J.A.,Catalan Institute of Nanoscience and Nanotechnology | Menendez J.A.,Girona Biomedical Research Institute
Cell Cycle | Year: 2015

The Nobel prized discovery of nuclear reprogramming is swiftly providing mechanistic evidence of a role for metabolism in the generation of cancer stem cells (CSC). Traditionally, the metabolic demands of tumors have been viewed as drivers of the genetic programming detected in cancer tissues. Beyond the energetic requirements of specific cancer cell states, it is increasingly recognized that metabolism per se controls epi-transcriptional networks to dictate cancer cell fate, i.e., metabolism can define CSC. Here I review the CSC-related metabolic features found in induced pluripotent stem (iPS) cells to provide an easily understandable framework in which the infrastructure and functioning of cellular metabolism might control the efficiency and kinetics of reprogramming in the rerouting of non-CSC to CSC-like cellular states. I suggest exploring how metabolism-dependent regulation of epigenetics can play a role in directing CSC states beyond conventional energetic demands of stage-specific cancer cell states, opening a new dimension of cancer in which the “physiological state” of CSC might be governed not only by cell-autonomous cues but also by local micro-environmental and systemic metabolo-epigenetic interactions. Forthcoming studies should decipher how specific metabolites integrate and mediate the overlap between the CSC-intrinsic “micro-epigenetics” and the “upstream” local and systemic “macro-epigenetics,” thus paving the way for targeted epigenetic regulation of CSCs through metabolic modulation including “smart foods” or systemic “metabolic nichotherapies.” © 2015 Taylor and Francis Group, LLC. Source


Lopez B.,University of Girona | Lopez B.,Girona Biomedical Research Institute | Pous C.,University of Girona | Pous C.,Girona Biomedical Research Institute | And 5 more authors.
Artificial Intelligence in Medicine | Year: 2011

Objective: Medical applications have special features (interpretation of results in medical metrics, experiment reproducibility and dealing with complex data) that require the development of particular tools. The eXiT*CBR framework is proposed to support the development of and experimentation with new case-based reasoning (CBR) systems for medical diagnosis. Method: Our framework offers a modular, heterogeneous environment that combines different CBR techniques for different application requirements. The graphical user interface allows easy navigation through a set of experiments that are pre-visualized as plots (receiver operator characteristics (ROC) and accuracy curves). This user-friendly navigation allows easy analysis and replication of experiments. Used as a plug-in on the same interface, eXiT*CBR can work with any data mining technique such as determining feature relevance. Results: The results show that eXiT*CBR is a user-friendly tool that facilitates medical users to utilize CBR methods to determine diagnoses in the field of breast cancer, dealing with different patterns implicit in the data. Conclusions: Although several tools have been developed to facilitate the rapid construction of prototypes, none of them has taken into account the particularities of medical applications as an appropriate interface to medical users. eXiT*CBR aims to fill this gap. It uses CBR methods and common medical visualization tools, such as ROC plots, that facilitate the interpretation of the results. The navigation capabilities of this tool allow the tuning of different CBR parameters using experimental results. In addition, the tool allows experiment reproducibility. © 2010 Elsevier B.V. Source


Corominas-Faja B.,Catalan Institute of Nanoscience and Nanotechnology | Corominas-Faja B.,Girona Biomedical Research Institute | Quirantes-Pine R.,University of Granada | Quirantes-Pine R.,Research and Development of Functional Food Center | And 14 more authors.
Aging | Year: 2012

Metabolomic fingerprint of breast cancer cells treated with the antidiabetic drug metformin revealed a significant accumulation of 5-formimino-tetrahydrofolate, one of the tetrahydrofolate forms carrying activated one-carbon units that are essential for the de novo synthesis of purines and pyrimidines. De novo synthesis of glutathione, a folate-dependent pathway interconnected with one-carbon metabolism was concomitantly depleted in response to metformin. End-product reversal studies demonstrated that thymidine alone leads to a significant but incomplete protection from metformin's cytostatic effects. The addition of the substrate hypoxanthine for the purine salvage pathway produces major rightward shifts in metformin's growth inhibition curves. Metformin treatment failed to activate the DNA repair protein ATM kinase and the metabolic tumor suppressor AMPK when thymidine and hypoxanthine were present in the extracellular milieu. Our current findings suggest for the first time that metformin can function as an antifolate chemotherapeutic agent that induces the ATM/AMPK tumor suppressor axis secondarily following the alteration of the carbon flow through the folate-related onecarbon metabolic pathways. © Corominas-Faja et al. Source


Cufi S.,Catalan Institute of Nanoscience and Nanotechnology | Cufi S.,Girona Biomedical Research Institute | Vazquez-Martin A.,Catalan Institute of Nanoscience and Nanotechnology | Vazquez-Martin A.,Girona Biomedical Research Institute | And 15 more authors.
Cell Cycle | Year: 2012

We have tested the hypothesis that the antidiabetic biguanide metformin can be used to manipulate the threshold for stress-induced senescence (SIS), thus accelerating the onset of cancer-protective cellular senescence in response to oncogenic stimuli. Using senescence-prone murine embryonic fibroblasts (MEFs), we assessed whether metformin treatment modified the senescence phenotype that is activated in response to DNA damaging inducers. Metformin significantly enhanced the number of MEFs entering a senescent stage in response to doxorubicin, an anthracycline that induces cell senescence by activating DNA damage signaling pathways (e.g., ATM/ATR) in a reactive oxygen species (ROS)-dependent manner. Using WI-38 and BJ-1 human diploid fibroblasts (HDFs), we explored whether metformin supplementation throughout their entire replicative lifespan may promote the early appearance of the biomarkers of replicative senescence. Chronic metformin significantly reduced HDFs' lifespan by accelerating both the loss of replicative potential and the acquisition of replicative senescence-related biomarkers (e.g., enlarged and flattened cell shapes, loss of arrayed arrangement, accumulation of intracellular and extracellular debris and SA-β-gal-positive staining). Metformin functioned as a bona fide stressful agent, inducing monotonic, dose-dependent, SIS-like responses in BJ-1 HDFs, which are highly resistant to ROS-induced premature senescence. Metformin-induced SIS in BJ-1 fibroblasts was accompanied by the striking activation of several microRNAs belonging to the miR-200s family (miR-200a, miR-141 and miR429) and miR-205, thus mimicking a recently described ability of ROS to chemosensitize cancer cells by specifically upregulating anti-EMT (epithelial-to-mesenchymal transition) miR-200s. Because the unlimited proliferative potential of stem cells results from their metabolic refractoriness to SIS, we finally tested if metformin treatment could circumvent the stress (e.g., ROS)-resistant phenotype of induced pluripotent stem cells (iPSCs). Metformin treatment drastically reduced both the number and the size of iPSC colonies and notably diminished the staining of the pluripotency marker alkaline phosphatase. Our current findings, altogether, reveal for the first time that metformin can efficiently lower the threshold for SIS to generate an "stressed" cell phenotype that becomes pre-sensitized to oncogenic-like stimuli, including DNA damaging, proliferative and/or stemness inducers. © 2012 Landes Bioscience. Source


Del Barco S.,Catalan Institute of Nanoscience and Nanotechnology | Del Barco S.,Girona Biomedical Research Institute | Vazquez-Martin A.,Girona Biomedical Research Institute | Vazquez-Martin A.,Catalan Institute of Nanoscience and Nanotechnology | And 11 more authors.
Oncotarget | Year: 2011

The biguanide metformin, a widely used drug for the treatment of type 2 diabetes, may exert cancer chemopreventive effects by suppressing the transformative and hyperproliferative processes that initiate carcinogenesis. Metformin's molecular targets in cancer cells (e.g., mTOR, HER2) are similar to those currently being used for directed cancer therapy. However, metformin is nontoxic and might be extremely useful for enhancing treatment efficacy of mechanism-based and biologically targeted drugs. Here, we first revisit the epidemiological, preclinical, and clinical evidence from the last 5 years showing that metformin is a promising candidate for oncology therapeutics. Second, the anticancer effects of metformin by both direct (insulin-independent) and indirect (insulin-dependent) mechanisms are discussed in terms of metformin-targeted processes and the ontogenesis of cancer stem cells (CSC), including Epithelial-to-Mesenchymal Transition (EMT) and microRNAs-regulated dedifferentiation of CSCs. Finally, we present preliminary evidence that metformin may regulate cellular senescence, an innate safeguard against cellular immortalization. There are two main lines of evidence that suggest that metformin's primary target is the immortalizing step during tumorigenesis. First, metformin activates intracellular DNA damage response checkpoints. Second, metformin attenuates the anti-senescence effects of the ATP-generating glycolytic metabotype-the Warburg effect-, which is required for self-renewal and proliferation of CSCs. If metformin therapy presents an intrinsic barrier against tumorigenesis by lowering the threshold for stress-induced senescence, metformin therapeutic strategies may be pivotal for therapeutic intervention for cancer. Current and future clinical trials will elucidate whether metformin has the potential to be used in preventive and treatment settings as an adjuvant to current cancer therapeutics. © Barco et al. Source

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