MicroRNAs are key regulators of hepatocellular carcinoma (HCC) cell dissemination—what we learned from microRNA-494

Producción CientíficaHepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, and it is well accepted that the poor outcome of HCC patients among others is caused by metastasis and tumor cell dissemination

Tumor cell load and heterogeneity estimation from diffusion-weighted MRI calibrated with histological data: an example from lung cancer

Producción CientíficaDiffusion-weighted magnetic resonance imaging (DWI) is a key non-invasive imaging technique for cancer diagnosis and tumor treatment assessment, reflecting Brownian movement of water molecules in tissues. Since densely packed cells restrict molecule mobility, tumor tissues produce usually higher signal (a.k.a. less attenuated signal) on isotropic maps compared with normal tissues. However, no general quantitative relation between DWI data and the cell density has been established. In order to link low-resolution clinical cross-sectional data with high-resolution histological information, we developed an image processing and analysis chain, which was used to study the correlation between the diffusion coefficient (D value) estimated from DWI and tumor cellularity from serial histological slides of a resected non-small cell lung cancer tumor. Color deconvolution followed by cell nuclei segmentation was performed on digitized histological images to determine local and cell-type specific 2d (two-dimensional) densities. From these, the 3d cell density was inferred by a model-based sampling technique, which is necessary for the calculation of local and global 3d tumor cell count. Next, DWI sequence information was overlaid with high-resolution CT data and the resected histology using prominent anatomical hallmarks for co-registration of histology tissue blocks and non-invasive imaging modalities' data. The integration of cell numbers information and DWI data derived from different tumor areas revealed a clear negative correlation between cell density and D value. Importantly, spatial tumor cell density can be calculated based on DWI data. In summary, our results demonstrate that tumor cell count and heterogeneity can be predicted from DWI data, which may open new opportunities for personalized diagnosis and therapy optimization

Genes associated with metabolic syndrome predict disease-free survival in stage II colorectal cancer patients. A novel link between metabolic dysregulation and colorectal cancer

Producción CientíficaStudies have recently suggested that metabolic syndrome and its components increase the risk of colorectal cancer. Both diseases are increasing in most countries, and the genetic association between them has not been fully elucidated. The objective of this study was to assess the association between genetic risk factors of metabolic syndrome or related conditions (obesity, hyperlipidaemia, diabetes mellitus type 2) and clinical outcome in stage II colorectal cancer patients. Expression levels of several genes related to metabolic syndrome and associated alterations were analysed by real-time qPCR in two equivalent but independent sets of stage II colorectal cancer patients. Using logistic regression models and cross-validation analysis with all tumour samples, we developed a metabolic syndrome-related gene expression profile to predict clinical outcome in stage II colorectal cancer patients. The results showed that a gene expression profile constituted by genes previously related to metabolic syndrome was significantly associated with clinical outcome of stage II colorectal cancer patients. This metabolic profile was able to identify patients with a low risk and high risk of relapse. Its predictive value was validated using an independent set of stage II colorectal cancer patients. The identification of a set of genes related to metabolic syndrome that predict survival in intermediate-stage colorectal cancer patients allows delineation of a high-risk group that may benefit from adjuvant therapy and avoid the toxic and unnecessary chemotherapy in patients classified as low risk. Our results also confirm the linkage between.Ministerio de Ciencia, Innovación y Universidades (AGL2010-21565, RyC 2008-03734, IPT-2011-1248-060000),y la Comunidad de Madrid (ALIBIRD, S2009/AGR-1469

Patch-based nonlinear image registration for gigapixel whole slide images

Producción CientíficaImage registration of whole slide histology images allows the fusion of fine-grained information-like different immunohistochemical stains-from neighboring tissue slides. Traditionally, pathologists fuse this information by looking subsequently at one slide at a time. If the slides are digitized and accurately aligned at cell level, automatic analysis can be used to ease the pathologist's work. However, the size of those images exceeds the memory capacity of regular computers. Methods: We address the challenge to combine a global motion model that takes the physical cutting process of the tissue into account with image data that is not simultaneously globally available. Typical approaches either reduce the amount of data to be processed or partition the data into smaller chunks to be processed separately. Our novel method first registers the complete images on a low resolution with a nonlinear deformation model and later refines this result on patches by using a second nonlinear registration on each patch. Finally, the deformations computed on all patches are combined by interpolation to form one globally smooth nonlinear deformation. The NGF distance measure is used to handle multistain images. Results: The method is applied to ten whole slide image pairs of human lung cancer data. The alignment of 85 corresponding structures is measured by comparing manual segmentations from neighboring slides. Their offset improves significantly, by at least 15%, compared to the low-resolution nonlinear registration. Conclusion/Significance: The proposed method significantly improves the accuracy of multistain registration which allows us to compare different antibodies at cell level

The ellagic acid derivative 4,4′-Di-O-methylellagic acid efficiently inhibits colon cancer cell growth through a mechanism involving WNT16

Producción CientíficaEllagic acid (EA) and some derivatives have been reported to inhibit cancer cell proliferation, induce cell cycle arrest, and modulate some important cellular processes related to cancer. This study aimed to identify possible structure-activity relationships of EA and some in vivo derivatives in their antiproliferative effect on both human colon cancer and normal cells, and to compare this activity with that of other polyphenols. Our results showed that 4,4′-di-O-methylellagic acid (4,4′-DiOMEA) was the most effective compound in the inhibition of colon cancer cell proliferation. 4,4′-DiOMEA was 13-fold more effective than other compounds of the same family. In addition, 4,4′-DiOMEA was very active against colon cancer cells resistant to the chemotherapeutic agent 5-fluoracil, whereas no effect was observed in nonmalignant colon cells. Moreover, no correlation between antiproliferative and antioxidant activities was found, further supporting that structure differences might result in dissimilar molecular targets involved in their differential effects. Finally, microarray analysis revealed that 4,4′-DiOMEA modulated Wnt signaling, which might be involved in the potential antitumor action of this compound. Our results suggest that structural-activity differences between EA and 4,4′-DiOMEA might constitute the basis for a new strategy in anticancer drug discovery based on these chemical modifications.Ministerio de Economía, Industria y Competitividad (AGL2013-48943-C2-2-R and IPT-2011-1248-060000)Comunidad de Madrid [Grant P2013/ABI-2728 ALIBIRD-CM

ColoLipidGene: Signature of lipid metabolism-related genes to predict prognosis in stage-II colon cancer patients

Lipid metabolism plays an essential role in carcinogenesis due to the requirements of tumoral cells to sustain increased structural, energetic and biosynthetic precursor demands for cell proliferation. We investigated the association between expression of lipid metabolism-related genes and clinical outcome in intermediate-stage colon cancer patients with the aim of identifying a metabolic profile associated with greater malignancy and increased risk of relapse. Expression profile of 70 lipid metabolismrelated genes was determined in 77 patients with stage II colon cancer. Cox regression analyses using c-index methodology was applied to identify a metabolic-related signature associated to prognosis. The metabolic signature was further confirmed in two independent validation sets of 120 patients and additionally, in a group of 264 patients from a public database. The combined analysis of these 4 genes, ABCA1, ACSL1, AGPAT1 and SCD, constitutes a metabolic-signature (ColoLipidGene) able to accurately stratify stage II colon cancer patients with 5-fold higher risk of relapse with strong statistical power in the four independent groups of patients. The identification of a group of 4 genes that predict survival in intermediate-stage colon cancer patients allows delineation of a high-risk group that may benefit from adjuvant therapy, and avoids the toxic and unnecessary chemotherapy in patients classified as low-risk groupThis work was supported by Ministerio de Ciencia e Innovación del Gobierno de España (Plan Nacional I + D + i AGL2013–48943-C2–2-R and IPT-2011–1248-060000), Comunidad de Madrid (P2013/ABI-2728. ALIBIRDCM) and European Union Structural Funds. CIBEREHD is funded by the Instituto de Salud Carlos III. This is a collaborative study between the Molecular Oncology Unit of The Institute of Advanced Studies of Madrid IMDEA Food and the Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD

Evaluación del extracto supercrítico de romero (Rosmarinus officinalis L.) como agente antitumoral: bases genómicas de su potencial aplicación clínica

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Química-Física Aplicada. Fecha de lectura: 18-03-201

Rosemary (Rosmarinus officinalis L.) extract as a potential complementary agent in anticancer therapy

Cancer remains an important cause of mortality nowadays and, therefore, new therapeutic approaches are still needed. Rosemary (Rosmarinus officinalis L.) has been reported to possess antitumor activities both in vitro and in animal studies. Some of these activities were attributed to its major components, such as carnosic acid, carnosol, ursolic acid, and rosmarinic acid. Initially, the antitumor effects of rosemary were attributed to its antioxidant activity. However, in recent years, a lack of correlation between antioxidant and antitumor effects exerted by rosemary was reported, and different molecular mechanisms were related to its tumor inhibitory properties. Moreover, supported by the U.S. Food and Drug Administration and the European Food and Safety Authority, specific compositions of rosemary extract were demonstrated to be safe for human health and used as antioxidant additive in foods, suggesting the potential easy application of this agent as a complementary approach in cancer therapy. In this review, we aim to summarize the reported anticancer effects of rosemary, the demonstrated molecular mechanisms related to these effects and the interactions between rosemary and currently used anticancer agents. The possibility of using rosemary extract as a complementary agent in cancer therapy in comparison with its isolated components is discussed.This work has been supported by the Spanish Ministry of Science and Innovation (Plan Nacional I+D+i AGL2013-48943-C2, IPT-2011-1248-060000), Comunidad de Madrid (ALIBIRD, P2013/ABI-2728. ALIBIRD-CM), Alfonso Martín Escudero Foundation, and European Union Structural Funds.Peer Reviewe

Production of supercritical Rosemary extracts and their effect on tumor progression

Trabajo presentado al 10th International Symposium on Supercritical Fluids celebrado en San Francisco (US) del 13 al 16 de mayo de 2012.Supercritical fluid technology is the most innovative method to recover bioactive compounds for use as supplements for functional foods. Particularly, the recovery of antioxidant compounds from different herbs is being a matter of continuous research and development. Besides their role as food stabilizers, antioxidants can protect cells against the effects of free radicals and thus, play an important role in heart disease, cancer and other diseases. Rosemary (Rosmarinus officinalis L.) has been recognized as one of the Lamiaceae plant with large antioxidant activity. Main substances associated with the antioxidant activity are the phenolic diterpenes such as carnosol, rosmanol, carnosic acid, methyl carnosate, and phenolic acids such as the rosmarinic and caffeic acids. Particularly, carnosic acid is accepted as the most abundant antioxidant present in rosemary. In this work, supercritical fluid technology was applied to produce rosemary extracts with different composition (phenolic compounds and volatile oil content) and thus, with different antioxidant power. For this purpose, pure CO2 and CO2 modified with ethanol were utilized as supercritical solvents, and diverse extraction conditions (temperature, pressure, amount of cosolvent and fractionation procedure) were applied. Selected extracts, from the variety of samples obtained, were used to study the capability of rosemary supercritical extracts to inhibit the proliferation of human liver carcinoma cells. Moreover, the cytostatic effect of the different selected extracts were determined, revealing a dose-dependent effect of the different compositions of the extracts on the response of human hepatocarcinoma cells to the potential antitumoral effect of rosemary.This work has been supported by project AGL2010-21565(subprogram ALI) and project INNSAMED IPT-300000-2010-34 (subprogram INNPACTO) from Ministerio de Ciencia e Innovación (Spain) and Comunidad Autónoma de Madrid (project ALIBIRD-S2009/AGR-1469).Peer Reviewe

Expression of MicroRNA-15b and the glycosyltransferase GCNT3 correlates with antitumor efficacy of rosemary diterpenes in colon and pancreatic cancer

Colorectal and pancreatic cancers remain important contributors to cancer mortality burden and, therefore, new therapeutic approaches are urgently needed. Rosemary (Rosmarinus officinalis L.) extracts and its components have been reported as natural potent antiproliferative agents against cancer cells. However, to potentially apply rosemary as a complementary approach for cancer therapy, additional information regarding the most effective composition, its antitumor effect in vivo and its main molecular mediators is still needed. In this work, five carnosic acid-rich supercritical rosemary extracts with different chemical compositions have been assayed for their antitumor activity both in vivo (in nude mice) and in vitro against colon and pancreatic cancer cells. We found that the antitumor effect of carnosic acid together with carnosol was higher than the sum of their effects separately, which supports the use of the rosemary extract as a whole. In addition, gene and microRNA expression analyses have been performed to ascertain its antitumor mechanism, revealing that up-regulation of the metabolic-related gene GCNT3 and down-regulation of its potential epigenetic modulator miR-15b correlate with the antitumor effect of rosemary. Moreover, plasmatic miR-15b down-regulation was detected after in vivo treatment with rosemary. Our results support the use of carnosic acid-rich rosemary extract as a complementary approach in colon and pancreatic cancer and indicate that GCNT3 expression may be involved in its antitumor mechanism and that miR-15b might be used as a non-invasive biomarker to monitor rosemary anticancer effect. © 2014 González-Vallinas et al.This work was supported by the Spanish Ministry of Science and Innovation (Plan Nacional I+D+i AGL2010-21565, RyC 2008-03734; IPT-2011-1248-060000); Comunidad de Madrid (ALIBIRD, S2009/AGR-1469); and European Union Structural Funds.Peer Reviewe