19 research outputs found
Dise帽o y explotaci贸n de un circuito de investigaci贸n traslacional en c谩ncer de pr贸stata
424 p.La investigaci贸n cl铆nica no basta por s铆 sola. Resulta imprescindible su interrelaci贸n con la investigaci贸n b谩sica. El biobanco es un nexo de uni贸n. Existe una falta de estructura en la adquisici贸n y manejo de datos relacionados con patolog铆as y pacientes. Esta falta de integraci贸n de datos limita nuestro conocimiento sobre factores que influyen en la enfermedad. El c谩ncer de pr贸stata representa el c谩ncer m谩s prevalente en el var贸n. El incremento anual esperado es un 3-4% anual. Su presentaci贸n var铆a desde indolente a mortal. Por otra parte, su tratamiento implica una p茅rdida importante de calidad de vida. Conocer en el momento del diagn贸stico a qu茅 tipo de tumor nos enfrentamos podr铆a evitar tratamientos innecesarios o determinar un tratamiento multimodal intenso de manera precoz.Objetivo: 1 Dise帽o de un circuito de investigaci贸n traslacional en un Servicio de Urolog铆a para la b煤squeda experimental de biomarcadores no invasivos en c谩ncer de pr贸stata. 2 Dise帽o de protocolo cl铆nico y de recogida de datos de pacientes con prostatectom铆a radical rob贸tica y b煤squeda de factores pron贸sticos cl铆nicos.Material y M茅todos: Estudio cl铆nico prospectivo de 1148 pacientes intervenidos de prostatectom铆a radical rob贸tica por c谩ncer de pr贸stata. Revisi贸n de la literatura para la definici贸n de factores pron贸sticos en cohorte entre 2009 y 2014 con un seguimiento de 5 a帽os. Creaci贸n de un circuito de investigaci贸n para inclusi贸n en biobanco de biofluidos y tejido prost谩tico de pacientes con c谩ncer de pr贸stata y de casos control con hiperplasia benigna de pr贸stata para estudios moleculares a partir de 2012. Resultados: Protocolo de actividad traslacional sobre c谩ncer de pr贸stata implantado en la rutina diaria de un Servicio de Urolog铆a distribuido a lo largo de citas concertadas el d铆a del diagn贸stico, d铆a de la programaci贸n quir煤rgica, d铆a anterior a la cirug铆a, d铆a de la cirug铆a y seguimiento posterior que ocupan un total de 20 minutos al paciente y 30 minutos al ur贸logo/a especializado en c谩ncer de pr贸stata, enfermer铆a y auxiliares. Dise帽o de base de datos en plataforma online. An谩lisis de los datos cl铆nicos de la cohorte y obtenci贸n de factores pron贸sticos de la misma. Se investigan factores de antecedentes del paciente, factores del tumor previos a la cirug铆a, factores de la t茅cnica, factores de la pieza quir煤rgica, factores de anatom铆a patol贸gica y factores de calidad de vida. Estos resultados son la base de estudios moleculares en los pacientes seleccionados con factores de mal pron贸stico.Conclusiones: La integraci贸n de la plataforma cl铆nica, biobanco e investigadores b谩sicos nos ha permitido a un hospital terciario participar en el desarrollo de biomarcadores no invasivos seleccionando los grupos de pacientes de mal pron贸stico. Se describe un nuevo score pron贸stico a帽adiendo la bilateralidad de la biopsia, ISUP 驴3; porcentaje de tumor en el cilindro afectado >30% e invasi贸n perineural asociada a linfovascular.CICbioGUN
Dise帽o y explotaci贸n de un circuito de investigaci贸n traslacional en c谩ncer de pr贸stata
424 p.La investigaci贸n cl铆nica no basta por s铆 sola. Resulta imprescindible su interrelaci贸n con la investigaci贸n b谩sica. El biobanco es un nexo de uni贸n. Existe una falta de estructura en la adquisici贸n y manejo de datos relacionados con patolog铆as y pacientes. Esta falta de integraci贸n de datos limita nuestro conocimiento sobre factores que influyen en la enfermedad. El c谩ncer de pr贸stata representa el c谩ncer m谩s prevalente en el var贸n. El incremento anual esperado es un 3-4% anual. Su presentaci贸n var铆a desde indolente a mortal. Por otra parte, su tratamiento implica una p茅rdida importante de calidad de vida. Conocer en el momento del diagn贸stico a qu茅 tipo de tumor nos enfrentamos podr铆a evitar tratamientos innecesarios o determinar un tratamiento multimodal intenso de manera precoz.Objetivo: 1 Dise帽o de un circuito de investigaci贸n traslacional en un Servicio de Urolog铆a para la b煤squeda experimental de biomarcadores no invasivos en c谩ncer de pr贸stata. 2 Dise帽o de protocolo cl铆nico y de recogida de datos de pacientes con prostatectom铆a radical rob贸tica y b煤squeda de factores pron贸sticos cl铆nicos.Material y M茅todos: Estudio cl铆nico prospectivo de 1148 pacientes intervenidos de prostatectom铆a radical rob贸tica por c谩ncer de pr贸stata. Revisi贸n de la literatura para la definici贸n de factores pron贸sticos en cohorte entre 2009 y 2014 con un seguimiento de 5 a帽os. Creaci贸n de un circuito de investigaci贸n para inclusi贸n en biobanco de biofluidos y tejido prost谩tico de pacientes con c谩ncer de pr贸stata y de casos control con hiperplasia benigna de pr贸stata para estudios moleculares a partir de 2012. Resultados: Protocolo de actividad traslacional sobre c谩ncer de pr贸stata implantado en la rutina diaria de un Servicio de Urolog铆a distribuido a lo largo de citas concertadas el d铆a del diagn贸stico, d铆a de la programaci贸n quir煤rgica, d铆a anterior a la cirug铆a, d铆a de la cirug铆a y seguimiento posterior que ocupan un total de 20 minutos al paciente y 30 minutos al ur贸logo/a especializado en c谩ncer de pr贸stata, enfermer铆a y auxiliares. Dise帽o de base de datos en plataforma online. An谩lisis de los datos cl铆nicos de la cohorte y obtenci贸n de factores pron贸sticos de la misma. Se investigan factores de antecedentes del paciente, factores del tumor previos a la cirug铆a, factores de la t茅cnica, factores de la pieza quir煤rgica, factores de anatom铆a patol贸gica y factores de calidad de vida. Estos resultados son la base de estudios moleculares en los pacientes seleccionados con factores de mal pron贸stico.Conclusiones: La integraci贸n de la plataforma cl铆nica, biobanco e investigadores b谩sicos nos ha permitido a un hospital terciario participar en el desarrollo de biomarcadores no invasivos seleccionando los grupos de pacientes de mal pron贸stico. Se describe un nuevo score pron贸stico a帽adiendo la bilateralidad de la biopsia, ISUP 驴3; porcentaje de tumor en el cilindro afectado >30% e invasi贸n perineural asociada a linfovascular.CICbioGUN
Clinical Implications of (Pro)renin Receptor (PRR) Expression in Renal Tumours
(1) Background: Renal cancer is one of the most frequent malignancies in Western countries, with an unpredictable clinical outcome, partly due to its high heterogeneity and the scarcity of reliable biomarkers of tumour progression. (Pro)renin receptor (PRR) is a novel receptor of the renin鈥揳ngiotensin system (RAS) that has been associated with the development and progression of some solid tumours by RAS-dependent and -independent mechanisms. (2) Methods: In this study, we analysed the immunohistochemical expression of PRR at the centre and border in a series of 83 clear-cell renal cell (CCRCCs), 19 papillary (PRCC) and 7 chromophobe (ChRCC) renal cell carcinomas, and the benign tumour renal oncocytoma (RO, n = 11). (3) Results: PRR is expressed in all the tumour subtypes, with higher mean staining intensity in ChRCCs and ROs. A high expression of PRR at the tumour centre and at the infiltrative front of CCRCC tissues is significantly associated with high grade, tumour diameter, local invasion and stage, and with high mortality risk by UCLA integrated staging system (UISS) scale. (4) Conclusions: These findings indicate that PRR is associated with the development and progression of renal tumours. Its potential as a novel biomarker for RCC diagnosis/prognosis and as a promising therapeutic target should be taken into account in the future.The work was funded by the Basque Government (ELKARTEK KK2018-00090 and KK-2020/00069)
Soluble PD-L1 Is an Independent Prognostic Factor in Clear Cell Renal Cell Carcinoma
(1). Background: Immunohistochemical (IHC) evaluation of programmed death-1 (PD-1) and its ligand (PD-L1) is being used to evaluate advanced malignancies with potential response to immune checkpoint inhibitors. We evaluated both plasma and tissue expression of PD-1 and PD-L1 in the same cohort of patients, including non-metastatic and metastatic clear cell renal cell carcinoma (CCRCC). Concomitant plasma and tissue expression of PD-1 and PD-L1 was evaluated with emphasis on diagnostic and prognostic implications. (2) Methods: we analyzed PD-1 and PD-L1 IHC expression in tumor tissues and soluble forms (sPD-1 and sPD-L1) in plasma from 89 patients with CCRCC, of which 23 were metastatic and 16 received systemic therapy. The primary endpoint was evaluation of overall survival using Kaplan-Meier analysis and the Cox regression model. Plasma samples from healthy volunteers were also evaluated. (3) Results: Interestingly, sPD-1 and sPD-L1 levels were lower in cancer patients than in controls. sPD-1 and sPD-L1 levels and their counterpart tissue expression both at the tumor center and infiltrating front were not associated. Higher expression of both PD-1 and PD-L1 were associated with tumor grade, necrosis and tumor size. PD-1 was associated to tumor stage (pT) and PD-L1 to metastases. sPD-1 and sPD-L1 were not associated with clinico-pathological parameters, although both were higher in patients with synchronous metastases compared to metachronous ones and sPD-L1 was also higher for metastatic patients compared to non-metastatic patients. sPD-1 was also associated with the International Metastatic Renal Cell Cancer Database Consortium (IMDC) prognostic groups in metastatic CCRCC and also to the Morphology, Attenuation, Size and Structure (MASS) response criteria in metastatic patients treated with systemic therapy, mainly tyrosine-kinase inhibitors. Regarding prognosis, PD-L1 immunostaining at the tumor center with and without the tumor front was associated with worse survival, and so was sPD-L1 at a cut-off >793 ng/mL. Combination of positivity at both the tissue and plasma level increased the level of significance to predict prognosis. (4) Conclusions: Our findings corroborate the role of PD-L1 IHC to evaluate prognosis in CCRCC and present novel data on the usefulness of plasma sPD-L1 as a promising biomarker of survival in this neoplasia.The work was funded by the Basque Government (ELKARTEK KK2018-00090 and KK-2020/00069)
Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression
Urine contains extracellular vesicles (EVs) that concentrate molecules and protect them from degradation. Thus, isolation and characterisation of urinary EVs could increase the efficiency of biomarker discovery. We have previously identified proteins and RNAs with differential abundance in urinary EVs from prostate cancer (PCa) patients compared to benign prostate hyperplasia (BPH). Here, we focused on the analysis of the metabolites contained in urinary EVs collected from patients with PCa and BPH. Targeted metabolomics analysis of EVs was performed by ultrahigh- performance liquid chromatography-mass spectrometry. The correlation between metabolites and clinical parameters was studied, and metabolites with differential abundance in PCa urinary EVs were detected and mapped into cellular pathways. We detected 248 metabolites belonging to different chemical families including amino acids and various lipid species. Among these metabolites, 76 exhibited significant differential abundance between PCa and BPH. Interestingly, urine EVs recapitulated many of the metabolic alterations reported in PCa, including phosphathidylcholines, acyl carnitines, citrate and kynurenine. Importantly, we found elevated levels of the steroid hormone, 3beta-hydroxyandros-5-en-17-one-3-sulphate (dehydroepiandrosterone sulphate) in PCa urinary EVs, in line with the potential elevation of androgen synthesis in this type of cancer. This work supports urinary EVs as a non-invasive source to infer metabolic changes in PCa.Urine contains extracellular vesicles (EVs) that concentrate molecules and protect them from degradation. Thus, isolation and characterisation of urinary EVs could increase the efficiency of biomarker discovery. We have previously identified proteins and RNAs with differential abundance in urinary EVs from prostate cancer (PCa) patients compared to benign prostate hyperplasia (BPH). Here, we focused on the analysis of the metabolites contained in urinary EVs collected from patients with PCa and BPH. Targeted metabolomics analysis of EVs was performed by ultrahigh- performance liquid chromatography-mass spectrometry. The correlation between metabolites and clinical parameters was studied, and metabolites with differential abundance in PCa urinary EVs were detected and mapped into cellular pathways. We detected 248 metabolites belonging to different chemical families including amino acids and various lipid species. Among these metabolites, 76 exhibited significant differential abundance between PCa and BPH. Interestingly, urine EVs recapitulated many of the metabolic alterations reported in PCa, including phosphathidylcholines, acyl carnitines, citrate and kynurenine. Importantly, we found elevated levels of the steroid hormone, 3beta-hydroxyandros-5-en-17-one-3-sulphate (dehydroepiandrosterone sulphate) in PCa urinary EVs, in line with the potential elevation of androgen synthesis in this type of cancer. This work supports urinary EVs as a non-invasive source to infer metabolic changes in PCa
Integrative analysis of transcriptomics and clinical data uncovers the tumor- suppressive activity of MITF in prostate cancer
The dysregulation of gene expression is an enabling hallmark of cancer. Computational analysis of transcriptomics data from human cancer specimens, complemented with exhaustive clinical annotation, provides an opportunity to identify core regulators of the tumorigenic process. Here we exploit well-annotated clinical datasets of prostate cancer for the discovery of transcriptional regulators relevant to prostate cancer. Following this rationale, we identify Microphthalmia-associated transcription factor (MITF) as a prostate tumor suppressor among a subset of transcription factors. Importantly, we further interrogate transcriptomics and clinical data to refine MITF perturbation-based empirical assays and unveil Crystallin Alpha B (CRYAB) as an unprecedented direct target of the transcription factor that is, at least in part, responsible for its tumor-suppressive activity in prostate cancer. This evidence was supported by the enhanced prognostic potential of a signature based on the concomitant alteration of MITF and CRYAB in prostate cancer patients. In sum, our study provides proof-of-concept evidence of the potential of the bioinformatics screen of publicly available cancer patient databases as discovery platforms, and demonstrates that the MITF-CRYAB axis controls prostate cancer biology
Transcriptomic profiling of urine extracellular vesicles reveals alterations of CDH3 in prostate cancer
Extracellular vesicles (EV) are emerging structures with promising properties for intercellular communication. In addition, the characterization of EV in biofluids is an attractive source of non-invasive diagnostic, prognostic and predictive biomarkers. Here we show that urinary EV (uEV) from prostate cancer (PCa) patients exhibit genuine and differential physical and biological properties compared to benign prostate hyperplasia (BPH). Importantly, transcriptomics characterization of uEVs led us to define the decreased abundance of Cadherin 3, type 1 (CDH3) transcript in uEV from PCa patients. Tissue and cell line analysis strongly suggested that the status of CDH3 in uEVs is a distal reflection of changes in the expression of this cadherin in the prostate tumor. CDH3 was negatively regulated at the genomic, transcriptional, and epigenetic level in PCa. Our results reveal that uEVs could represent a non-invasive tool to inform about the molecular alterations in PCa
PI3K-regulated Glycine N-methyltransferase is required for the development of prostate cancer
[EN] Glycine N-Methyltransferase (GNMT) is a metabolic enzyme that integrates metabolism and epigenetic regulation. The product of GNMT, sarcosine, has been proposed as a prostate cancer biomarker. This enzyme is predominantly expressed in the liver, brain, pancreas, and prostate tissue, where it exhibits distinct regulation. Whereas genetic alterations in GNMT have been associated to prostate cancer risk, its causal contribution to the development of this disease is limited to cell line-based studies and correlative human analyses. Here we integrate human studies, genetic mouse modeling, and cellular systems to characterize the regulation and function of GNMT in prostate cancer. We report that this enzyme is repressed upon activation of the oncogenic Phosphoinositide-3-kinase (PI3K) pathway, which adds complexity to its reported dependency on androgen signaling. Importantly, we demonstrate that expression of GNMT is required for the onset of invasive prostate cancer in a genetic mouse model. Altogether, our results provide further support of the heavy oncogenic signal-dependent regulation of GNMT in prostate cancer.We are grateful to the Carracedo lab for valuable input, to Drs. Ana M. Aransay, James D. Sutherland and F. Elortza for technical advice, and Drs. Michelle Clasquin, Katie Sellers and Katya Marjon at Agios Pharmaceuticals for performing, processing and analyzing the metabolomics experiments. We thank the Basque Biobank for Research (BIOEF) for the support with prostate specimen acquisition and management. A.A-A. was funded by the Basque Government (predoctoral fellowship). V.T. is funded by Fundaci贸n Vasca de Innovaci贸n e Investigaci贸n Sanitarias, BIOEF (BIO15/CA/052), the AECC J.P. Bizkaia, the Basque Department of Health (2016111109) and the MICINN RTI2018-097267-B-I00. I.M. is supported by Fundaci贸n Cris Contra el C谩ncer (PR_TPD_2020-19). The work of A. Carracedo is supported by the Basque Department of Industry, Tourism and Trade (Elkartek), the department of education (IKERTALDE IT1106-16) and health (RIS3), the BBVA foundation, the MICINN (SAF2016-79381-R; PID2019-108787RB-I00 (FEDER/EU); Severo Ochoa Excellence Accreditation SEV-2016-0644; Excellence Networks RED2018-102769-T), the AECC (GCTRA18006CARR), Vencer el C谩ncer Foundation, La Caixa Foundation (ID 100010434), under the agreement LCF/PR/HR17/ and the European Research Council (Starting Grant 336343, PoC 754627, Consolidator Grant 819242). CIBERONC was co-funded with FEDER funds and funded by ISCIII. We are grateful for the support of Mondravember and Movembergara. A.E. was supported by MCIN/AEI/10.13039/501100011033 and the EU programme NextGenerationEU/PRTR (IJC2020-043583-I). The work of JM Mato was supported by NIH grant R01CA172086 and SAF2017-88041-R. EB is funded by the MICINN (BFU2016-76872-R (FEDER/EU), PID2019-108112RB-I00, and Excellence Networks SAF2017-90794-REDT)
The metabolic co-regulator PGC1伪 suppresses prostate cancer metastasis
Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewiring. Here we show that the transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1伪 (PGC1伪) suppresses prostate cancer progression and metastasis. A metabolic co-regulator data mining analysis unveiled that PGC1伪 is downregulated in prostate cancer and associated with disease progression. Using genetically engineered mouse models and xenografts, we demonstrated that PGC1伪 opposes prostate cancer progression and metastasis. Mechanistically, the use of integrative metabolomics and transcriptomics revealed that PGC1伪 activates an oestrogen-related receptor alpha (ERR伪)-dependent transcriptional program to elicit a catabolic state and metastasis suppression. Importantly, a signature based on the PGC1伪鈥揈RR伪 pathway exhibited prognostic potential in prostate cancer, thus uncovering the relevance of monitoring and manipulating this pathway for prostate cancer stratification and treatment
Comparative miRNA Analysis of Urine Extracellular Vesicles Isolated through Five Different Methods
Urine extracellular vesicles are a valuable low-invasive source of information, especially for the cells of the genitourinary tract. In the search for biomarkers, different techniques have been developed to isolate and characterize the cargo of these vesicles. In the present work, we compare five of these different isolation methods (three commercial isolation kits, ultracentrifugation, and lectin-based purification) and perform miRNA profiling using a multiplex miRNA assay. The results showed high correlation through all isolation techniques, and 48 out of 68 miRNAs were detected above the detection limit at least 10 times. The results obtained by multiplex assay were validated through Taqman qPCR. In addition, using this technique combined with a clinically friendly extracellular vesicle (uEV)-enrichment method, we performed the analysis of selected miRNAs in urine from patients affected with bladder cancer, benign prostate hyperplasia, or prostate cancer. Importantly, we found that those miRNAs could be detected in almost 100% of the samples, and no significant differences were observed between groups. Our results support the feasibility of analyzing exosomes-associated miRNAs using a methodology that requires a small volume of urine and is compatible with a clinical environment and high-throughput analysis