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Barcelona, Spain

Puig M.,University of Barcelona | Puig M.,Institute dInvestigacions Biomediques August Pi i Sunyer | Lugo R.,University of Barcelona | Gabasa M.,University of Barcelona | And 9 more authors.
Molecular Cancer Research | Year: 2015

The crucial role of tumor-associated fibroblasts (TAF) in cancer progression is now clear in non-small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here, the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were dissected. Fibroblasts were cultured on substrata engineered to exhibit normal- or tumor-like stiffnesses at different serumconcentrations, and critical regulatory processes were elucidated. In control fibroblasts from nonmalignant tissue, matrix stiffening alone increased fibroblast accumulation, and this mechanical effect was dominant or comparable with that of soluble growth factors up to 0.5% serum. The stimulatory cues ofmatrix rigidity were driven by β1 integrin mechanosensing through FAK (pY397), and were associated with a posttranscriptionally driven rise in β1 integrin expression. The latter mechano-regulatory circuit was also observed in TAFs but in a subtype-specific fashion, because SCC-TAFs exhibited higher FAK (pY397), β1 expression, and ERK1/2 (pT202/Y204) than ADC-TAFs. Moreover, matrix stiffening induced a larger TAF accumulation in SCC-TAFs (>50%) compared with ADC-TAFs (10%-20%). In contrast, SCC-TAFs were largely serum desensitized, whereas ADC-TAFs responded to high serum concentration only. These findings provide the first evidence of subtype-specific regulation of NSCLC-TAF accumulation. Furthermore, these data support that therapies aiming to restore normal lung elasticity and/or β1 integrin-dependent mechano regulation may be effective against SCC-TAFs, whereas inhibiting stromal growth factor signaling may be effective against ADC-TAFs. Implications: This study reveals distinct mechanisms underlying the abnormal accumulation of tumor-supporting fibroblasts in two major subtypes of lung cancer, which will assist the development of personalized therapies against these cells. ©2014 AACR. Source


Vilar-Coromina N.,Autonomous University of Barcelona | Miro-Queralt J.,Servei dAnatomia Patologica | Cano-Bautista A.,Unitat dEpidemiologia I Registre de Cancer de Girona | Vilardell-Gil L.,Unitat dEpidemiologia I Registre de Cancer de Girona | And 3 more authors.
Medicina Clinica | Year: 2011

Background and objective: We aimed to assess the population-based incidence trends of non-melanoma skin cancer (NMSC): squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). Patients and method: From January 1994 to December 2007, 9,247 patients diagnosed with NMSC were recruited in the population-based Cancer Registry of Girona. Incidence rates were calculated with age-adjusted according to the Word standard population (WASR) by a direct method and reported as number of new cases per 100,000 person-year. To evaluate incidence trends by age group we used specific rates for these groups (45-64, > 64 years). We excluded patients younger than 45 years. Joinpoint method was used to estimate the average annual percentage change (AAPC) for the whole study period according to histologic and age groups. Results: Age-adjusted incidence was 55.74 per 10 5 person-year; it was higher in males (67.13) than in females (46.9). Age-adjusted incidence for BCC was higher compared with the incidence for SCC (44.56 and 11.18 respectively). Age-adjusted incidence rate for NMSC for both sexes increased from 48.53 (1994-95) to 60.54 (2004-05) with an AAPC of 2.30%, which was higher in females (2.65%) than in males (1.99%). Conclusions: There has been a significant increase in the incidence of NMSC in our area, particularly evident for SCC, and it is more important in patients older than 64 years and in females. © 2010 Elsevier España, S.L. All rights reserved. Source


Robles C.,Catalan Institute of Nanoscience and Nanotechnology | Poloczek A.,Johns Hopkins University | Casabonne D.,Catalan Institute of Nanoscience and Nanotechnology | Casabonne D.,CIBER ISCIII | And 7 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2012

Background: Merkel cell polyomavirus (MCV) has been identified as the cause of Merkel cell carcinoma. The increased incidence of chronic lymphocytic leukemia in Merkel cell cancer cohorts and the lymphotropic properties of the virus suggest a possible viral association with lymphomagenesis. To investigate this potential role, we explored seroreactivity against MCV VP1 capsids within the Epilymph case-control study in Spain. Methods: Serum samples from 468 incident lymphomas, categorized into up to 11 entities, and 522 controls frequency matched by age, sex, and recruitment center were tested for MCV antibodies by enzyme immunoassay using Virus-Like-Particles. Adjusted multinomial logistic regression was used to estimate the OR and 95% confidence interval (CI) associated to MCV seroprevalence. Immunosuppressed subjects were excluded. Results: MCV seroprevalence was 82% in controls and 85% in lymphoma cases. Among 11 lymphoma categories, MCV seropositivity was significantly higher in diffuse large B-cell lymphomas (DLBCL; 96.4%; OR = 6.1, 95%CI = 1.9-19.8), as compared with controls. MCV prevalences were also higher in follicular lymphoma, lymphoplasmacytic lymphoma, chronic lymphocytic leukemia, Hodgkin lymphoma, and mature T-cell lymphoma but differences did not reach statistical significance. Lower prevalences were observed for multiple myeloma and other B-cell lymphoma. Exclusion of samples collected after start of treatment did not change the results. In a subset analysis, no significant association was observed between BKV and JCV seroprevalence and DLBCL. Conclusion: The association observed between serologic evidence of MCV exposure and DLBCL warrants further research. Impact: MCV might be involved in the pathway of DLBCL and other lymphomas. ©2012 AACR. Source


Cendrowski J.,Epithelial Carcinogenesis Group | Sanchez-Arevalo Lobo V.J.,Epithelial Carcinogenesis Group | Sendler M.,University of Greifswald | Salas A.,Servei dAnatomia Patologica | And 7 more authors.
Gut | Year: 2015

Objective Pancreatic acinar cell maturation is dependent on the activity of the pancreas transcription factor 1 (PTF1) complex. Induction of pancreatitis leads to MAP kinase activation and transient suppression of the acinar differentiation programme. We investigated the role of MAP kinase-interacting kinase 1 (Mnk1) in mouse exocrine pancreas development and in the response to secretagogue-induced pancreatitis. Design Mnk1 expression was analysed using immunohistochemistry, RT-qPCR and western blotting. Ptf1a binding to Mnk1 was assessed by chromatin immunoprecipitation and qPCR. Acute pancreatitis was induced in wild type and Mnk1-/- mice by 7 h intraperitoneal injections of caerulein. In vitro amylase secretion and trypsinogen activation were assessed using freshly isolated acinar cells. In vivo secretion was quantified by secretin-stimulated MRI. Results Mnk1 is expressed at the highest levels in pancreatic acinar cells and is a direct PTF1 target. Mnk1 is activated upon induction of pancreatitis and is indispensable for eIF4E phosphorylation. The pancreas of Mnk1-/- mice is histologically normal. Digestive enzyme content is significantly increased and c-Myc and Ccnd1 levels are reduced in Mnk1-/- mice. Upon induction of acute pancreatitis, Mnk1-/- mice show impaired eIF4E phosphorylation, activation of c-Myc and down regulation of zymogen content. Acinar cells show defective relocalisation of digestive enzymes, polarity defects and impaired secretory response in vitro and in vivo. Conclusions Mnk1 is a novel pancreatic acinar cellspecific stress response kinase that regulates digestive enzyme abundance and eIF4E phosphorylation. It is required for the physiological secretory response of acinar cells and for the homeostatic response to caerulein administration during acute pancreatitis. Source


Prat E.,Institute Of Biotecnologia I Biomedicina | del Rey J.,Institute Of Biotecnologia I Biomedicina | Ponsa I.,Institute Of Biotecnologia I Biomedicina | Nadal M.,Institute Catala dOncologia IDIBELL | And 6 more authors.
Urology | Year: 2010

Objectives: To classify bladder tumors according to their genomic imbalances and evaluate their association with patient's outcome. Methods: Sixty-three superficially and minimally invasive bladder tumors were analyzed by conventional comparative genomic hybridization. Subtelomeric screening in 15 of these tumors was performed by multiplex ligation-dependent probe amplification. Results: Losses of 9q and 9p (32% and 25% of all cases, respectively) as well as gains of chromosomes Xq and Xp (28% and 25%, respectively) were the most frequent chromosome imbalances. Losses of 8p and gains in 1q and 8q were detected in >20% of cases. Tumors were classified into 3 groups according to their individualized pattern of gains and losses. The largest group was characterized by few chromosome imbalances, presenting 77% and 49% of the Ta and T1 tumors, respectively. Another group characterized by chromosomal gains, was composed of equal number of Ta and T1 tumors, with +1q and +17q gains being the most common imbalances. A minority group was characterized by chromosomal losses on 11q, 5q, and 6q. The multiplex ligation-dependent probe amplification study showed good correlation with comparative genomic hybridization results. With regard to the biological significance of this classification, a remarkable fact is that this minority group composed mainly of T1 tumors, showed a significant decrease in patient overall survival. Conclusions: Our data suggest that superficial carcinomas of the bladder can be subdivided into a larger number of subclasses than had previously been expected. Our results also demonstrate a decreased survival among patients whose tumors show more genomic losses than gains. Crown Copyright © 2010. Source

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