The complex life of DICKKOPF-1 in cancer cells

This work is licensed under a Creative Commons Attribution 4.0 International License.The role of DICKKOPF (DKK)-1 in human cancer is controversial. DKK-1 behaves as an inhibitor of the canonical Wnt/β-catenin signaling pathway acting at the plasma membrane, although several studies have proposed effects that are independent of the inhibition of β-catenin transcriptional activity, in some cases mediated by the activation of c-Jun N-terminal kinase (JNK). Recently, a proportion of DKK-1 protein has been found within the nucleus of human intestinal epithelial cells following an apical-to-basal crypt decreasing gradient, and in that of colon carcinoma cells. Moreover, we show here that in the human mammary gland DKK-1 is also present within the nucleus of many differentiated luminal epithelial cells and in that of a small proportion of myoepithelial cells. Nuclear DKK-1 binds to actively transcribed chromatin and regulates the expression of specific genes, some of which are involved in cell proliferation, survival and stemness, and in the defense against xenobiotics. This may explain the finding that while DKK-1 is downregulated more rapidly in the nucleus than in the cytosol during colon carcinoma progression, its expression remains high in a percentage of patients who do not respond to chemotherapy. Available data suggest that the accumulation of DKK-1 in the nucleus of colon carcinoma cells depends on signals from the surrounding tumor microenvironment.Work in authors' laboratories is supported by grants from Ministerio de Economía y Competitividad of Spain-Fondo Europeo de Desarrollo Regional (FEDER) (SAF2013-43468-R), Comunidad de Madrid (S2010/BMD-2344 Colomics2), and FEDER-Instituto de Salud Carlos III (RD12/0036/0021; RD12/0036/0051, PT13/0010/0012 and PI12/01552).Peer reviewe

Wnt and vitamin D at the crossroads in solid cancer

The Wnt/β-catenin signaling pathway is aberrantly activated in most colorectal cancers and less frequently in a variety of other solid neoplasias. Many epidemiological and experimental studies and some clinical trials suggest an anticancer action of vitamin D, mainly against colorectal cancer. The aim of this review was to analyze the literature supporting the interference of Wnt/β-catenin signaling by the active vitamin D metabolite 1α,25-dihydroxyvitamin D3. We discuss the molecular mechanisms of this antagonism in colorectal cancer and other cancer types. Additionally, we summarize the available data indicating a reciprocal inhibition of vitamin D action by the activated Wnt/β-catenin pathway. Thus, a complex mutual antagonism between Wnt/β-catenin signaling and the vitamin D system seems to be at the root of many solid cancers. Abnormal activation of the Wnt/β-catenin pathway is common in many types of solid cancers. Likewise, a large proportion of cancer patients have vitamin D deficiency. In line with these observations, Wnt/β-catenin signaling and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active vitamin D metabolite, usually have opposite effects on cancer cell proliferation and phenotype. In recent years, an increasing number of studies performed in a variety of cancer types have revealed a complex crosstalk between Wnt/β-catenin signaling and 1,25(OH)2D3. Here we review the mechanisms by which 1,25(OH)2D3 inhibits Wnt/β-catenin signaling and, conversely, how the activated Wnt/β-catenin pathway may abrogate vitamin D action. The available data suggest that interaction between Wnt/β-catenin signaling and the vitamin D system is at the crossroads in solid cancers and may have therapeutic applications.The work in the authors’ laboratory is funded by the Agencia Estatal de Investigación (PID2019-104867RB-I00/AEI/10.13039/501100011033), the Agencia Estatal de Investigación—Fondo Europeo de Desarrollo Regional (SAF2016-76377-R, MINECO/AEI/FEDER, EU), the Ministerio de Economía y Competitividad (SAF2017-90604-REDT/NuRCaMeIn), and the Instituto de Salud Carlos III—Fondo Europeo de Desarrollo Regional (CIBERONC; CB16/12/00273

Retos de la docencia en ciencias sociales en educación secundaria

Con el presente trabajo, se ha pretendido dar unas claves generales de los que consideramos los más apremiantes retos a afrontar que tiene la enseñanza de las ciencias sociales en los próximos años. Los cuatro están intrínsecamente relacionados y ponen su objetivo primordial y final en educar a la sociedad actual para el mundo de hoy y de mañana

Clinico-pathological features, outcomes and impacts of COVID-19 pandemic on patients with early-onset colorectal cancer: A single-Institution Experience

The rising incidence of colorectal cancer (CRC) among young patients is alarming. We aim to characterize the clinico-pathological features and outcomes of patients with early-onset CRC (EOCRC), as well as the impacts of COVID-19 pandemic. Methods: We included all patients with pathologically confirmed diagnoses of CRC at Hospital Universitario La Paz from October 2016 to December 2021. The EOCRC cut-off age was 50 years old. Results: A total of 1475 patients diagnosed with CRC were included, eighty (5.4%) of whom had EOCRC. Significant differences were found between EOCRC and later-onset patients regarding T, N stage and metastatic presentation at diagnosis; perineural invasion; tumor budding; high-grade tumors; and signet ring cell histology, with all issues having higher prevalence in the early-onset group. More EOCRC patients had the RAS/ BRAF wild type. Chemotherapy was administered more frequently to patients with EOCRC. In the metastatic setting, the EOCRC group presented a significantly longer median OS. Regarding the COVID-19 pandemic, more patients with COVID-19 were diagnosed with metastatic disease (61%) in the year after the lockdown (14 March 2020) than in the pre-pandemic EOCRC group (29%). Conclusions: EOCRC is diagnosed at a more advanced stage and with worse survival features in localized patients. More patients with EOCRC were diagnosed with metastatic disease in the year after the COVID-19 pandemic lockdown. The long-term consequences of COVID-19 are yet to be determinedThe work in the authors’ laboratory is funded by the Instituto de Salud Carlos III (ISCIII) and the Fondo Europeo de Desarrollo Regional (FEDER) (ICI20/00057, CIBERONC/CB16/12/00273, and CIBERONC/CB16/12/00398), as well as the Comunidad de Madrid (S2022/BMD-7212

Vitamin D and Wnt3A have additive and partially overlapping modulatory effects on gene expression and phenotype in human colon fibroblasts

The Wnt/β-catenin signalling pathway is essential for intestinal epithelium homeostasis, but its aberrant activation is a hallmark of colorectal cancer (CRC). Several studies indicate that the bioactive vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits proliferation and promotes epithelial differentiation of colon carcinoma cells in part through antagonism of the Wnt/β-catenin pathway. It is now accepted that stromal fibroblasts are crucial in healthy and pathologic intestine: pericryptal myofibroblasts are constituents of the stem cell niche and cancer-associated fibroblasts (CAFs) contribute to CRC progression. However, studies on the combined action of 1,25(OH)2D3 and Wnt factors in colon fibroblasts are lacking. Here we show by global transcriptomic studies that 1,25(OH)2D3 and Wnt3A have profound, additive, partially overlapping effects on the gene expression profile of CCD-18Co human colon myofibroblasts. Moreover, 1,25(OH)2D3 and Wnt3A inhibit CCD-18Co cell proliferation and migration, while 1,25(OH)2D3 reduces, but Wnt3A increases, their capacity to contract collagen gels (a marker of fibroblast activation). These data were largely confirmed in patient-derived primary colon normal fibroblasts and CAFs, and in fibroblasts from other origins. Our results indicate that 1,25(OH)2D3 and Wnt3A are strong regulators of colon fibroblast biology and contribute to a better knowledge of intestinal homeostasis and stromal fibroblast action in CRCThe work in the authors’ laboratories is supported by the Spanish Ministerio de Ciencia, Innovación y Universidades - Fondo Europeo de Desarrollo Regional (FEDER) (SAF2016-76377-R, SAF2017-90604-REDT), Consejo Superior de Investigaciones Científicas (201820I058), and Instituto de Salud Carlos III - FEDER (CIBERONC, CB16/12/00273; CIBERES, CB15/00037

Epigenetic repression of ROR2 has a Wnt-mediated, pro-tumourigenic role in colon cancer

9 páginas, 4 figuras.-- et al.[Background]: Wnt factors control cell differentiation through semi-independent molecular cascades known as the β-catenin-dependent (canonical) and -independent (non-canonical) Wnt signalling pathways. Genetic and epigenetic alteration of components of the canonical Wnt signalling pathway is one of the primary mechanisms underlying colon cancer. Despite increasing evidence of the role of the non-canonical pathways in tumourigenesis, however, the underlying molecular mechanisms are poorly understood. [Results]: Here we report that the receptor tyrosine kinase-like orphan receptor 2 (ROR2), a transmembrane receptor for Wnt factors that activates non-canonical pathways, is frequently repressed by aberrant promoter hypermethylation in human colon cancer cell lines and primary tumours. By restoring ROR2 activity in colon cancer cells harbouring ROR2 promoter hypermethylation, we show that the role of ROR2 in colon cancer cells is mediated, at least in part, by canonical Wnt and that its epigenetic-dependent loss can be pro-tumourigenic. [Conclusions]: Our data show the importance of epigenetic alterations of ROR2 in colon cancer, highlighting the close interconnection between canonical and non-canonical Wnt signalling pathways in this type of tumour.AM is funded by the Spanish Ministerio de Ciencia e Innovación (MICINN; SAF2007-60341, ISCIII-RETIC RD06/0020/0009), VC receives a fellowship from the Spanish FPU Research Programme, EL and CH are recipients of fellowships from the Spanish FIS Research Programme. The Instituto Universitario de Oncología is supported by Obra Social Cajastur, Spain. This work was supported by the MICINN (PI061267; PS09/02454; Ref. 200820I172).Peer reviewe

Registro de paisajes de interés cultural de Andalucía: criterios y metodología

La importancia que están adquiriendo los estudios y prácticas sobre el paisaje hacen de este recurso espacial uno de los grandes protagonistas de todas las políticas públicas que tienen incidencia territorial. Por otro lado, los compromisos adquiridos al reconocer el Convenio Europeo del Paisaje obligan a las instancias públicas a dar respuestas a situaciones y problemas que precisan reflexión previa y metodologías de análisis rigurosas al tiempo que flexibles en relación con este objeto de estudio. Además, en los estudios sobre paisaje, la categoría de paisajes culturales o patrimoniales, asimilables a los paisajes protegidos del Convenio, ofrece una nueva escala en la que entender los valores de los bienes culturales. Superados como paradigma de la tutela patrimonial, los conjuntos históricos y los entornos se revelan insuficientes para una responsabilidad de protección que se fija ahora en la escala general del territorio. Esto motiva no sólo un cambio de escala, sino también un cambio en la concepción de la propia protección. Este artículo pretende, a través de la presentación de los paisajes de interés cultural, proporcionar nuevas claves, métodos y temas de debate sobre cómo entender y gestionar el patrimonio cultural y hacer de éste un verdadero factor de calidad de poblaciones y territorios

Balance y perspectivas del Registro de Paisajes de Interés Cultural de Andalucía

El Convenio Europeo del Paisaje (Consejo de Europa, 2000), en vigor en España desde el 1 de marzo de 2008, detalla en su capítulo II (‘Medidas nacionales’) una serie de obligaciones para los distintos estados firmantes entre las que relacionan (art. 6) la identificación y cualificación de paisajes, mediante el análisis de sus características (caracterización) y la consideración de los valores particulares que les atribuyen las Partes y la población interesadas (en nuestro caso, sus valores como patrimonio cultural).El Registro de Paisajes de Interés Cultural de Andalucía (R-PICA) es un cuerpo de datos homogéneo y normalizado que recoge una completa y diversa información sobre áreas territoriales que han sido seleccionadas por ser depositarias de valores patrimoniales, culturales e históricos, que han participado y son testigos actuales de su formación como un paisaje cultural reconocible y significativo de Andalucía. Con la primera caracterización de cobertura regional de una selección de paisajes culturales, más de 100 por el momento, se habrá consolidado una metodología innovadora con la que se consigue la integración de diferentes fuentes de información y disciplinas científicas

Mindfulness-based Interventions For The Treatment Of Substance And Behavioral Addictions: A Systematic Review

Background: Emotion (dys) regulation as well as the interventions for improving these difficulties are receiving a growing attention in the literature. The aim of the present paper was to conduct a systematic review about the efficacy of mindfulness-based interventions (MBIs) in both substance and behavioral addictions (BAs). Method: A literature search was conducted using Cochrane, PubMed, and Web of Science. Fifty-four randomized controlled trials published in English since 2009 to April 2017 were included into a narrative synthesis. Results: Mindfulness-based interventions were applied in a wide range of addictions, including substance use disorders (from smoking to alcohol, among others) and BAs (namely, gambling disorder). These treatments were successful for reducing dependence, craving, and other addiction-related symptoms by also improving mood state and emotion dysregulation. The most commonly used MBI approaches were as follows: Mindfulness-Based Relapse Prevention, Mindfulness Training for Smokers, or Mindfulness-Oriented Recovery Enhancement, and the most frequent control group in the included studies was Treatment as Usual (TAU). The most effective approach was the combination of MBIs with TAU or other active treatments. However, there is a lack of studies showing the maintenance of the effect over time. Therefore, studies with longer follow-ups are needed. Conclusion: The revised literature shows support for the effectiveness of the MBIs. Future research should focus on longer follow-up assessments as well as on adolescence and young population, as they are a vulnerable population for developing problems associated with alcohol, drugs, or other addictions