Unleashing the Diagnostic, Prognostic and Therapeutic Potential of the Neuronostatin/GPR107 System in Prostate Cancer

Certain components of the somatostatin-system play relevant roles in Prostate Cancer (PCa), whose most aggressive phenotype (Castration-Resistant-PCa (CRPC)) remains lethal nowadays. However, neuronostatin and the G protein-coupled receptor 107 (GPR107), two novel members of the somatostatin-system, have not been explored yet in PCa. Consequently, we investigated the pathophysiological role of NST/GPR107-system in PCa. GPR107 expression was analyzed in well-characterized PCa patient′s cohorts, and functional/mechanistic assays were performed in response to GPR107-silencing and NST-treatment in PCa cells (androgen-dependent (AD: LNCaP) and androgen-independent (AI: 22Rv1/PC-3), which are cell models of hormone-sensitive and CRPC, respectively), and normal prostate cells (RWPE-1 cell-line). GPR107 was overexpressed in PCa and associated with key clinical parameters (e.g., advance stage of PCa, presence of vascular invasion and metastasis). Furthermore, GPR107-silencing inhibited proliferation/migration rates in AI-PCa-cells and altered key genes and oncogenic signaling-pathways involved in PCa aggressiveness (i.e., KI67/CDKN2D/MMP9/PRPF40A, SST5TMD4/AR-v7/In1-ghrelin/EZH2 splicing-variants and AKT-signaling). Interestingly, NST treatment inhibited proliferation/migration only in AI-PCa cells and evoked an identical molecular response than GPR107-silencing. Finally, NST decreased GPR107 expression exclusively in AI-PCa-cells, suggesting that part of the specific antitumor effects of NST could be mediated through a GPR107-downregulation. Altogether, NST/GPR107-system could represent a valuable diagnostic and prognostic tool and a promising novel therapeutic target for PCa and CRPC

Clinical Utility of Ghrelin-O-Acyltransferase (GOAT) Enzyme as a Diagnostic Tool and Potential Therapeutic Target in Prostate Cancer

Recent data suggested that plasma Ghrelin O-Acyl Transferase enzyme (GOAT) levels could represent a new diagnostic biomarker for prostate cancer (PCa). In this study, we aimed to explore the diagnostic and prognostic/aggressiveness capacity of GOAT in urine, as well as to interrogate its putative pathophysiological role in PCa. We analysed urine/plasma levels of GOAT in a cohort of 993 patients. In vitro (i.e., cell-proliferation) and in vivo (tumor-growth in a xenograft-model) approaches were performed in response to the modulation of GOAT expression/activity in PCa cells. Our results demonstrate that plasma and urine GOAT levels were significantly elevated in PCa patients compared to controls. Remarkably, GOAT significantly outperformed PSA in the diagnosis of PCa and significant PCa in patients with PSA levels ranging from 3 to 10 ng/mL (the so-called PSA grey-zone). Additionally, urine GOAT levels were associated to clinical (e.g., Gleason-score, PSA levels) and molecular (e.g., CDK2/CDK6/CDKN2A expression) aggressiveness parameters. Indeed, GOAT overexpression increased, while its silencing/blockade decreased cell-proliferation in PCa cells. Moreover, xenograft tumors derived from GOAT-overexpressing PCa (DU145) cells were significantly higher than those derived from the mock-overexpressing cells. Altogether, our results demonstrate that GOAT could be used as a diagnostic and aggressiveness marker in urine and a therapeutic target in PCa

Oncogenic Role of Secreted Engrailed Homeobox 2 (EN2) in Prostate Cancer

Engrailed variant-2 (EN2) has been suggested as a potential diagnostic biomarker; however, its presence and functional role in prostate cancer (PCa) cells is still controversial or unknown. Here, we analyzed 1) the expression/secretion profile of EN2 in five independent samples cohorts from PCa patients and controls (prostate tissues and/or urine) to determine its utility as a PCa biomarker; and 2) the functional role of EN2 in normal (RWPE1) and tumor (LNCaP/22Rv1/PC3) prostate cells to explore its potential value as therapeutic target. EN2 was overexpressed in our two cohorts of PCa tissues compared to control and in tumor cell lines compared with normal-like prostate cells. This profile was corroborated in silico in three independent data sets [The Cancer Genome Atlas(TCGA)/Memorial Sloan Kettering Cancer Center (MSKCC)/Grasso]. Consistently, urine EN2 levels were elevated and enabled discrimination between PCa and control patients. EN2 treatment increased cell proliferation in LNCaP/22Rv1/PC3 cells, migration in RWPE1/PC3 cells, and PSA secretion in LNCaP cells. These effects were associated, at least in the androgen-sensitive LNCaP cells, with increased AKT and androgen-receptor phosphorylation levels and with modulation of key cancer-associated genes. Consistently, EN2 treatment also regulated androgen-receptor activity (full-length and splicing variants) in androgen-sensitive 22Rv1 cells. Altogether, this study demonstrates the potential utility of EN2 as a non-invasive diagnostic biomarker for PCa and provides novel and valuable information to further investigate its putative utility to develop new therapeutic tools in PCa

Cuentos de nunca acabar. Aproximaciones desde la interculturalidad

Cuentos de nunca acabar. Aproximaciones desde la interculturalidad, surge después de la pandemia y su imposibilidad de socializar “en persona” con los compañeros de eventuales encuentros, porque la Comprensión Lectora tenía que reinventarse para su nueva reflexión cognitiva, adaptación contextual y reconstrucción del conocimiento. Este renovado enfoque de la realidad postpandemia, concebido en el marco de la educación intercultural comunitaria, busca potencializar los entornos naturales, sociales y culturales como recursos de aprendizaje multidisciplinario a través del lenguaje animado de los cuentos. En este marco, había que dinamizar la asignatura de Comunicación Oral y Escrita, que se dicta en los Primeros Niveles de los Centros de Apoyo de Otavalo, Cayambe, Latacunga y Riobamba, mediante un eje transversal donde los estudiantes escriban fundamentados en valores de la cosmovisión andina, considerando que provienen de varios lugares de la sierra y amazonía ecuatoriana. Todo surgió del encuentro presencial de un sábado cualquiera donde los estudiantes realizaban ejercicios narrativos, logrando una apreciable respuesta de imaginación, más emotiva que la clásica tarea de las Unidades, tanto así que, pasados unos días, seguían llegando sus escritos a mi correo. Entonces nos pusimos manos a la obra, cada estudiante tendría dos opciones como Actividad Integradora, la primera consistía en escribir un cuento de su propia inspiración, y la segunda analizar un clásico para comentar sus valores y antivalores. La mayor parte de estudiantes decidió escribir su propio cuento, de donde se escogieron algunas participaciones que podrían considerarse originales, para una edición que, respetando la transcripción de la tradición oral que prima en los sectores comunitarios, nos concretamos en revisar la puntuación y ortografía para publicarlos. Con esto buscamos innovar la Actividad Integradora, por algo más práctico y operativo para configurar los Objetos de Aprendizaje que buscamos. Así nació, en medio del camino, este libro de Cuentos de nunca acabar. Aproximaciones desde la interculturalidad, que ponemos en sus manos. Hernán Hermosa Mantilla Quito, junio de 202

Caracterització de les alteracions moleculars dels carcinomes basocel·lulars esporàdics

El carcinoma basocel•lular (CBC) és la neoplàsia més freqüent en l’ésser humà. La importància d’aquest tumor rau tant en la gran morbiditat que produeix com en l’enorme despesa sanitària que ocasiona als sistemes de salut de gairebé tot el món. Malgrat que el seu tractament és essencialment quirúrgic, existeixen casos on no està indicat aquest abordatge terapèutic i seria interessant el fet de conèixer les alteracions moleculars que comporten la formació de la neoplàsia per tal d’establir possibles dianes farmacològiques. Per aquestes raons hem cregut convenient aprofundir en l’estudi d’aquest tumor, centrant-nos en la fisiopatologia i intentant cultivant-lo “in vitro”. A través de l’estudi de la síndrome de Gorlin-Goltz s’ha establert la importància de la via Sonic hedgehog (Shh) en la fisopatologia del CBC. Nosaltres, mitjançant tècniques com l’immunoblot i la immunohistoquímica (mesurant els nivells de proteïna Gli1) hem determinat que aquesta via està activada en aproximadament la meitat dels casos de CBC esporàdic, confirmant les dades que es coneixen sobre aquest tema. Analitzant vies alternatives, hem trobat mostres amb alta activitat de b-catenina sense afectació de la via Shh i això ens fa pensar que la via Wnt pot tenir un paper fonamental en aquests casos. Hem detectat per immunoblot l’acumulació de b-catenina en la meitat dels casos estudiats, relacionat-se de forma directa amb l’activitat proliferativa de la neoplasia.El carcinoma basocelular (CBC) es la neoplasia más frecuente en el ser humano. La importancia de este tumor radica tanto en la gran morbilidad que produce como en el enorme gasto sanitario que ocasiona a los sistemas de salud de casi todo el mundo. A pesar de que su tratamiento es esencialmente quirúrgico, existen casos donde no está indicado este abordaje terapéutico y sería interesante el hecho de conocer las alteraciones moleculares que comportan la formación la neoplasia para establecer posibles dianas farmacológicas. Por estas razones hemos creído conveniente profundizar en el estudio de este tumor, centrándonos en la fisiopatología e intentando su cultivo “in vitro”. A través del estudio del síndrome de Gorlin-Goltz se ha establecido la importancia de la via Sonic hedgehog (Shh) en la fisiopatología del CBC. Nosotros, mediante técnicas como el inmunoblot y la inmunohistoquímica (midiendo los niveles de proteína Gli1) hemos determinado que esta vía está activada en aproximadamente la mitad de los casos de CBC esporádico, confirmando los datos que se conocían sobre este tema. Analizando vías alternativas, hemos encontrado muestras con alta actividad de b-catenina sin afectación de la vía Shh y esto nos hace pensar que la vía Wnt puede tener un papel fundamental en estos casos. Hemos detectado por inmunoblot la acumulación de b-catenina en la mitad de los casos estudiados, relacionándose de forma directa con la actividad proliferativa de la neoplasia.Basal cell carcinoma (BCC) is the most common malignancy in humans. The importance of this tumor lies both in the high morbidity produced as in the high costs caused to the health systems of whole world. Although its treatment is essentially surgical, there are cases where it is not indicated this therapeutic approach, then it would be interesting to know the molecular alterations that involve the formation of this neoplasm to establish potential drug targets.For these reasons we have decided to study this tumor, focusing on the physiopathology and their culture "in vitro". Through the study of Gorlin-Goltz syndrome, the importance of the Sonic hedgehog pathway (Shh) in the pathophysiology of BCC was well established. Using techniques such as immunoblotting and immunohistochemistry (measuring protein levels Gli1), we have determined that this pathway is activated in about half of cases of sporadic BCC, confirming the previously known data. Analyzing alternative pathways, we found samples with high activity of b-catenin pathway without affecting Shh. This fact makes us think that the Wnt pathway may have a important role in these cases. We detected by immunoblot the accumulation b-catenin in half of the cases studied, interacting directly with the proliferative activity of the neoplasm

Erk1/2 activation in stromal fibroblasts from sporadic basal cell carcinomas

BACKGROUND Constitutive activation of the Erk pathway can lead to oncogenic transformation. However, the Erk pathway is not activated in human basal cell carcinomas (BCCs); although in animal models, this seems to be important. OBJECTIVE To help understand the role of Erk activity in BCC formation. MATERIALS AND METHODS The authors assayed the specific levels of phosphorylated Erk by immunohistochemistry in BCCs and normal skin biopsies. They have also analyzed Erk activation by immunoblot in fibroblasts isolated from BCC. RESULTS By immunohistochemical analysis, the authors have observed that 10 of BCCs (56%) did not show phosphor-Erk staining in tumor masses and 7 (40%) showed a gradient staining exhibiting phospho-Erk only in the epidermal side of tumor masses. Remarkably, 15 BCC samples (83%) showed phospho-Erk accumulation in stroma. Six of the 9 independent cultures of dermal fibroblasts isolated from BCC maintained Erk activation “in vitro.” CONCLUSION The authors propose that there is a specific cell-type regulation of Erk activity in BCC, and this feature may be relevant during BCC formation. Stroma region from BCCs showed Erk activation and reduced proliferation. Conversely, Erk activation is barely detectable in proliferative BCCs

Dermatofibrosarcoma protuberans sobre cicatriz de apendicectomía

El dermatofibrosarcoma protuberans (DFSP) es un tumor cutáneo relativamente raro, con una incidencia aproximada de 4 casos por cada millón de habitantes y año1,2. Ahora bien, es el sarcoma cutáneo más frecuente, representando el 2-6% de todos los sarcomas de la piel. Suele aparecer de novo sobre piel sana, pero de forma excepcional han sido descritos algunos casos sobre cicatrices de radioterapia o quemadura

Biomarkers Found in the Tumor Interstitial Fluid may Help Explain the Differential Behavior Among Keratinocyte Carcinomas

Altres ajuts: This work was funded by the Spanish Ministry of Innovation and Science MICINN (PID2019-104859GB-I00) and by Generalitat de Catalunya (2017-SGR-569). This work was supported by IRBLleida Biobank (B.0000682) and PLATAFORMA BIOBANCOS PT20/0021. "The proteomics analyses were performed in the IJC Proteomics Unit. The IJC Proteomics Unit is part of the Spanish Platform of Molecular and Bioinformatics Resources (ProteoRed), Instituto de Salud Carlos III (PT13/0001)." For detailed "Experimental procedures" for publication, please, contact the Proteomics Unit. Special thanks to Eddie Chalecki lluMme. M. R.-S. is the recipient of a TALENT grant from Lleida Institute for Biomedical Research-Dr Pifarré Foundation supported by Diputació de Lleida. M. G.-V. (FPU17/00229) was supported by a predoctoral fellowship from Ministerio de Educación, Cultura y Deportes.Basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (SCCs) are the most frequent types of cancer, and both originate from the keratinocyte transformation, giving rise to the group of tumors called keratinocyte carcinomas (KCs). The invasive behavior is different in each group of KC and may be influenced by their tumor microenvironment. The principal aim of the study is to characterize the protein profile of the tumor interstitial fluid (TIF) of KC to evaluate changes in the microenvironment that could be associated with their different invasive and metastatic capabilities. We obtained TIF from 27 skin biopsies and conducted a label-free quantitative proteomic analysis comparing seven BCCs, 16 SCCs, and four normal skins. A total of 2945 proteins were identified, 511 of them quantified in more than half of the samples of each tumoral type. The proteomic analysis revealed differentially expressed TIF proteins that could explain the different metastatic behavior in both KCs. In detail, the SCC samples disclosed an enrichment of proteins related to cytoskeleton, such as Stratafin and Ladinin-1. Previous studies found their upregulation positively correlated with tumor progression. Furthermore, the TIF of SCC samples was enriched with the cytokines S100A8/S100A9. These cytokines influence the metastatic output in other tumors through the activation of NF-kB signaling. According to this, we observed a significant increase in nuclear NF-kB subunit p65 in SCCs but not in BCCs. In addition, the TIF of both tumors was enriched with proteins involved in the immune response, highlighting the relevance of this process in the composition of the tumor environment. Thus, the comparison of the TIF composition of both KCs provides the discovery of a new set of differential biomarkers. Among them, secreted cytokines such as S100A9 may help explain the higher aggressiveness of SCCs, while Cornulin is a specific biomarker for BCCs. Finally, the proteomic landscape of TIF provides key information on tumor growth and metastasis, which can contribute to the identification of clinically applicable biomarkers that may be used in the diagnosis of KC, as well as therapeutic targets